title: Pan (2015 film)

text: In the United States and Canada, the film grossed $5.2 million on its opening day. In its opening weekend, the film grossed $15.3 million, below the studio's $20 million projection, and finished third at the box office. Several factors have been attributed to the financial failure of "Pan". "Forbes" blogger Scott Mendelson attributed this to the absence of notable movie stars. Despite the presence of Jackman, "like any number of would-be big stars who are best known for a certain franchise, his opening weekend strength dips when he's not playing his trademark character." Outside of the "X-Men" films, his biggest openings are "Van Helsing" ($51 million) and the $27 million debuts of "Real Steel" and "Les Misérables". "Variety" described the departure of the film in tone and writings that made earlier Peter Pan stories and films a success, from Jackman's role as Blackbeard to the inclusion of contemporary pop songs from Nirvana and the Ramones which is peculiar for a children's film adaptation. "Without the Disney seal of approval, audiences are a bit wary of these fairy tale adaptations," said Jeff Bock, a box office analyst with Exhibitor Relations. He added, "It veered off the Peter Pan path quite extensively and it was just too far left of center for a generation that grew up with "Hook" and sees that as the definitive account." Warner Bros. declined to discuss "Pan"s box office results.


title: Pan (2015 film)

text: "Pan" also struggled internationally, grossing $20.4 million on its opening weekend from 54 markets from over 11,000 screens. 3D comprised 85% of the opening gross. The film was released in Australia on September 24, 2015, to take advantage of the prime September school holidays, where it grossed $1.5 million in its opening weekend. Elsewhere, it opened in the U.K. with $4.1 million, and No. 1 in Mexico ($2.9 million), Brazil ($1.8 million), Indonesia, Malaysia and Thailand and No. 2 in Russia and the CIS with $2 million (behind "The Martian"), Spain with $1.7 million (behind "Regression"), Hong Kong, Singapore and the Philippines.


title: Pan (2015 film)

text: "The Hollywood Reporter" estimated that the film cost $275 million to produce and market worldwide—while "The New York Times" reported at least $250 million—and noted that the financial losses by Warner Bros. could finish anywhere between $130 to $150 million. The site suggested that if the film overperformed in China—the world's second largest movie market—the losses could have been lower. Opening in China on October 22, 2015, it failed to meet expectations. Based on its production cost and factoring in the percentage of ticket sales kept by theater owners, analysts estimated that "Pan" needed to take in at least $400–500 million worldwide to break even. The financial loss incurred by "Pan" puts it alongside "Tomorrowland" and "Jupiter Ascending" as one of the biggest box office failures of 2015.


title: Pan (2015 film)

text: On Rotten Tomatoes, the film has an approval rating of 27% based on 202 reviews and an average rating of 4.60/10. The site's critical consensus reads, ""Pan" finds a few bursts of magic in its prequel treatment of classic characters, though not enough to offset the rushed plot and shrill, CGI-fueled action." On Metacritic, the film has a score of 36 out of 100 based on 35 critics, indicating "generally unfavorable reviews". Audiences polled by CinemaScore gave the film an average grade of "B+" on an A+ to F scale, while PostTrak reported filmgoers gave it a 78% overall positive score.


title: Pan (2015 film)

text: A.O. Scott of "The New York Times" called the action scenes "murky and chaotic" and stated, "The dominant emotion in "Pan" is the desperation of the filmmakers, who frantically try to pander to a young audience they don’t seem to respect, understand or trust." The main characters lacked chemistry and depth according to Todd McCarthy of "The Hollywood Reporter", who added that with the exception of Levi Miller's Pan, "the characters don't reasonably comport with one's pre-existing images of them". He also called a good portion of the film "a seriously extended chase that possesses hefty CGI-propelled dynamics but absolutely no suspense and a very limited sense of fun". Andrew Barker of "Variety" praised the film's technical achievements and action sequences but found it depressing overall: ""Pan" swaps puckish mischief and innocence for doses of Steampunk design, anachronistic music, a stock “chosen one” narrative and themes of child labor, warfare and unsustainable mineral mining exchanges".


title: Pan (2015 film)

text: In a more positive review, Bill Zwecker of "Chicago Sun-Times" gave the film three out of four stars, calling Levi Miller "a truly wonderful cinematic discovery" and praising the film's "thrilling action sequences, vivid costumes and well-executed special effects".


title: Pan (2015 film)

text: While promoting the film "Darkest Hour" in 2017, Wright said he almost quit directing and considered retirement following the box office failure of "Pan": "I had just made this $100 million flop. It was a dark, difficult time. I didn’t know if I was going to make any more movies, I didn’t know that I wanted to make movies anymore, to be honest."


title: As It Was

text: "As It Was" is a song by British singer Harry Styles, released through Erskine and Columbia on 1 April 2022 as the lead single from his third studio album, "Harry's House" (2022). The song was written by Styles alongside the song's producers Kid Harpoon and Tyler Johnson.


title: As It Was

text: "As It Was" received positive reviews from critics and entered at the top of the UK Singles Chart, becoming Styles's second number-one single after "Sign of the Times" in April 2017. "As It Was" spent ten weeks at the top of the UK Singles Chart, becoming the longest-running number-one single of 2022 in his home country. Also his second number one single in the US, the song spent 15 weeks atop the "Billboard" Hot 100, becoming the longest-running US number one by a UK act and the fourth-longest-running number one in the chart's history.


title: As It Was

text: "As It Was" topped the charts in 35 countries, including Australia, Austria, Belgium, Canada, Croatia, Denmark, France, Germany, Greece, Ireland, Lithuania, the Netherlands, New Zealand, Singapore and Sweden.


title: As It Was

text: Harry Styles announced the title of his third studio album as "Harry's House" on 23 March 2022, unveiling its artwork, a 40-second trailer and the album's release date as 20 May 2022. Five days later, he announced the title of its lead single as "As It Was", along with pictures of him in a "sequined, sleeveless red outfit" and its release date as 1 April 2022. Simultaneously, posters bearing the lyrics "It's not the same as it was" and a picture of Styles sitting on a big ball appeared in various cities. He released a teaser of the music video on 30 March, which included an "energetic drum beat" and a "sunny electric guitar riff", and depicted him in a red jumpsuit spinning in circles atop a motorised turntable.


