document_title: Twenty One Pilots

question_text: when did the twenty one pilots hiatus start

text: Twenty One Pilots

text: History

text: 2009–2011: Formation, No Phun Intended, and self-titled album Twenty One Pilots

text:
External video

 The original line-up performing

text: Interview with the original line-up

text: Tyler Joseph first met future bandmate Nicholas "Nick" Thomas at a young age while playing little league basketball in Columbus, Ohio.[3] The two remained friends as Thomas transferred into Joseph's school for eighth grade and throughout the duration of high school as well.[4][5]

text: Joseph began playing music after finding an old keyboard in his closet, a Christmas gift from his mother, and mimicking radio melodies.[6][7] After seeing a songwriter perform at a High Street club, Joseph rejected an opportunity to play basketball at Otterbein University, along with a scholarship to the university. From around 2007 to 2008, Joseph recorded a solo album entitled No Phun Intended in his basement. Nick Thomas contributed guitar to several songs on the album,[3] and collaborated on the song "Trees", which was to become a signature Twenty One Pilots song.[8]

text: While attending Ohio State University, Joseph met Texas-born future bandmate Christopher "Chris" Salih at a party. Salih came from a musical background and consulted Joseph about starting a band. Impressed by the recording studio Salih had built in his house, Joseph agreed and began sharing his ideas. Just before their first performance, Joseph invited Thomas to join them as a bassist despite never having played the instrument before. In 2009, the group moved into a house of their own, where their first album was conceptualized and recorded in the basement.[9][3]

text: The band initially played for a wide variety of audiences at clubs and venues around the Columbus area. Playing at metal, hardcore, and electronic venues influenced Joseph to experiment with these disparate styles with his songwriting. To catch the attention of unfamiliar or disinterested attendees, the band began to experiment with costumes and on-stage acrobatics.[9]

text: Now going by "Twenty One Pilots",[4][5] the group released their debut, self-titled album, Twenty One Pilots, on December 29, 2009, and began touring the rest of Ohio. Their initial marketing was very grassroots; Joseph's mother would stand outside of Ohio State University giving away tickets to his shows.[10] During this time, the band participated in "Battle of the Band" contests at The Alrosa Villa and The Basement, important Columbus music venues.[11][12] In 2010, the band posted two officially unreleased tracks to their SoundCloud account.[13] These included a cover of "Jar of Hearts" by Christina Perri and a remixed interpretation of "Con te partirò (Time to Say Goodbye)" by Andrea Bocelli and Sarah Brightman; the latter would become the first song local drummer Josh Dun heard from the group.[14][14]

text: 2011–2012: Departure of Chris Salih and Nick Thomas and Regional at Best

text: Salih left on May 8, 2011 to focus on work, and Thomas left the next month on June 3, 2011 to focus on schooling, both posting farewell notes on the band's official Facebook page.[15][16] Before departing the project, Salih invited Guitar Center co-worker and friend of the group Josh Dun (former touring drummer for House of Heroes),[5][17] to take his place in the band. Impressed by the band's potential and Joseph's creative vision, Dun abandoned plans to pursue drumming in Nashville and joined the project only a few weeks before Thomas left the group.[18]

text: Both Salih and Thomas remained involved with the band's production for some time after their departure.[19] Thomas briefly attended school in North Carolina, but moved back into Joseph and Dun's house in Columbus a year after his departure and began to manage their merchandise. Thomas remained a part of the merchandise distribution crew throughout the production of Blurryface and continues to stay actively involved in the band's tour cycle.[20] Thomas has since relocated to Savannah, Georgia where he resides today.[21] Salih co-founded the carpentry company "Elmwood Custom Goods", where he works as an account manager[22] and resides in Columbus.

