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Ibuprofen

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Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation.<ref name="AHFS2016" /> This includes painful menstrual periods, migraines, and rheumatoid arthritis.<ref name="AHFS2016" /> It can be taken orally (by mouth) or intravenously.<ref name="AHFS2016" /> It typically begins working within an hour.<ref name="AHFS2016" />

Common side effects include heartburn, nausea, indigestion, and abdominal pain.<ref name="AHFS2016" /> Potential side effects include gastrointestinal bleeding.<ref name="BNF67">Template:Cite book</ref> Long-term use has been associated with kidney failure, and rarely liver failure, and it can exacerbate the condition of people with heart failure.<ref name="AHFS2016" /> At low doses, it does not appear to increase the risk of myocardial infarction (heart attack); however, at higher doses it may.<ref name="BNF67" /> Ibuprofen can also worsen asthma.<ref name="BNF67" /> While its safety in early pregnancy is unclear,<ref name="AHFS2016" /> it appears to be harmful in later pregnancy, so it is not recommended during that period.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It works by inhibiting the production of prostaglandins by decreasing the activity of the enzyme cyclooxygenase (COX).<ref name="AHFS2016" /> Ibuprofen is a weaker anti-inflammatory agent than other NSAIDs.<ref name="BNF67" />

Ibuprofen was discovered in 1961 by Stewart Adams and John Nicholson<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> while working at Boots UK Limited and initially sold as Brufen.<ref name = plat12>Template:Cite journal</ref> It is available under a number of brand names including Advil, Brufen, Motrin, and Nurofen.<ref name="AHFS2016">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Ibuprofen was first sold in 1969 in the United Kingdom and in 1974 in the United States.<ref name=AHFS2016/><ref name = plat12/> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2016/> In 2022, it was the 33rd most commonly prescribed medication in the United States, with more than 17Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:TOC limit

Medical usesEdit

File:200mg ibuprofen tablets.jpg
Example of some 200 mg ibuprofen tablets
File:Ibuprofen syrup.jpg
A 150 ml bottle (100 mg/5 ml dosage) of ibuprofen, sold in Greece

Ibuprofen is used primarily to treat fever (including post-vaccination fever), mild to moderate pain (including pain relief after surgery), painful menstruation, osteoarthritis, dental pain, headaches, and pain from kidney stones. About 60% of people respond to any NSAID; those who do not respond well to a particular one may respond to another.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A Cochrane medical review of 51 trials of NSAIDs for the treatment of lower back pain found that "NSAIDs are effective for short-term symptomatic relief in patients with acute low back pain".<ref>Template:Cite journal</ref>

It is used for inflammatory diseases such as juvenile idiopathic arthritis and rheumatoid arthritis.<ref name="BNF">Template:Cite book</ref><ref name="AMH">Template:Cite book</ref> It is also used for pericarditis and to close a patent ductus arteriosus in a premature baby.<ref name="Pedea EPAR">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="AHFS2016" /><ref name="Alabed2014">Template:Cite journal</ref><ref name="Rostas2016">Template:Cite journal</ref>

Ibuprofen lysineEdit

In some countries, ibuprofen lysine (the lysine salt of ibuprofen, sometimes called "ibuprofen lysinate") is licensed for treatment of the same conditions as ibuprofen; the lysine salt is used because it is more water-soluble.<ref>Template:Cite journal</ref> However, subsequent studies have shown no statistical differences between the lysine salt and ibuprofen base.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

In 2006, ibuprofen lysine was approved in the United States by the Food and Drug Administration (FDA) for closure of patent ductus arteriosus in premature infants weighing between Template:Cvt, who are no more than 32 weeks gestational age when usual medical management (such as fluid restriction, diuretics, and respiratory support) is not effective.<ref>Template:Cite journal</ref>

Adverse effectsEdit

Adverse effects include nausea, heartburn, indigestion, diarrhea, constipation, gastrointestinal ulceration, headache, dizziness, rash, salt and fluid retention, and high blood pressure.<ref name="AHFS2016" /><ref name="AMH"/><ref>Template:Cite journal</ref>