title: As It Was

text: Music critics described the song as a guitar-driven synth-pop track, a noticeable shift from Styles's rock-oriented sounds. Chris Willman of "Variety" noted that it takes heavy inspiration from Depeche Mode and A-ha, while also suggesting that it adopted a style similar to the Weeknd's 2019 single "Blinding Lights". EUPHORIA. Magazine felt that Styles was inspired by James Bay's 2018 single "Pink Lemonade", adding that the two songs sound "eerily similar". Lyrically, "As It Was" is rooted in personal transitions and depicts a feeling of loss and loneliness.


title: As It Was

text: "As It Was" received critical acclaim. "NME"s Rhian Daly gave the song five out of five stars, describing it as "not a million miles away from where "Fine Line" left off, but hardly retreading old ground." According to Daly, the track suggests "Harry's House" will solidify Styles "as one of the current pop landscapes' greats". Beau Beaumont-Thomas of "The Guardian" also rated the song five stars and called it "one of his very best", writing, "Many will pore over the gossipy, self-referential lyrics, but Styles's song is for everyone: an effervescent, high-tempo hit to have you clicking your heels." In his review for "Rolling Stone", Rob Sheffield regarded "As It Was" as one of Styles's most "emotionally powerful" songs, calling it a "daring change-up" and a "straight-from-the-heart cry that's also an irresistible dance-floor challenge." Sahar Ghadirian of "Clash" magazine deemed it a "powerhouse" and Styles "at his most vulnerable". Ghadirian appreciated the "dream fusion" of synth-pop with electro rock and commented that the bells end the song on "a euphoric high". Thania Garcia of "Variety" magazine described the song as being "new wave-inspired".


title: As It Was

text: "Evening Standard" reviewer Jochan Embley meanwhile found the track inferior to the singer's previous singles "Watermelon Sugar" and "Adore You", but wrote that Styles and his collaborators "still know how to make an instantly enjoyable tune". Olivia Horn of "Pitchfork" was less impressed and bemoaned that the song "winds down without any real payoff", citing the circuitousness of the lyrics as "a frequent shortcoming in Styles' songwriting."


title: As It Was

text: "As It Was" was an immediate success; it earned the Guinness World Records title for the most streamed track on Spotify within 24 hours by a male artist, and broke the Apple Music streaming record for most first-day streams for a 2022 release. The song also opened atop the "Billboard" Global 200 with the greatest global streaming week of 2022, becoming Styles's first number-one on the tally.


title: As It Was

text: In the United Kingdom, "As It Was" became Styles's second solo number-one on the singles chart, debuting with the biggest sales and streaming weeks of any single in 2022. It spent ten weeks at number one on the UK singles chart, becoming the longest-running number one of the year in the UK. It became the most-streamed track (149.6 million streams), most physically purchased (12,000 units), most digitally downloaded (47,000 units) and overall, best-selling (1.3 million equivalent units) track in the UK in 2022, .


title: As It Was

text: "As It Was" entered at number one on the "Billboard" Hot 100, becoming Styles' second number-one single after "Watermelon Sugar" (2019). The song garnered the most single-day streams on Spotify in the United States, surpassing Olivia Rodrigo's "Drivers License" (2021). After the single's debut at No. 1, "As It Was" fell out of the No. 1 position and returned multiple times between April and September 2022; when it returned to No. 1 for the week ending 3 September 2022, it became the first song ever to have five separate runs in the top position. "As It Was" spent 15 weeks atop the "Billboard" Hot 100, becoming the longest-running US number one by a UK act, the longest-running No. 1 with no accompanying artists (i.e. a solo-billed song) and the fourth longest running number-one in the charts history.


title: As It Was

text: "As It Was" spent 18 weeks at number one on the Canadian Hot 100 and peaked at number one in Australia, Austria, Belgium, Croatia, Denmark, Germany, Greece, Ireland, Israel, Lithuania, the Netherlands, New Zealand, Slovakia, Sweden, and Switzerland.


title: As It Was

text: "As It Was" ranked as the most popular song on Spotify and the second most popular song on Apple Music in 2022.


title: As It Was

text: The music video for "As It Was" was released alongside the song. In the clip, Styles joins dancer Mathilde Lin on a turning platform and performs choreography in the Barbican to release negative emotions. The video was filmed in London: apart from the Barbican Centre, it was also filmed at Lindley Hall near the Houses of Parliament, and the penguin pool at London Zoo. It was directed by Tanu Muino, who stated that directing for Styles was "a bucket list dream come true" but, on the second day of shooting, Muino's home country of Ukraine was invaded by Russia, rendering the process a "bittersweet" experience; nevertheless, Muino and her team from Ukraine "poured so much love into this video and you can see it on screen. It will be a music video I will never forget and now I can happily retire." On YouTube, the video has received over 337 million views and 6.1 million likes as of October 2022.


title: As It Was

text: Styles performed "As It Was" for the first time at the Coachella Valley Music and Arts Festival on 15 April and 22 April.


title: Didgeridoo

text: The didgeridoo (; also spelt didjeridu, among other variants) is a wind instrument, played with vibrating lips to produce a continuous drone while using a special breathing technique called circular breathing. The didgeridoo was developed by Aboriginal peoples of northern Australia at least 1,000 years ago, and is now in use around the world, though still most strongly associated with Indigenous Australian music. In the Yolŋu languages of the indigenous people of northeast Arnhem Land the name for the instrument is the yiḏaki, or more recently by some, mandapul. In the Bininj Kunwok language of West Arnhem Land it is known as mako.


title: Didgeridoo

text: A didgeridoo is usually cylindrical or conical, and can measure anywhere from long. Most are around long. Generally, the longer the instrument, the lower its pitch or key. Flared instruments play a higher pitch than unflared instruments of the same length.


title: Didgeridoo

text: There are no reliable sources of the exact age of the didgeridoo. Archaeological studies suggest that people of the Kakadu region in Northern Australia have been using the didgeridoo for less than 1,000 years, based on the dating of rock art paintings. A clear rock painting in Ginga Wardelirrhmeng, on the northern edge of the Arnhem Land plateau, from the freshwater period (that had begun 1500 years ago) shows a didgeridoo player and two song-men participating in an Ubarr ceremony. It is thus thought that it was developed by Aboriginal peoples of northern Australia, possibly in Arnhem Land.


title: Didgeridoo

text: T. B. Wilson's "Narrative of a Voyage Round the World" (1835) includes a drawing of an Aboriginal man from Raffles Bay on the Cobourg Peninsula (about east of Darwin) playing the instrument. Others observed such an instrument in the same area, made of bamboo and about long. In 1893, English palaeontologist Robert Etheridge, Junior observed the use of "three very curious trumpets" made of bamboo in northern Australia. There were then two native species of bamboo growing along the Adelaide River, Northern Territory".