text: With a new lineup consisting of only Joseph and Dun, Twenty One Pilots self-released their second album, Regional at Best, on July 8, 2011. The album was accompanied by a free CD release show on the grounds of New Albany High School. While Salih and Thomas were involved with the conceptualization of the album, neither they nor Dun claim to have had much involvement with its production, which was handled nearly exclusively by Joseph.[19] The album features Joseph's brother Zack on the track "Kitchen Sink" and Joseph's college acquaintance Jocef on the track "Be Concerned".[23][24]

text: In November 2011, after months of cultivating a fan base in the Columbus area via social media interaction and constant touring, the band played a sold out concert at Columbus' Newport Music Hall. This notable accomplishment for an unsigned local group caught the attention of several record labels interested in seeing if the band's appeal could stretch outside of Ohio.[25]

text: That same year, the duo put out two free, otherwise unreleased songs via their email newsletter: the original version of "House of Gold" and "Two".[26][27] On February 11, 2012, the band released a music video on YouTube for an unreleased song titled "Goner".[28] "Goner" was rewritten and again recorded for its release on Blurryface in 2015.[29]

text: Joseph and Dun embarked on the Regional at Best Tour with rock band CHALLENGER!,[30][31] documenting it in a series of videos uploaded to the Twenty One Pilots YouTube channel.[32][33]

text: 2013–2014: Fueled by Ramen record deal, Vessel, and Quiet Is Violent World Tour

text: In April 2012, the band announced their signing to Atlantic Records subsidiary Fueled by Ramen, the label responsible for the commercial success of popular alternative artists like Panic! at the Disco and Paramore, during a sold out show at the Lifestyle Communities Pavilion.[5][27] On July 17, 2012, they released their debut Fueled by Ramen recording, an EP entitled Three Songs.[34][35] The next month, the band embarked on a short tour with Neon Trees and Walk the Moon.[25]

text: Tyler Joseph successfully negotiated to maintain ownership of the preceding self-titled album, which remains available digitally. However, as part of a signing agreement in 2012 with record label Fueled by Ramen, rights to Regional at Best were transferred to the label, meaning that Regional at Best was discontinued and removed from digital markets.[36] Regional at Best tracks "Slowtown", "Anathema", "Ruby", "Be Concerned" (featuring Jocef), and "Clear" have since been made commercially unavailable,[37] and physical copies of the album are now rare and highly sought after.[38][39]

text: On November 12, 2012, the official music video for "Holding on to You", directed by Jordan Bahat, was released on YouTube.[40] On January 7 and April 19, 2013, the band released music videos for "Guns for Hands" and "Car Radio", respectively, both directed by Mark Eshleman of Reel Bear Media.[41][42][43]

text: In an interview with the Huffington Post, Joseph described Regional at Best as a "glorified mixtape" and confirmed that songs from that project would reappear on their debut studio album.[44] Ultimately, five tracks from Regional at Best – "Guns for Hands", "Holding on to You", "Ode to Sleep", "Car Radio", and "Trees" – were re-recorded and released for their third album.[8] "Lovely" was also re-recorded and released as a single exclusive to Japan on April 17, 2013[45][46]

text: Twenty One Pilots' third album, Vessel, was released January 8, 2013; it would reach No. 21 on the Billboard 200, No. 9 on the Digital Albums chart, No. 17 on the Internet Albums chart, No. 15 on the Rock Albums Chart, and No. 10 on the Alternative Albums Chart.[47][48] The album release also supported the band's first charting single, "Holding on to You", which reached 11 on the Billboard Alternative Songs chart. Additionally, the singles "Guns for Hands" and "Lovely" reached No. 21 and No. 67, respectively, on the Japan Hot 100 after "Lovely" was released as a promotional single for the band's trip to Japan.[45][46] "Glowing Eyes", "Kitchen Sink", and "Forest" appeared unchanged as bonus tracks on the UK version of Vessel.[49]

text: In May 2013, Fall Out Boy announced that Twenty One Pilots would serve as opening acts on the Save Rock and Roll Arena Tour the following fall, along with Panic! at the Disco.[50]

text: On August 8, 2013, Twenty One Pilots performed "House of Gold" on Conan in their late night debut.[51][52] On October 2, the music video for the song was uploaded onto YouTube.[53]