Infrequent adverse effects include esophageal ulceration, heart failure, high blood levels of potassium, kidney impairment, confusion, and bronchospasm.<ref name="AMH"/> Ibuprofen can exacerbate asthma, sometimes fatally.<ref name="Lancet1987-Ayres">Template:Cite journal</ref>

Allergic reactions, including anaphylaxis, may occur.<ref>Template:Cite journal</ref> Ibuprofen may be quantified in blood, plasma, or serum to demonstrate the presence of the drug in a person having experienced an anaphylactic reaction, confirm a diagnosis of poisoning in people who are hospitalized, or assist in a medicolegal death investigation. A monograph relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in people who have overdosed has been published.<ref name=Baselt>Template:Cite book</ref>

In October 2020, the U.S. FDA required the drug label to be updated for all NSAID medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.<ref name="FDA PR 20201015">Template:Cite press release Template:PD-notice</ref><ref name="FDA safety 20201015">{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref>

Cardiovascular riskEdit

Along with several other NSAIDs, chronic ibuprofen use is correlated with the risk of progression to hypertension in women, though less than for paracetamol (acetaminophen),<ref>Template:Cite journal</ref> and myocardial infarction (heart attack),<ref>Template:Cite journal</ref> particularly among those chronically using higher doses. On 9 July 2015, the U.S. FDA toughened warnings of increased heart attack and stroke risk associated with ibuprofen and related NSAIDs; the NSAID aspirin is not included in this warning.<ref name="FDA-20150709">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The European Medicines Agency (EMA) issued similar warnings in 2015.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

SkinEdit

Along with other NSAIDs, ibuprofen has been associated with the onset of bullous pemphigoid or pemphigoid-like blistering.<ref name="Chan">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As with other NSAIDs, ibuprofen has been reported to be a photosensitizing agent,<ref>Template:Cite journal</ref> but it is considered a weak photosensitizing agent compared to other members of the 2-arylpropionic acid class. Like other NSAIDs, ibuprofen is an extremely rare cause of the autoimmune diseases Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Rainsford" />

PregnancyEdit

The National Health Service recommends against the use of ibuprofen for more than 3 days in pregnancy as it can affect the fetus' kidneys and circulatory system. Paracetamol is considered a safer alternative.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A 2012 Canadian study of pregnant women suggested that those taking any type or amount of NSAIDs (including ibuprofen, diclofenac, and naproxen) were 2.4 times more likely to miscarry than those not taking the medications.<ref>Template:Cite journal</ref> However, a 2014 Israeli study found no increased risk of miscarriage in the group of mothers using NSAIDs and noted that two previous studies, including the 2012 Canadian study, "did not adjust for important known risk factors" which may have exposed those results to residual confounding.<ref>Template:Cite journal</ref>

InteractionsEdit

AlcoholEdit

Drinking alcohol when taking ibuprofen may increase the risk of stomach bleeding.<ref name="drugs">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

AspirinEdit

According to the FDA, "ibuprofen can interfere with the antiplatelet effect of low-dose aspirin, potentially rendering aspirin less effective when used for cardioprotection and stroke prevention". Allowing sufficient time between doses of ibuprofen and immediate-release (IR) aspirin can avoid this problem. The recommended elapsed time between a dose of ibuprofen and a dose of aspirin depends on which is taken first. It would be 30 minutes or more for ibuprofen taken after IR aspirin, and 8 hours or more for ibuprofen taken before IR aspirin. However, this timing cannot be recommended for enteric-coated aspirin. If ibuprofen is taken only occasionally without the recommended timing, though, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal.<ref name='FDA2006'>{{#invoke:citation/CS1|citation |CitationClass=web }}

Paracetamol (acetaminophen)Edit

Ibuprofen combined with paracetamol is considered generally safe in children for short-term usage.<ref>Template:Cite journal</ref>

OverdoseEdit

Ibuprofen overdose has become common since it was licensed for over-the-counter (OTC) use. Many overdose experiences are reported in the medical literature, although the frequency of life-threatening complications from ibuprofen overdose is low.<ref>Template:Cite journal</ref> Human responses in cases of overdose range from an absence of symptoms to a fatal outcome despite intensive-care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen and include abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, ear ringing, and nystagmus. Rarely, more severe symptoms such as gastrointestinal bleeding, seizures, metabolic acidosis, hyperkalemia, low blood pressure, slow heart rate, fast heart rate, atrial fibrillation, coma, liver dysfunction, acute kidney failure, cyanosis, respiratory depression, and cardiac arrest have been reported.<ref>Template:Cite journal</ref> The severity of symptoms varies with the ingested dose and the time elapsed; however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs.