title: Didgeridoo

text: According to A. P. Elkin, in 1938, the instrument was "only known in the eastern Kimberley [region in Western Australia] and the northern third of the Northern Territory".


title: Didgeridoo

text: The name "didgeridoo" is not of Aboriginal Australian linguistic origin and is considered to be an onomatopoetic word. The earliest occurrences of the word in print include a 1908 edition of the "Hamilton Spectator" referring to a did-gery-do' (hollow bamboo)", a 1914 edition of "The Northern Territory Times and Gazette", and a 1919 issue of "Smith's Weekly", in which it was referred to as a "didjerry" and was said to produce the sound "didjerry, didjerry, didjerry and so on ad infinitum".


title: Didgeridoo

text: A rival explanation, that "didgeridoo" is a corruption of the Irish Gaelic phrase or , is controversial. or is a noun that, depending on the context, may mean "trumpeter", "hummer", "crooner" or "puffer", while means "black", and means "native".


title: Didgeridoo

text: There are numerous names for the instrument among the Aboriginal peoples of northern Australia, none of which closely resemble the word "didgeridoo" (see below). Some didgeridoo enthusiasts, scholars and Aboriginal people advocate using local language names for the instrument.


title: Didgeridoo

text: "Yiḏaki" (transcribed "yidaki" in English, sometimes spelt "yirdaki") is one of the most commonly used names although, strictly speaking, it refers to a specific type of the instrument made and used by the Yolngu peoples of north-east Arnhem Land. Some Yolngu people began using the word "mandapul" after 2011, out of respect for the passing of a Manggalili man who had a name sounding similar to yidaki.


title: Didgeridoo

text: In west Arnhem Land, it is known as a "mako", a name popularised by virtuoso player David Blanasi, a Bininj man, whose language was Kunwinjku, and who brought the didgeridoo to world prominence. However the mako is slightly different from the Yiḏaki: usually shorter, and sounding somewhat different – a slightly fuller and richer sound, but without the "overtone" note.


title: Didgeridoo

text: There are at least 45 names for the didgeridoo, several of which suggest its original construction of bamboo, such as "bambu", "bombo", "kambu", and "pampu", which are still used in the "lingua franca" by some Aboriginal people. The following are some of the more common regional names.


title: Didgeridoo

text: A didgeridoo is usually cylindrical or conical, and can measure anywhere from long. Most are around long. Generally, the longer the instrument, the lower its pitch or key. However, flared instruments play a higher pitch than unflared instruments of the same length.


title: Didgeridoo

text: The didgeridoo is classified as a wind instrument and is similar in form to a straight trumpet, but made of wood. It has also been called a dronepipe.


title: Didgeridoo

text: Traditional didgeridoos are usually made from hardwoods, especially the various eucalyptus species that are endemic to northern and central Australia. Generally the main trunk of the tree is harvested, though a substantial branch may be used instead. Traditional didgeridoo makers seek suitably hollow live trees in areas with obvious termite activity. Termites attack these living eucalyptus trees, removing only the dead heartwood of the tree, as the living sapwood contains a chemical that repels the insects. Various techniques are employed to find trees with a suitable hollow, including knowledge of landscape and termite activity patterns, and a kind of tap or knock test, in which the bark of the tree is peeled back, and a fingernail or the blunt end of a tool, such as an axe, is knocked against the wood to determine if the hollow produces the right resonance. Once a suitably hollow tree is found, it is cut down and cleaned out, the bark is taken off, the ends trimmed, and the exterior is shaped; this results in a finished instrument. A rim of beeswax may be applied to the mouthpiece end.


title: Didgeridoo

text: Non-traditional didgeridoos can be made from native or non-native hard woods (typically split, hollowed and rejoined), glass, fibreglass, metal, agave, clay, resin, PVC piping and carbon fibre. These typically have an upper inside diameter of around down to a bell end of anywhere between and have a length corresponding to the desired key. The end of the pipe can be shaped and smoothed to create a comfortable mouthpiece or an added mouthpiece can be made of any shaped and smoothed material such as rubber, a rubber stopper with a hole or beeswax.


title: Didgeridoo

text: Modern didgeridoo designs are distinct from the traditional Australian Aboriginal didgeridoo, and are innovations recognised by musicologists. Didgeridoo design innovation started in the late 20th century, using non-traditional materials and non-traditional shapes. The practice has sparked, however, a good deal of debate among indigenous practitioners and non-indigenous people about its aesthetic, ethical, and legal issues.


title: Didgeridoo

text: Didgeridoos can be painted by their maker or a dedicated artist using traditional or modern paints while others retain the natural wood grain design with minimal or no decoration.


title: Didgeridoo

text: A didgeridoo can be played simply by producing a vibrating sound of the lips to produce the basic drone. More advanced playing involves the technique known as circular breathing. The circular breathing technique requires breathing in through the nose whilst simultaneously using the muscles of the cheeks to compress the cheeks and release the stored air out of the mouth. By using this technique, a skilled player can replenish the air in their lungs, and with practice they can sustain a note for as long as desired. Recordings exist of modern didgeridoo players playing continuously for more than 40 minutes; Mark Atkins on "Didgeridoo Concerto" (1994) plays for over 50 minutes continuously. Although circular breathing does eliminate the need to stop playing to take a breath, discomfort might still develop during a period of extended play due to chapped lips or other oral discomfort.


title: Didgeridoo

text: The didgeridoo functions "...as an aural kaleidoscope of timbres" and "the extremely difficult virtuoso techniques developed by expert performers find no parallel elsewhere."


title: Didgeridoo

text: The didgeridoo virtuoso and composer William Barton has expanded the role of the instrument in the concert hall both with his own orchestral and chamber music works and with those written or arranged for him by prominent Australian composer Peter Sculthorpe.


title: Didgeridoo

text: A termite-bored didgeridoo has an irregular shape that, overall, usually increases in diameter towards the lower end. This shape means that its resonances occur at frequencies that are not harmonically spaced in frequency. This contrasts with the harmonic spacing of the resonances in a cylindrical plastic pipe, whose resonant frequencies fall in the ratio 1:3:5 etc. The second resonance of a didgeridoo (the note sounded by overblowing) is usually around an 11th higher than the fundamental frequency (a frequency ratio of 8:3).