text: On March 17, 2014, Twenty One Pilots performed a set at the mtvU Woodie Awards during SXSW.[54] On April 13, Twenty One Pilots performed "Car Radio" at the 2014 MTV Movie Awards.[55] On April 28, the band performed "Car Radio" on Late Night with Seth Meyers.[56]

text: In 2014, Twenty One Pilots played a number of music festivals and other events around the United States, such as Lollapalooza,[57] Bonnaroo,[58] Boston Calling, and Firefly.[59] Requests from many of these cities were incorporated into the band's first headlining tour, the Quiet Is Violent World Tour, which began in September 2014 and ended in November of the same year.[60]

text: On December 31, 2014, the band released a music video for the song "Ode to Sleep". Composed of footage captured by the band's creative director, Mark C. Eshleman of Reel Bear Media, from three concerts over the preceding three years, the video depicted the band's rapid growth from their origins as a small local band to a nationally-popular alternative act, an upward trend that would continue into the next album cycle.[61][62]

text: 2015–present: Blurryface and Emotional Roadshow World Tour

text: One of Twenty One Pilots' many dynamic performances

text: On March 16, 2015, the band announced that a new album, Blurryface, was to be released on May 19.[63] They also released the first single, "Fairly Local", on March 17.[64][65] Their second single of the album, "Tear in My Heart", and its music video were released on April 5, 2015.[66][67] On April 28, "Stressed Out", the third single from the album, was released along with a music video.[68][69][70][71] "Stressed Out" became the group's highest selling single, peaking at No. 2 on the U.S. Billboard Hot 100, and No. 1 on both Alternative Songs and Hot Rock Songs charts and surpassing one billion views on YouTube.[72][73]

text: Blurryface was released two days early on May 17, 2015, and sold 134,000 copies in the first week in the United States, becoming the band's first No. 1 album on the Billboard 200.[74] On May 22, 2016, Blurryface won in the category of "Top Rock Album" at the Billboard Music Awards, while the band won the category of "Top Rock Artist".[75]

text: The band began the Blurryface Tour on May 11, 2015, in Glasgow, Scotland. The tour spanned the United States, Australia, South East Asia, Japan and Europe.[76] The U.S. section began September 8, 2015 and featured Echosmith and Finish Ticket as openers.[77]

text: Twenty One Pilots performed "Stressed Out" on Late Night with Seth Meyers on September 14, 2015.[78]

text: The band announced a London show in February 2016, and later announced a run of UK dates, with a second London date added. The band Transviolet served as openers.[79] This run of UK dates ended the initial Blurryface Tour.

text: Soon after, the band announced a second tour for the Blurryface album, the Emotional Roadshow World Tour, which started in Cincinnati on May 31, 2016.[80] The tour covered the United States, Canada, Mexico, Europe, and Australia.[81][82] Chef'Special and Mutemath opened for the American leg.[83] Irish singer Bry joined the tour for its European leg.[84]

text: On June 16, 2016, the band released the song "Heathens" as the first single from the Suicide Squad soundtrack, earlier than the expected release date of June 24, after the song leaked onto the Internet on June 15.[85][86][87] A music video for the song was released on June 21, 2016.[88][89] "Heathens" plays during the ending credits of the film.[90]

text: Twenty One Pilots became only the third rock act to have two singles simultaneously chart in the top five of the Billboard Hot 100, joining the Beatles and Elvis Presley, in addition to becoming the third duo to accomplish this feat, after OutKast in 2003 and Macklemore & Ryan Lewis ten years later.[91]

text: The band contributed a cover of the piano ballad "Cancer" by My Chemical Romance to the tribute album Rock Sound Presents: The Black Parade.[92][93] An animated lyric video followed the release of the song.[94]

text: Twenty One Pilots featured as the musical guest on Saturday Night Live on October 8, 2016, performing orchestra-accompanied versions of "Heathens" and "Ride" in what Rolling Stone called their "most high profile performance yet".[95] The band later performed a medley of "Heathens" and "Stressed Out" on the American Music Awards of 2016, where they also accepted their first awards on American television for Favorite Pop/Rock Duo and Favorite Alternative Rock Artist.[96]