The correlation between the severity of symptoms and measured ibuprofen plasma levels is weak. Toxic effects are unlikely at doses below 100Template:Nbspmg/kg, but can be severe above 400Template:Nbspmg/kg (around 150 tablets of 200Template:Nbspmg units for an average adult male);<ref name = Clinicalmedicine2003-Volans>Template:Cite journal</ref> however, large doses do not indicate the clinical course is likely to be lethal.<ref>Template:Cite journal</ref> A precise lethal dose is difficult to determine, as it may vary with age, weight, and concomitant conditions of the person.

Treatment to address an ibuprofen overdose is based on how the symptoms present. In cases presenting early, decontamination of the stomach is recommended. This is achieved using activated charcoal; charcoal absorbs the drug before it can enter the bloodstream. Gastric lavage is now rarely used, but can be considered if the amount ingested is potentially life-threatening, and it can be performed within 60 minutes of ingestion. Purposeful vomiting is not recommended.<ref>Template:Cite journal</ref> Most ibuprofen ingestions produce only mild effects, and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and kidney function monitored.<ref name="Clinicalmedicine2003-Volans"/> Since ibuprofen has acidic properties and is also excreted in the urine, forced alkaline diuresis is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, the kidneys' excretion of the unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit.<ref>Template:Cite journal</ref>

PharmacologyEdit

Ibuprofen works by inhibiting cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes into various prostaglandins (which mediate pain, inflammation, and fever) and thromboxane A2 (which stimulates platelet aggregation and promotes blood clot formation).

Like aspirin and indomethacin, ibuprofen is a nonselective COX inhibitor, in that it inhibits two isoforms of cyclooxygenase, COX-1 and COX-2. The analgesic, antipyretic, and anti-inflammatory activity of NSAIDs appears to operate mainly through inhibition of COX-2, which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 instead would be responsible for unwanted effects on the gastrointestinal tract.<ref>Template:Cite journal</ref> However, the role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain, and different compounds cause different degrees of analgesia and gastric damage.<ref>Template:Cite journal</ref>

IC50 of ibuprofen<ref>Template:Cite journal</ref>
Enzyme IC50 [μM]
COX-1 13
COX-2 370

Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer.<ref name="DrugBank">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The R-enantiomer is converted through a series of three main enzymes. These enzymes include acyl-CoA-synthetase, which converts the R-enantiomer to (−)-R-ibuprofen I-CoA; 2-arylpropionyl-CoA epimerase, which converts (−)-R-ibuprofen I-CoA to (+)-S-ibuprofen I-CoA; and hydrolase, which converts (+)-S-ibuprofen I-CoA to the S-enantiomer.<ref name=Rainsford>Template:Cite book</ref> In addition to the conversion of ibuprofen to the S-enantiomer, the body can metabolize ibuprofen to several other compounds, including numerous hydroxyl, carboxyl and glucuronyl metabolites. Virtually all of these have no pharmacological effects.<ref name=Rainsford/>

Unlike most other NSAIDs, ibuprofen also acts as an inhibitor of Rho kinase and may be useful in recovery from spinal cord injury.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Another unusual activity is inhibition of the sweet taste receptor.<ref>Template:Cite journal</ref>

PharmacokineticsEdit

After oral administration, peak serum concentration is reached after 1Template:Ndash2 hours, and up to 99% of the drug is bound to plasma proteins.<ref>Template:Cite journal</ref> The majority of ibuprofen is metabolized and eliminated within 24 hours in the urine; however, 1% of the unchanged drug is removed through biliary excretion.<ref name="DrugBank" />

MetabolismEdit

Ibuprofen mainly undergoes hepatic metabolism. The following table shows potential pathways of ibuprofen metabolism. Both hydroxymetabolites and carboxyl-ibuprofen are inactive.<ref>Template:Cite journal</ref>