title: Didgeridoo

text: The vibration produced by the player's lips has harmonics in the ratio 1:2:3 etc. However, the non-harmonic spacing of the instrument's resonances means that the harmonics of the fundamental note are not systematically assisted by instrument's resonances, as is usually the case for Western wind instruments (e.g., in the low range of the clarinet, the 1st, 3rd, and 5th harmonics of the reed are assisted by resonances of the bore).


title: Didgeridoo

text: Sufficiently strong resonances of the vocal tract can strongly influence the timbre of the instrument.


title: Didgeridoo

text: At some frequencies, whose values depend on the position of the player's tongue, resonances of the vocal tract inhibit the oscillatory flow of air into the instrument.


title: Didgeridoo

text: These formants, and especially their variation during the inhalation and exhalation phases of circular breathing, give the instrument its readily recognizable sound.


title: Didgeridoo

text: Other variations in the didgeridoo's sound can be made by adding vocalizations to the drone. Most of the vocalizations are related to sounds emitted by Australian animals, such as the dingo or the kookaburra. To produce these sounds, the players use their vocal folds to produce the sounds of the animals whilst continuing to blow air through the instrument. The results range from very high-pitched sounds to much lower sounds involving interference between the lip and vocal fold vibrations. Adding vocalizations increases the complexity of the playing.


title: Didgeridoo

text: Charlie McMahon, who formed the group Gondwanaland, was one of the first non-Aboriginal players to gain fame as a professional didgeridoo player. He has toured internationally with Midnight Oil. He invented the didjeribone, a sliding didgeridoo made from two lengths of plastic tubing; its playing style is somewhat in the manner of a trombone.


title: Didgeridoo

text: The didgeridoo has been used by a number of modern bands in various types of music. Some examples include:


title: Didgeridoo

text: Early songs by the acid jazz band Jamiroquai featured didgeridoo player Wallis Buchanan, including the band's first single "When You Gonna Learn", which features prominent didgeridoo in the introduction and solo sections.


title: Didgeridoo

text: Ambient artist Steve Roach uses it in his collaborative work "" with Australian Aboriginal artist David Hudson and cellist Sarah Hopkins, as well as "Dreamtime Return".


title: Didgeridoo

text: Chris Brooks, lead singer of the New Zealand hard rock band Like a Storm uses the didgeridoo in some songs including "Love the Way You Hate Me" from their album "".


title: Didgeridoo

text: Kate Bush made extensive use of the didgeridoo played by Australian musician Rolf Harris on her album "The Dreaming", which was written and recorded after a holiday in Australia.


title: Didgeridoo

text: Traditionally, the didgeridoo was played as an accompaniment to ceremonial dancing and singing and for solo or recreational purposes. For Aboriginal peoples of northern Australia, the yidaki is still used to accompany singers and dancers in cultural ceremonies. For the Yolngu people, the yidaki is part of their whole physical and cultural landscape and environment, comprising the people and spirit beings which belong to their country, kinship system and the Yolngu Matha language. It is connected to Yolngu Law and underpinned by ceremony, in song, dance, visual art and stories.


title: Didgeridoo

text: Pair sticks, sometimes called clapsticks ("bilma" or "bimla" by some traditional groups), establish the beat for the songs during ceremonies. The rhythm of the didgeridoo and the beat of the clapsticks are precise, and these patterns have been handed down for many generations. In the Wangga genre, the song-man starts with vocals and then introduces "bilma" to the accompaniment of didgeridoo.


title: Didgeridoo

text: Traditionally, only men play the didgeridoo and sing during ceremonial occasions; playing by women is sometimes discouraged by Aboriginal communities and elders. In 2008, publisher HarperCollins apologized for its book "The Daring Book for Girls", which openly encouraged girls to play the instrument after Aboriginal academic Mark Rose described such encouragement as "extreme cultural insensitivity" and "an extreme faux pas... part of a general ignorance that mainstream Australia has about Aboriginal culture." However, Linda Barwick, an ethnomusicologist, said that though traditionally women have not played the didgeridoo in ceremony, in informal situations there is no prohibition in the Dreaming Law. For example, in 1966, ethnomusicologist Alice Marshall Moyle made a recording in Borroloola of Jemima Wimalu, a Mara woman from the Roper River, proficiently playing the didgeridoo. In 1995, musicologist Steve Knopoff observed Yirrkala women performing "djatpangarri" songs that are traditionally performed by men and in 1996, ethnomusicologist Elizabeth MacKinley reported women of the Yanyuwa group giving public performances.


title: Didgeridoo

text: Although there is no prohibition in the area of the didgeridoo's origin, such restrictions have been applied by other Indigenous communities. The didgeridoo was introduced to the Kimberleys in the early 20th century but it was only much later, such as in Rose's 2008 criticism of "The Daring Book for Girls", that Aboriginal men showed adverse reactions to women playing the instrument and prohibitions are especially evident in the South East of Australia. The belief that women are prohibited from playing is widespread among non-Aboriginal people and is also common among Aboriginal communities in Southern Australia; some ethnomusicologists believe that the dissemination of the taboo belief and other misconceptions is a result of commercial agendas and marketing. The majority of commercial didgeridoo recordings available are distributed by multinational recording companies and feature non-Aboriginal people playing a New Age style of music with liner notes promoting the instrument's spirituality which misleads consumers about the didgeridoo's secular role in traditional Aboriginal culture.


title: Didgeridoo

text: The taboo is particularly strong among many Aboriginal groups in the South East of Australia, where it is forbidden and considered "cultural theft" for non-Aboriginal women, and especially performers of New Age music regardless of gender, to play or even touch a didgeridoo.


title: Didgeridoo

text: A 2006 study reported in the "British Medical Journal" found that learning and practising the didgeridoo helped reduce snoring and obstructive sleep apnea by strengthening muscles in the upper airway, thus reducing their tendency to collapse during sleep. In the study, intervention subjects were trained in and practiced didgeridoo playing, including circular breathing and other techniques. Control subjects were asked not to play the instrument. Subjects were surveyed before and after the study period to assess the effects of intervention. A small 2010 study noted improvements in the asthma management of Aboriginal teens that incorporated didgeridoo playing. Critics point out that the study used only 25 patients practicing at home for a few hours per day.