text: Joseph and Dun collaborated with alternative rock band Mutemath, for a five-song EP, TOPxMM, composed of remixes and reimaginings of five tracks from Blurryface. The EP was uploaded onto the band's official website free of charge on December 19; a twenty-five-minute long video of the bands recording the songs live in studio was also released on the band's YouTube channel.[97][98][99][100]

text: On February 12, 2017, Twenty One Pilots won a Grammy Award for "Stressed Out" in the Best Pop Duo/Group Performance category. The band stripped to their underwear before taking the stage, with Joseph claiming in their acceptance speech that this was a fulfillment of a promise the duo had made each other in their early days as a local Columbus band.[2][101][102]

text: On March 27, 2017, the band began selling tickets for what they called a "Tour De Columbus", a five-date hometown tour taking place in June 2017.[103] The duo performed at several small venues they first played as a local band including The Basement, Newport Music Hall, and Express Live!, before ending their tour cycle with arena shows at Nationwide Arena and Value City Arena.[104]

text: In an interview with Alternative Press in November 2016, Twenty One Pilots stated that after their last show, they will be "going dark" to focus on new music. Joseph stated that he would like to focus on lyrical content of the music, and bring the music back to the "authenticity, lyrics, delivery, and fearlessness of songwriting" similar to that of the self-titled album.[105] The band is currently taking a self-described hiatus; their last activity came in July 2017 in the form of posts on social media depicting an eye closing over lyrics from several of their songs.[106][107]

text: They received a Gold certification by the RIAA) for their song "Hometown" in March 2018 becoming the first musicians in the digital era to have every song featured on a full-length album achieve at least gold status.[108][109][110]

text: Involvement with Christian organization Five14

text: The members Joseph, Dun,[111][112][113] and Salih all have associations with local Columbus, Ohio church Five14 – Joseph and Dun contributing four of fourteen tracks to Five14-produced album Clear by artist Travis Whittaker (known as simply as "Whittaker") and the gospel band "New Albany Music".[114][115] In 2011, Joseph was also the lead star in Five14 Church's three episode mockumentary entitled "The (moderately inspiring tale of the) Longboard Rodeo Tango".[116][117][118] According to the mockumentary, Joseph was an intern at the church at the time. On December 24, 2013, Christmas Eve, Joseph participated and sang "O come, O come, Emmanuel" at Five14 Church's Christmas With the Stars in New Albany, Ohio. The official video of the performance was uploaded to YouTube on February 14, 2014.[119] He also performed a magic segment with the church's host and emcee, David McCreary for the show.[120][121]

text: As of December 2017, former Twenty One Pilots member Chris Salih frequently performs shows at the church.[122][123][124]

text: Musical style and influences

text: Although both members of the band are Christians and their songs often contain some allusions to religious themes, Twenty One Pilots is not considered and never intended to be a Christian band.[125][126]

text: The band's musical style has been described as alternative hip hop,[127][128][129] electropop,[127][130][131] indie pop,[132][133][134] pop rock,[135][136] rap rock,[137][138] and alternative rock.[139][137] They have also been described as rock,[140][141] pop,[134][142][143][140] electronica,[143][134][140] emo rap,[137] indie rock,[140] pop-rap,[127] hip hop,[132][142][143] indietronica,[132] and, in the case of Blurryface, reggae.[144][145][5]

text: Ultimately, it is difficult to categorize the band using a single genre only, since they bridge so many.[146] This has been attributed partly to the fact that both Joseph and Dun are self-taught musicians, meaning that while producing their work they broke many musical conventions that they were not aware of, including staying confined to a single genre.[147]

text: Instrumentally, Twenty One Pilots bring a mix of piano (sometimes an electronic keyboard or a keytar), synthesizers, drums (sometimes mixed with electronic drums), vocals, and occasionally the ukulele and bass. Lyrically, their songs are written by Joseph, who incorporates both sung and rapped lyrics. Music journalist Carl Wilson has noted that Joseph's rapping is often compared to that of Macklemore, yet he wrote "but among the ranks of post-Eminem white rappers, I find Joseph more probing, sardonic, and expressive."[148] Joseph has stated that he never intended to become a rapper, but that when attempting to fit poetry which he had written with music, he found that rapping elements of it was the only way for it to fit within the song.[149]