Hepatic metabolism of ibuprofen<ref name=":0">Template:Cite journal</ref><ref name=":1">Template:Cite journal</ref><ref name=":2">{{#invoke:citation/CS1|citation
CitationClass=web

}}</ref>

Drug substrate Other substrates Enzymes Products Side products
ibuprofen n/d n/d 1-hydroxyibuprofen
ibuprofen oxygen, protons, NADPH CYP3A4, CYP2C19, CYP2C8, CYP2C9 2-hydroxyibuprofen NADP, water
ibuprofen oxygen, protons, NADPH CYP2C8, CYP2C9, CYP2C19 3-hydroxyibuprofen NADP, water
3-hydroxyibuprofen water, oxygen CYP2C9 carboxyl-ibuprofen hydrogen peroxide
ibuprofen uridine diphosphate glucuronic acid UDP-glucuronosyltransferase (1-1, 1-3, 1-9, 1-10, 2B4, 2B7) ibuprofen glucuronide uridine 5'-diphosphate

ChemistryEdit

Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like ethanol (66.18Template:Nbspg/100Template:NbspmL at 40Template:Nbsp°C for 90% EtOH), methanol, acetone and dichloromethane.<ref name="MD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The original synthesis of ibuprofen by the Boots Group started with the compound isobutylbenzene. The synthesis took six steps. Firstly, isobutylbenzene undergoes Friedel-Crafts acylation with acetic anhydride, yielding p-isobuthylphenyl methyl ketone. Then, through Darzens reaction with ethyl chloroacetate, a α,β-epoxyester is obtained. Then, in acidic environment, it undergoes decarboxylation and hydrolysis, yielding an aldehyde bearing one more carbon atom than the initial ketone. Then, it goes through a reaction with hydroxylamine, yielding a corresponding oxime. Later, it is converted into a nitrile and hydrolyzed into ibuprofen.<ref>Template:Cite journal</ref>

File:Boots synthesis of ibuprofen.png
Boots synthesis of ibuprofen


A modern, greener technique with fewer waste byproducts (23% of total product mass vs. 60% theoretical value) for the synthesis involves only three steps and was developed in the 1980s by the Celanese Chemical Company.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web

}}</ref> The synthesis is initiated with the acylation of isobutylbenzene using the recyclable Lewis acid catalyst hydrogen fluoride.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The following catalytic hydrogenation of isobutylacetophenone is performed with either Raney nickel or palladium on carbon to lead into the key-step, the carbonylation of 1-(4-isobutylphenyl)ethanol. This is achieved by a PdCl2(PPh3)2 catalyst, at around 50 bar of CO pressure, in the presence of HCl (10%).<ref>Template:Cite patent Template:Webarchive</ref> The reaction presumably proceeds through the intermediacy of the styrene derivative (acidic elimination of the alcohol) and (1-chloroethyl)benzene derivative (Markovnikow addition of HCl to the double bond).<ref>Template:Cite journal</ref>

File:Synthesis of ibuprofen.jpg
Modern synthesis of ibuprofen

StereochemistryEdit

File:Ibuprofen enantiomers labelled from xtal.svg
File:Ibuprofen-3D-balls.png File:(S)-ibuprofen-3D-balls.png
(R)-ibuprofen (S)-ibuprofen

Ibuprofen, like other 2-arylpropionate derivatives such as ketoprofen, flurbiprofen and naproxen, contains a stereocenter in the α-position of the propionate moiety. The product sold in pharmacies is a racemic mixture of the S and R-isomers. The S (dextrorotatory) isomer is the more biologically active; this isomer has been isolated and used medically (see dexibuprofen for details).<ref name = MD/>

The isomerase enzyme, alpha-methylacyl-CoA racemase, converts (R)-ibuprofen into the (S)-enantiomer.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

(S)-ibuprofen, the eutomer, harbors the desired therapeutic activity. The inactive (R)-enantiomer, the distomer, undergoes a unidirectional chiral inversion to offer the active (S)-enantiomer. That is, when the ibuprofen is administered as a racemate the distomer is converted in vivo into the eutomer while the latter is unaffected.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

HistoryEdit

File:Ibuprofen Blue Plaque, BioCity, Nottingham 01.jpg
The Royal Society of Chemistry blue plaque at BioCity Nottingham