title: Syntax

text: In linguistics, syntax () is the study of how words and morphemes combine to form larger units such as phrases and sentences. Central concerns of syntax include word order, grammatical relations, hierarchical sentence structure (constituency), agreement, the nature of crosslinguistic variation, and the relationship between form and meaning (semantics). There are numerous approaches to syntax that differ in their central assumptions and goals.


title: Syntax

text: The word "syntax" comes from Ancient Greek roots: "coordination", which consists of "syn", "together", and "táxis", "ordering".


title: Syntax

text: The field of syntax contains a number of various topics that a syntactic theory is often designed to handle. The relation between the topics is treated differently in different theories, and some of them may not be considered to be distinct but instead to be derived from one another (i.e. word order can be seen as the result of movement rules derived from grammatical relations).


title: Syntax

text: One basic description of a language's syntax is the sequence in which the subject (S), verb (V), and object (O) usually appear in sentences. Over 85% of languages usually place the subject first, either in the sequence SVO or the sequence SOV. The other possible sequences are VSO, VOS, OVS, and OSV, the last three of which are rare. In most generative theories of syntax, the surface differences arise from a more complex clausal phrase structure, and each order may be compatible with multiple derivations. However, word order can also reflect the semantics or function of the ordered elements.


title: Syntax

text: Another description of a language considers the set of possible grammatical relations in a language or in general and how they behave in relation to one another in the morphosyntactic alignment of the language. The description of grammatical relations can also reflect transitivity, passivization, and head-dependent-marking or other agreement. Languages have different criteria for grammatical relations. For example, subjecthood criteria may have implications for how the subject is referred to from a relative clause or coreferential with an element in an infinite clause.


title: Syntax

text: Constituency is the feature of being a constituent and how words can work together to form a constituent (or "phrase"). Constituents are often moved as units, and the constituent can be the domain of agreement. Some languages allow discontinuous phrases in which words belonging to the same constituent are not immediately adjacent but are broken up by other constituents. Constituents may be recursive, as they may consist of other constituents, potentially of the same type.


title: Syntax

text: The "Aṣṭādhyāyī" of Pāṇini, from c. 4th century BC in Ancient India, is often cited as an example of a premodern work that approaches the sophistication of a modern syntactic theory since works on grammar had been written long before modern syntax came about. In the West, the school of thought that came to be known as "traditional grammar" began with the work of Dionysius Thrax.


title: Syntax

text: For centuries, a framework known as , first expounded in 1660 by Antoine Arnauld in a book of the same title, dominated work in syntax: as its basic premise the assumption that language is a direct reflection of thought processes and so there is a single most natural way to express a thought.


title: Syntax

text: However, in the 19th century, with the development of historical-comparative linguistics, linguists began to realize the sheer diversity of human language and to question fundamental assumptions about the relationship between language and logic. It became apparent that there was no such thing as the most natural way to express a thought and so logic could no longer be relied upon as a basis for studying the structure of language.


title: Syntax

text: The Port-Royal grammar modeled the study of syntax upon that of logic. (Indeed, large parts of Port-Royal Logic were copied or adapted from the "Grammaire générale".) Syntactic categories were identified with logical ones, and all sentences were analyzed in terms of "subject – copula – predicate". Initially, that view was adopted even by the early comparative linguists such as Franz Bopp.


title: Syntax

text: The central role of syntax within theoretical linguistics became clear only in the 20th century, which could reasonably be called the "century of syntactic theory" as far as linguistics is concerned. (For a detailed and critical survey of the history of syntax in the last two centuries, see the monumental work by Giorgio Graffi (2001).)


title: Syntax

text: There are a number of theoretical approaches to the discipline of syntax. One school of thought, founded in the works of Derek Bickerton, sees syntax as a branch of biology, since it conceives of syntax as the study of linguistic knowledge as embodied in the human mind. Other linguists (e.g., Gerald Gazdar) take a more Platonistic view since they regard syntax to be the study of an abstract formal system. Yet others (e.g., Joseph Greenberg) consider syntax a taxonomical device to reach broad generalizations across languages.


title: Syntax

text: Syntacticians have attempted to explain the causes of word-order variation within individual languages and cross-linguistically. Much of such work has been done within the framework of generative grammar, which holds that syntax depends on a genetic endowment common to the human species. In that framework and in others, linguistic typology and universals have been primary explicanda.


title: Syntax

text: Alternative explanations, such as those by functional linguists, have been sought in language processing. It is suggested that the brain finds it easier to parse syntactic patterns that are either right- or left-branching but not mixed. The most-widely held approach is the performance–grammar correspondence hypothesis by John A. Hawkins, who suggests that language is a non-innate adaptation to innate cognitive mechanisms. Cross-linguistic tendencies are considered as being based on language users' preference for grammars that are organized efficiently and on their avoidance of word orderings that cause processing difficulty. Some languages, however, exhibit regular inefficient patterning such as the VO languages Chinese, with the adpositional phrase before the verb, and Finnish, which has postpositions, but there are few other profoundly exceptional languages. More recently, it is suggested that the left- versus right-branching patterns are cross-linguistically related only to the place of role-marking connectives (adpositions and subordinators), which links the phenomena with the semantic mapping of sentences.


title: Syntax

text: Dependency grammar is an approach to sentence structure in which syntactic units are arranged according to the dependency relation, as opposed to the constituency relation of phrase structure grammars. Dependencies are directed links between words. The (finite) verb is seen as the root of all clause structure and all the other words in the clause are either directly or indirectly dependent on the root. Some prominent dependency-based theories of syntax are the following:


title: Syntax

text: Lucien Tesnière (1893–1954) is widely seen as the father of modern dependency-based theories of syntax and grammar. He argued vehemently against the binary division of the clause into subject and predicate that is associated with the grammars of his day (S → NP VP) and remains at the core of most phrase structure grammars. In the place of that division, he positioned the verb as the root of all clause structure.


title: Syntax

text: Categorial grammar is an approach in which constituents combine as function and argument, according to combinatory possibilities specified in their syntactic categories. For example, other approaches might posit a rule that combines a noun phrase (NP) and a verb phrase (VP), but CG would posit a syntactic category "NP" and another "NP\S", read as "a category that searches to the left (indicated by \) for an NP (the element on the left) and outputs a sentence (the element on the right)." Thus, the syntactic category for an intransitive verb is a complex formula representing the fact that the verb acts as a function word requiring an NP as an input and produces a sentence level structure as an output. The complex category is notated as (NP\S) instead of V. The category of transitive verb is defined as an element that requires two NPs (its subject and its direct object) to form a sentence. That is notated as (NP/(NP\S)), which means, "A category that searches to the right (indicated by /) for an NP (the object) and generates a function (equivalent to the VP) which is (NP\S), which in turn represents a function that searches to the left for an NP and produces a sentence."