text: Band name, iconography and fandom

text: Joseph came up with the band's name while studying All My Sons by Arthur Miller, a play about a man whose choice to send out faulty airplane parts for the good of his business and family caused the death of twenty one pilots during World War II. Joseph explains that the story's themes of moral dilemma and choosing between the easy and the right decision inspired the name and formation of the band.[150][151] "Bicycle Thief" and "Chill Coat" were among some of the rejected band names.[152]

text: The band's name was originally stylized as "twenty | one | pilots" on their earlier cover art; however, by the time of their second album Regional at Best, the formatting was changed to "twenty øne piløts" with slashes through the O's.

text: Former Twenty One Pilots member Chris Salih stated in an interview that Mark C. Eshleman, a longtime friend of and creative director for Twenty One Pilots, created the band's logo by "messing around with shapes". Joseph found the arrangement to resonate with him.[124]

text: In regard to their logo, Joseph stated in an interview that:

text: It means Twenty One Pilots, the logo does. Why it means Twenty One Pilots, is it really goes along with one of our songs called "Kitchen Sink". The whole concept of that song is that I feel that humans are always struggling all the time when it comes to purpose, trying to figure out what their purpose is, what purpose even is, what's the point, justifying your own existence. A lot of kids and people my age struggle with "what's the point", and with the logo, what it really means is it's an encouragement. When someone asks me what the logo means to me, the logo means something to me because I made it mean something to me. That's the point. The point is that I created something that only I understand and whether or not I decide to disclose the meaning of it, that's the beginning of purpose for me. The meaning of purpose for me, is by creating something, if it be by writing lyrics, painting a picture, by expressing yourself through art if it's photography or music or theater, or whatever it is. It doesn't have to be artistic, but if you create something and only you know the meaning of it, that's the beginning of purpose for you. When you're in the room by yourself trying to decide whether to stay alive, you can tell yourself "I should probably stay alive because I'm the only one who knows the meaning of that thing", so the logo is an encouragement for people to create. That's what it means.[153]

text: According to the band, their purpose for making music is "to make people think", as well as encourage them to find joy in what they come to believe in life.[150]

text: The band's fandom has been dubbed the "Skeleton Clique" or just the Clique, in reference to the band's use of skeleton iconography in many performances, graphics, and music videos. The Skeleton Clique are represented in the band's official iconography by logos of a skull and alien head atop lines resembling keys.[154] Salih speculates that Tyler Joseph himself originally used the term "Clique" to identify with his fans.[155]

text: During the 2017 Tour de Columbus, Twenty One Pilots hosted a public art show, dubbed "Artopia", exclusively for Clique-related artwork at the Nationwide Arena.[156]

text: Band members

text: Current members

text:
Tyler Joseph – lead vocals, piano, keyboards, synthesizers, ukulele, bass (2009–present)
Josh Dun – drums, percussion (2011–present)

text: Past members

text:
Nick Thomas – bass, piano, keyboards (2009–2011), backing vocals (2009), merchandise distribution (present)
Chris Salih – drums, percussion (2009–2011)

text: Discography

text:
Twenty One Pilots (2009)
Regional at Best (2011)
Vessel (2013)
Blurryface (2015)

text: Concert tours

text: Headlining

text:
Regional at Best Tour headlining alongside CHALLENGER! (2011)[30][31][32][33]
Mostly November Tour (2012)[157]
Quiet Is Violent Tour (2014)[60]
Blurryface Tour (2015–16)[63][158]
Emotional Roadshow World Tour (2016–17)[159][160][161]
Tour De Columbus (2017)[162][163]

text: Opening act

text: Save Rock and Roll Tour with Fall Out Boy and Panic! at the Disco (2013)[50][164]

text: Awards and nominations


document_title: Ibuprofen

question_text: when did ibuprofen become available over the counter

root

text: Ibuprofen

text: Medical uses[edit]