Ibuprofen was derived from propionic acid by the research arm of Boots Group during the 1960s.<ref name = pmid1569234>Template:Cite journal</ref> The name is derived from the 3 functional groups: isobutyl (ibu) propionic acid (pro) phenyl (fen).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to aspirin.<ref name = plat12/><ref name=IJCP03/> The molecule was discovered and synthesized by a team led by Stewart Adams, with a patent application filed in 1961.<ref name=plat12/> Adams initially tested the drug as treatment for his hangover.<ref>Template:Cite newsTemplate:Subscription required</ref> In 1985, Boots's worldwide patent for ibuprofen expired and generic products were launched.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The medication was launched as a treatment for rheumatoid arthritis in the United Kingdom in 1969, and in the United States in 1974. Later, in 1983 and 1984, it became the first NSAID (other than aspirin) to be available over-the-counter (OTC) in these two countries.<ref name = plat12/><ref name = IJCP03>Template:Cite journal</ref> Boots was awarded the Queen's Award for Technical Achievement in 1985 for the development of the drug.<ref>Template:Cite press release</ref>

In November 2013, work on ibuprofen was recognized by the erection of a Royal Society of Chemistry blue plaque at Boots' Beeston Factory site in Nottingham,<ref name="rsc.org">Template:Cite press release</ref> which reads:

<templatestyles src="Template:Blockquote/styles.css" />

In recognition of the work during the 1980s by The Boots Company PLC on the development of ibuprofen which resulted in its move from prescription-only status to over-the-counter sale, therefore expanding its use to millions of people worldwide{{#if:|{{#if:|}}

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and another at BioCity Nottingham, the site of the original laboratory,<ref name="rsc.org" /> which reads:

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In recognition of the pioneering research work, here on Pennyfoot Street, by Dr Stewart Adams and Dr John Nicholson in the Research Department of Boots which led to the discovery of ibuprofen used by millions worldwide for the relief of pain.{{#if:|{{#if:|}}

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Availability and administrationEdit

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File:Bottle of Ibuprofen tablets with cap removed and tablets in front.jpg
A bottle of generic ibuprofen

Ibuprofen was made available by prescription in the United Kingdom in 1969 and in the United States in 1974.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Ibuprofen is the international nonproprietary name (INN), British Approved Name (BAN), Australian Approved Name (AAN) and United States Adopted Name (USAN). In the United States, it has been sold under the brand-names Motrin and Advil since 1974<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and 1984,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> respectively.

In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the brand name Caldolor.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite press release</ref>

Ibuprofen can be taken orally (by mouth) and intravenously.<ref name=AHFS2016/>

ResearchEdit

Ibuprofen is sometimes used for the treatment of acne because of its anti-inflammatory properties, and has been sold in Japan in topical form for adult acne.<ref>Template:Cite journal</ref><ref name=inpharma>Template:Cite journal</ref> As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up).<ref>Template:Cite journal</ref> NSAIDs are of unclear utility in the prevention and treatment of Alzheimer's disease.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Ibuprofen has been associated with a lower risk of Parkinson's disease and may delay or prevent it. Aspirin, other NSAIDs, and paracetamol (acetaminophen) had no effect on the risk for Parkinson's.<ref>Template:Cite journal</ref> In March 2011, researchers at Harvard Medical School announced that ibuprofen had a neuroprotective effect against the risk of developing Parkinson's disease.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> People regularly consuming ibuprofen were reported to have a 38% lower risk of developing Parkinson's disease, but no such effect was found for other pain relievers, such as aspirin and paracetamol. Use of ibuprofen to lower the risk of Parkinson's disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems.<ref name=urj2011>Template:Cite journal</ref>

Some dietary supplements might be dangerous to take along with ibuprofen and other NSAIDs, but Template:As of, more research needs to be conducted to be certain. These supplements include those that can prevent platelet aggregation, including ginkgo, garlic, ginger, bilberry, dong quai, feverfew, ginseng, turmeric, meadowsweet (Filipendula ulmaria), and willow (Salix spp.); those that contain coumarin, including chamomile, horse chestnut, fenugreek and red clover; and those that increase the risk of bleeding, like tamarind.<ref>Template:Cite journal</ref>

ReferencesEdit

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External linksEdit

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