title: Syntax

text: Tree-adjoining grammar is a categorial grammar that adds in partial tree structures to the categories.


title: Syntax

text: Theoretical approaches to syntax that are based upon probability theory are known as stochastic grammars. One common implementation of such an approach makes use of a neural network or connectionism.


title: Syntax

text: Functionalist models of grammar study the form–function interaction by performing a structural and a functional analysis.


title: Syntax

text: Generative syntax is the study of syntax within the overarching framework of generative grammar. Generative theories of syntax typically propose analyses of grammatical patterns using formal tools such as phrase structure grammars augmented with additional operations such as syntactic movement. Their goal in analyzing a particular language is to specify rules which generate all and only the expressions which are well-formed in that language. In doing so, they seek to identify innate domain-specific principles of linguistic cognition, in line with the wider goals of the generative enterprise. Generative syntax is among the approaches that adopt the principle of the autonomy of syntax by assuming that meaning and communicative intent is determined by the syntax, rather than the other way around.


title: Syntax

text: Generative syntax was proposed in the late 1950s by Noam Chomsky, building on earlier work by Zellig Harris, Louis Hjelmslev, and others. Since then, numerous theories have been proposed under its umbrella:


title: Syntax

text: The Cognitive Linguistics framework stems from generative grammar but adheres to evolutionary, rather than Chomskyan, linguistics. Cognitive models often recognise the generative assumption that the object belongs to the verb phrase. Cognitive frameworks include the following:


title: Luxembourgish

text: Luxembourgish ( ; also "Luxemburgish", "Luxembourgian", "Letzebu(e)rgesch"; Luxembourgish: ) is a West Germanic language that is spoken mainly in Luxembourg. About 400,000 people speak Luxembourgish worldwide.


title: Luxembourgish

text: As a standard form of the Moselle Franconian language, Luxembourgish has similarities with other varieties of High German and the wider group of West Germanic languages. The status of Luxembourgish as an official language in Luxembourg and the existence there of a regulatory body have removed Luxembourgish, at least in part, from the domain of Standard German, its traditional .


title: Luxembourgish

text: Luxembourgish was considered a German dialect like many others until about World War II but then it underwent ausbau, that is it created its own standard form in vocabulary, grammar and spelling and therefore is seen today as an independent language, an ausbau language.


title: Luxembourgish

text: Due to the fact that Luxembourgish has a maximum of some 285,000 native speakers, resources in the language like books, newspapers, magazines, television, internet etc. are limited. Since most Luxembourgers also speak Standard German and French there is strong competition with these two which both have very large language resources and therefore the use of Luxembourgish up to now remains quite limited.


title: Luxembourgish

text: Luxembourgish belongs to the West Central German group of High German languages and is the primary example of a Moselle Franconian language.


title: Luxembourgish

text: Luxembourgish is considered the national language of Luxembourg and also one of the three administrative languages, alongside German and French.


title: Luxembourgish

text: In Luxembourg, 77% of citizens can speak Luxembourgish. Luxembourgish is also spoken in the Arelerland region of Belgium (part of the Province of Luxembourg) and in small parts of Lorraine in France.


title: Luxembourgish

text: In the German Eifel and Hunsrück regions, similar local Moselle Franconian dialects of German are spoken. The language is also spoken by a few descendants of Luxembourg immigrants in the United States and Canada.


title: Luxembourgish

text: Other Moselle Franconian dialects are spoken by ethnic Germans long settled in Transylvania, Romania (Siebenbürgen).


title: Luxembourgish

text: Moselle Franconian dialects outside the Luxembourg state border tend to have far fewer French loanwords, and these mostly remain from the French Revolution.


title: Luxembourgish

text: The political party that places the greatest importance on promoting, using and preserving Luxembourgish is the Alternative Democratic Reform Party (ADR) and its electoral success in the 1999 election pushed the CSV-DP government to make knowledge of it a criterion for naturalisation. It is currently also the only political party in Luxembourg that wishes to implement written laws also in Luxembourgish and that wants Luxembourgish to be an officially recognized language of the European Union. In this context, in 2005, politician Jean Asselborn of LSAP rejected a demand made by ADR to make Luxembourgish an official language of the European Union citing financial reasons and the suffiency of official German and French.


title: Luxembourgish

text: There are several distinct dialect forms of Luxembourgish including Areler (from Arlon), Eechternoacher (Echternach), Kliärrwer (Clervaux), Miseler (Moselle), Stater (Luxembourg), Veiner (Vianden), Minetter (Southern Luxembourg) and Weelzer (Wiltz). Further small vocabulary differences may be seen even between small villages.


title: Luxembourgish

text: Increasing mobility of the population and the dissemination of the language through mass media such as radio and television are leading to a gradual standardisation towards a "Standard Luxembourgish" through the process of koineization.


title: Luxembourgish

text: There is no distinct geographic boundary between the use of Luxembourgish and the use of other closely related High German dialects (for example, Lorraine Franconian); it instead forms a dialect continuum of gradual change.


title: Luxembourgish

text: Spoken Luxembourgish is relatively hard to understand for speakers of German who are generally not familiar with Moselle Franconian dialects (or at least other West Central German dialects). They can usually read the language to some degree. For those Germans familiar with Moselle Franconian dialects, it is relatively easy to understand and speak Luxembourgish as far as the everyday vocabulary is concerned. The large number of French loanwords in Luxembourgish may hamper communication about certain topics, or with certain speakers (who use many French loanwords).


title: Luxembourgish

text: A number of proposals for standardising the orthography of Luxembourgish can be documented, going back to the middle of the 19th century. There was no officially recognised system until the adoption of the "OLO" () on 5 June 1946. This orthography provided a system for speakers of all varieties of Luxembourgish to transcribe words the way they pronounced them, rather than imposing a single, standard spelling for the words of the language. The rules explicitly rejected certain elements of German orthography (, the use of and , the capitalisation of nouns). Similarly, new principles were adopted for the spelling of French loanwords.


title: Luxembourgish

text: This proposed orthography, so different from existing "foreign" standards that people were already familiar with, did not enjoy widespread approval.