text: Ibuprofen is used primarily to treat fever (including postimmunisation 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.[11]

tag: p

text: It is used for inflammatory diseases such as juvenile idiopathic arthritis and rheumatoid arthritis.[12][13] It is also used for pericarditis and patent ductus arteriosus.[14]

text: Ibuprofen lysine[edit]

text: 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.[15] In 2006, ibuprofen lysine was approved in the US by the Food and Drug Administration (FDA) for closure of patent ductus arteriosus in premature infants weighing between 500 and 1,500 grams (1 and 3 lb), who are no more than 32 weeks gestational age when usual medical management (such as fluid restriction, diuretics, and respiratory support) is not effective.[16]

text: Adverse effects[edit]

text: Adverse effects include nausea, dyspepsia, diarrhea, constipation, gastrointestinal ulceration/bleeding, headache, dizziness, rash, salt and fluid retention, and hypertension.[13][17]

text: Infrequent adverse effects include esophageal ulceration, heart failure, hyperkalemia, renal impairment, confusion, and bronchospasm.[13] Ibuprofen can exacerbate asthma, sometimes fatally.[18]

text: 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 hospitalized patients, or assist in a medicolegal death investigation. A monograph relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in overdose patients has been published.[19]

text: Cardiovascular risk[edit]

text: Along with several other NSAIDs, chronic ibuprofen use has been found correlated with risk of hypertension[20] and myocardial infarction (heart attack),[21] particularly among those treated chronically using high doses. In older hypertensive patients treated with hydrochlorothiazide, ibuprofen at a high daily dose was found to significantly increase systolic blood pressure.[22] On 9 July 2015, the US 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.[23]

text: Skin[edit]

text: Along with other NSAIDs, ibuprofen has been associated with the onset of bullous pemphigoid or pemphigoid-like blistering.[24] As with other NSAIDs, ibuprofen has been reported to be a photosensitising agent,[25] but it is considered a weak photosensitising agent compared to other members of the 2-arylpropionic acid class. Like other NSAIDs, ibuprofen is an extremely rare cause of the autoimmune disease Stevens–Johnson syndrome (SJS).[26][27] Ibuprofen is also an extremely rare cause of Lyell's Syndrome (toxic epidermal necrolysis).[28]

text: Interactions[edit]

text: Drinking alcohol when taking ibuprofen may increase the risk of stomach bleeding.[29]

text: According to the US Food and Drug Administration (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 eight hours or more for ibuprofen taken before IR aspirin. However, this timing cannot be recommended for enteric-coated aspirin. But, if ibuprofen is taken only occasionally without the recommended timing, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal.[30]

text: Overdose[edit]

text: Ibuprofen overdose has become common since it was licensed for OTC use. Many overdose experiences are reported in the medical literature, although the frequency of life-threatening complications from ibuprofen overdose is low.[31] Human response in cases of overdose ranges from absence of symptoms to 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, tinnitus, and nystagmus. Rarely, more severe symptoms, such as gastrointestinal bleeding, seizures, metabolic acidosis, hyperkalaemia, hypotension, bradycardia, tachycardia, atrial fibrillation, coma, liver dysfunction, acute renal failure, cyanosis, respiratory depression, and cardiac arrest have been reported.[32] 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.

text: Correlation between severity of symptoms and measured ibuprofen plasma levels is weak. Toxic effects are unlikely at doses below 100 mg/kg, but can be severe above 400 mg/kg (around 150 tablets of 200 mg units for an average man);[33] however, large doses do not indicate the clinical course is likely to be lethal.[34] A precise lethal dose is difficult to determine, as it may vary with age, weight, and concomitant conditions of the individual person.

text: Therapy is largely symptomatic. In cases presenting early, gastric decontamination is recommended. This is achieved using activated charcoal; charcoal adsorbs the drug before it can enter the systemic circulation. 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. Emesis is not recommended.[35] The majority of ibuprofen ingestions produce only mild effects and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and renal function monitored.[33] 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, renal excretion of unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit.[36] Symptomatic therapy for hypotension, gastrointestinal bleeding, acidosis, and renal toxicity may be indicated. On occasion, close monitoring in an intensive-care unit for several days is necessary. A patient who survives the acute intoxication usually experiences no late sequelae.

text: Miscarriage[edit]

text: A study of pregnant women suggests 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 drugs.[37] However, an Israeli study found no increased risk of miscarriage in the group of mothers using NSAIDs.[38]

text: Pharmacology[edit]

text: NSAIDs such as ibuprofen work by inhibiting the cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are mediators of pain, inflammation, and fever) and to thromboxane A2 (which stimulates platelet aggregation, leading to the formation of blood clots).

text: 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.[39] 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.[40]

text: 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.[41] 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.[28] 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.[28]

text: Chemistry[edit]

text: Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like ethanol (66.18 g/100mL at 40°C for 90% EtOH), methanol, acetone and dichloromethane.[42]

text: The original synthesis of ibuprofen by the Boots Group started with the compound 2-methylpropylbenzene. The synthesis took six steps. A modern, greener technique for the synthesis involves only three steps.[43]

text: Stereochemistry[edit]

text:
(R)-ibuprofen

(S)-ibuprofen

tag: table

text: It is an optically active compound with both S and R-isomers, of which the S (dextrorotatory) isomer is the more biologically active; this isomer has also been isolated and used medically (see dexibuprofen for details).[42]

text: Ibuprofen is produced industrially as a racemate. The compound, like other 2-arylpropionate derivatives (including ketoprofen, flurbiprofen, naproxen, etc.), does contain a stereocenter in the α-position of the propionate moiety. So two enantiomers of ibuprofen occur, with the potential for different biological effects and metabolism for each enantiomer. Indeed, the (S)-(+)-ibuprofen (dexibuprofen) was found to be the active form both in vitro and in vivo.[citation needed]

text: An isomerase (alpha-methylacyl-CoA racemase) converts (R)-ibuprofen to the active (S)-enantiomer.[44][45][46]

text: History[edit]

text: Ibuprofen was derived from propionic acid by the research arm of Boots Group during the 1960s.[47] Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to aspirin.[7][48] It was discovered by a team led by Stewart Adams and the patent application was filed in 1961.[7] Adams initially tested the drug as treatment for his hangover.[49] The drug 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.[7][48] Dr. Adams was subsequently awarded an OBE in 1987. Boots was awarded the Queen's Award for Technical Achievement for the development of the drug in 1987.[7]

text: Society and culture[edit]

text: Marketing[edit]

text: Ibuprofen was made available under prescription in the United Kingdom in 1969, and in the United States in 1974.[50] In the years since, the good tolerability profile, along with extensive experience in the population, as well as in so-called phase-IV trials (postapproval studies), have resulted in the availability of ibuprofen OTC in pharmacies worldwide, as well as in supermarkets and other general retailers.[citation needed] Ibuprofen is its INN, BAN, AAN and USAN approved name. Advil is manufactured by Pfizer and has been on the market since 1984.

text: North America[edit]

text: Ibuprofen is commonly available in the United States up to the FDA's 1984 dose limit OTC, rarely used higher by prescription.[51] In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the trade name Caldolor.[52][53]

text: Research[edit]

text:
This section needs to be updated. Please update this article to reflect recent events or newly available information.
Last update: PMID 25227314, PMID 25644018 (November 2017)

text: 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.[54][55] As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up).[56] In some studies, ibuprofen showed superior results compared with a placebo in the prevention of Alzheimer's disease, when given in low doses over a long time.[57][58]

text: 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.[59] In March 2011, researchers at Harvard Medical School announced in Neurology that ibuprofen had a neuroprotective effect against the risk of developing Parkinson's disease.[60][61][62] 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.[63]

text: Some dietary supplements might be dangerous to take along with ibuprofen and other NSAIDs, but as of 2016 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 and willow, those that contain coumarin, including chamomile, horse chestnut, fenugreek and red clover, and those that increase the risk of bleeding, like tamarind.[64]