title: Luxembourgish

text: A more successful standard eventually emerged from the work of the committee of specialists charged with the task of creating the "Luxemburger Wörterbuch", published in 5 volumes between 1950 and 1977. The orthographic conventions adopted in this decades-long project, set out in Bruch (1955), provided the basis of the standard orthography that became official on 10 October 1975. Modifications to this standard were proposed by the "Permanent Council of the Luxembourguish language" and adopted officially in the spelling reform of 30 July 1999. A detailed explanation of current practice for Luxembourgish can be found in Schanen & Lulling (2003).


title: Luxembourgish

text: The Luxembourgish alphabet consists of the 26 Latin letters plus three letters with diacritics: , , and . In loanwords from French and Standard German, other diacritics are usually preserved:


title: Luxembourgish

text: In German loanwords, the digraphs and indicate the diphthong , which does not appear in native words.


title: Luxembourgish

text: Like many other varieties of Western High German, Luxembourgish has a rule of final "n"-deletion in certain contexts. The effects of this rule (known as the "Eifel Rule") are indicated in writing, and therefore must be taken into account when spelling words and morphemes ending in or . For example:


title: Luxembourgish

text: Luxembourgish has three genders (masculine, feminine, and neuter), and three cases (nominative, accusative, and dative). These are marked morphologically on determiners and pronouns. As in German, there is no morphological gender distinction in the plural.


title: Luxembourgish

text: As seen above, Luxembourgish has plural forms of "en" ("a, an"), namely "eng" in the nominative/accusative and "engen" in the dative. They are not used as indefinite articles, which—as in German and English—do not exist in the plural, but they do occur in the compound pronouns "wéi en" ("what, which") and "sou en" ("such"). For example: "wéi eng Saachen" ("what things"); "sou eng Saachen" ("such things"). Moreover, they are used before numbers to express an estimation: "eng 30.000 Spectateuren" ("some 30,000 spectators").


title: Luxembourgish

text: Distinct nominative forms survive in a few nominal phrases such as "der Däiwel" ("the devil") and "eiser Herrgott" ("our Lord"). Rare examples of the genitive are also found: "Enn des Mounts" ("end of the month"), "Ufanks der Woch" ("at the beginning of the week"). The functions of the genitive are normally expressed using a combination of the dative and a possessive determiner: e.g. "dem Mann säi Buch" (lit. "to the man his book", i.e. "the man's book"). This is known as a periphrastic genitive, and is a phenomenon also commonly seen in dialectal and colloquial German, and in Dutch.


title: Luxembourgish

text: The forms of the personal pronouns are given in the following table (unstressed forms appear in parentheses):


title: Luxembourgish

text: The 2pl form is also used as a polite singular (like French "vous", see T-V distinction); the forms are capitalised in writing:


title: Luxembourgish

text: Like most varieties of colloquial German, but even more invariably, Luxembourgish uses definite articles with personal names. They are obligatory and not to be translated:


title: Luxembourgish

text: A feature Luxembourgish shares with only some western dialects of German is that women and girls are most often referred to with forms of the "neuter" pronoun "hatt":


title: Luxembourgish

text: Luxembourgish morphology distinguishes two types of adjective: attributive and predicative. Predicative adjectives appear with verbs like "sinn" ("to be"), and receive no extra ending:


title: Luxembourgish

text: Attributive adjectives are placed before the noun they describe, and change their ending according to the grammatical gender, number, and case:


title: Luxembourgish

text: Curiously, the definite article changes with the use of an attributive adjective: feminine "d<nowiki>'</nowiki>" goes to "déi" (or "di"), neuter "d<nowiki>'</nowiki>" goes to "dat", and plural "d<nowiki>'</nowiki>" changes to "déi".


title: Luxembourgish

text: The comparative in Luxembourgish is formed analytically, i.e. the adjective itself is not altered (compare the use of -"er" in German and English; "tall" → "taller", "klein" → "kleiner"). Instead it is formed using the adverb "méi": e.g. "schéin" → "méi schéin"


title: Luxembourgish

text: The superlative involves a synthetic form consisting of the adjective and the suffix "-st": e.g. "schéin" → "schéinst " (compare German "schönst", English "prettiest"). Attributive modification requires the emphatic definite article and the inflected superlative adjective:


title: Luxembourgish

text: Predicative modification uses either the same adjectival structure or the adverbial structure "am"+ -"sten": e.g. "schéin" → "am schéinsten":


title: Luxembourgish

text: Several other adjectives also have comparative forms, not commonly used as normal comparatives, but in special senses:


title: Luxembourgish

text: Luxembourgish exhibits "verb second" word order in clauses. More specifically, Luxembourgish is a V2-SOV language, like German and Dutch. In other words, we find the following finite clausal structures:


title: Luxembourgish

text: These rules interact so that in subordinate clauses, the finite verb and any non-finite verbs must all cluster at the end. Luxembourgish allows different word orders in these cases:


title: Luxembourgish

text: Luxembourgish (like Dutch and German) allows prepositional phrases to appear after the verb cluster in subordinate clauses:


title: Luxembourgish

text: Luxembourgish has borrowed many French words. For example, the word for a bus driver is "Buschauffeur" (as in Dutch and Swiss German), which would be "Busfahrer" in German and "chauffeur de bus" in French.


title: Luxembourgish

text: Some words are different from Standard German, but have equivalents in German dialects. An example is "Gromperen" (potatoes – German: "Kartoffeln"). Other words are exclusive to Luxembourgish.


title: Luxembourgish

text: Neologisms in Luxembourgish include both entirely new words, and the attachment of new meanings to old words in everyday speech. The most recent neologisms come from the English language in the fields of telecommunications, computer science, and the Internet.


title: Luxembourgish

text: Between 2000 and 2002, Luxembourgish linguist Jérôme Lulling compiled a lexical database of 125,000-word forms as the basis for the first Luxembourgish spellchecker (Projet C.ORT.IN.A).


title: Luxembourgish

text: The LaF ("Lëtzebuergesch als Friemsprooch" – Luxembourgish as a Foreign Language) is a set of four language proficiency certifications for Luxembourgish and follows the ALTE framework of language examination standards. The tests are administered by the Institut National des Langues Luxembourg.


title: Luxembourgish

text: The "Centre for Luxembourg Studies" at the University of Sheffield was founded in 1995 on the initiative of Professor Gerald Newton. It is supported by the government of Luxembourg which funds an endowed chair in Luxembourg Studies at the university.


title: Luxembourgish

text: The first class of students to study the language outside of the country as undergraduate students began their studies at the 'Centre for Luxembourg Studies' at Sheffield in the academic year 2011–2012.


title: Luxembourgish

text: UNESCO declared Luxembourgish to be an endangered language in 2019, adding it to its "Atlas of the World's Languages in Danger".


title: Luxembourgish

text: Additionally, some local media have argued that the Luxembourgish language is at risk of disappearing, and that it should be considered an endangered language. Even though the government claims that more people than ever are able to speak Luxembourgish, these are absolute numbers and often include the many naturalized citizens who have passed the "Sproochentest," a language test that certifies the knowledge of merely A.2. in speaking and B.1. in understanding.


title: Luxembourgish

text: Luxembourgish language expert and historian argues that not only the absolute number of Luxembourgish speakers should be considered when defining the status of a language, but also the proportion of speakers in a country. Noting that the proportion of native Luxembourgish speakers has decreased in recent decades, Atten believes that Luxembourgish will inevitably disappear, stating:


title: Luxembourgish

text: ""It is simple math, if there are about 70% foreigners and about 30% Luxembourgers (which is the case in Luxembourg City), then it can impossibly be said that Luxembourgish is thriving. That would be very improbable.""


title: Luxembourgish

text: Alain Atten also points out that the situation is even more dramatic, since the cited percentages take only the residents of Luxembourg into account, excluding the 200,000 cross-border-workers present in the country on a daily basis. This group plays a major role in the daily use of languages in Luxembourg, thus further lowering the percentage of Luxembourgish speakers present in the country.


title: Luxembourgish

text: The following numbers are based on statistics by "STATEC" (those since 2011) and show that the percentage of the population that is able to speak Luxembourgish has been constantly diminishing for years (Note that the 200,000 cross-border workers are not included in this statistic):


title: Luxembourgish

text: It has also been argued that two very similar languages, Alsatian and Lorraine Franconian, which were very broadly spoken by the local populations at the beginning of the 20th century in Alsace and in Lorraine respectively, have been nearly completely supplanted by French, and that a similar fate could also be possible for Luxembourgish. Another example of the replacement of Luxembourgish by French occurred in Arelerland (historically a part of Luxembourg, today in Belgium), where the vast majority of the local population spoke Luxembourgish as a native language well into the 20th century. Today, Luxembourgish is nearly extinct in this region, having been replaced by French.


title: Luxembourgish

text: According to some Luxembourgish news media and members of (an association for the preservation and promotion of the language), the biggest threat to the existence of Luxembourgish is indeed French, since French is the predominant language of most official documents and street signs in Luxembourg, thus considerably weakening the possibilitiy for Luxembourgish learners to practice the newly learned language. In most cases this passively forces expats to learn French instead of Luxembourgish.


title: Luxembourgish

text: In 2021 it was announced that public announcements in Luxembourgish (and in German as well) at Luxembourg Airport would cease; it would only be using French and English for future public announcements. This will cause Luxembourgish to go unused at Luxembourg Airport after many decades. declared itself to be hugely upset by this new governmental measure, citing that other airports in the world seem to have no problems making public announcements in multiple languages. According to a poll conducted by AL, 92.84% of the Luxembourgish population wished to have public announcements to be made in Luxembourgish at Luxembourg Airport.


title: Luxembourgish

text: Further fears of Luxembourgish's replacement by French were fueled in 2021 when ("Association de Soutien aux Travailleurs Immigrés") wished to see Luxembourgish removed as the national language of Luxembourg (as written in the constitution), claiming that the national language of Luxembourg should by law be defined as the one that is most used in the local population, hinting that French would be the better choice.


title: Luxembourgish

text: According to ADR politician Fred Keup, Luxembourgish is already on its way to complete replacement by French.


title: Billboard Year-End Hot 100 singles of 2010

text: "Billboard" publishes annual lists of songs based on chart performance over the course of a year based on Nielsen Broadcast Data Systems and SoundScan information. For 2010, the list for the top 100 "Billboard" Hot 100 Year-End songs was published on December 8, calculated with data from December 5, 2009 to November 27, 2010. At the number-one position was Kesha's "Tik Tok", which stayed atop the Hot 100 for nine weeks. This achievement made her the first woman in the history of the chart to top the Year-End Hot 100 with a debut single.


title: Clozapine

text: Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson's disease. Clozapine is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, after resistance to earlier neuroleptic treatment is established.


title: Clozapine

text: The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark study in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis who had already shown an inadequate response to other antipsychotics. While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalization. In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs. In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it. In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.


title: Clozapine

text: Compared to other antipsychotics, clozapine has an increased risk of blood dyscrasias, in particular agranulocytosis, in the first 18 weeks of treatment. After one year, this risk reduces to that associated with most antipsychotics. Clozapine's use is therefore reserved for people who have not responded to two other antipsychotics and is only done with stringent blood monitoring. Overall, despite the concerns relating to blood and other side effects, clozapine use is associated with a reduced mortality, especially from suicide which is a major cause of premature death in people with schizophrenia. The risk of clozapine related agranulocytosis and neutropenia warranted the mandatory use of stringent risk monitoring and management systems, which have reduced the risk of death from these adverse events to around 1 in 7,700. The association between clozapine use and specific bloods dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in Finland. At the time it was not clear if this exceeded the established rate of this side effect which is also found in other antipsychotics and although the drug was not completely withdrawn, its use became limited. Clozapine became widely available in the early 1990s and remains the only treatment likely to be effective in treating resistant schizophrenia.


title: Clozapine

text: Common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, weight gain, and dizziness. Clozapine is not normally associated with tardive dyskinesia (TD) and is recommended as the drug of choice when this is present, although some case reports describe clozapine-induced TD. Other serious risks include seizures, myocarditis (inflammation of the heart), hyperglycemia (high blood glucose levels), and constipation. The use of this drug can rarely result in clozapine-induced gastric hypomotility syndrome which may lead to bowel obstruction and death, and in older people with psychosis, as a result of dementia it may lead to an increased risk of death. The mechanism of action is not entirely clear in the current medical literature. Clozapine is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.


title: Clozapine

text: Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine. The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967 Wander AG was acquired by Sandoz. Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany and in Finland in 1975. Early testing was performed in the United States around the same time. In 1975, 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern. Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period. The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic diversity in the region. Whilst the drug continued to be manufactured by Sandoz, and remained available in Europe, development in the U.S. halted.


title: Clozapine

text: Interest in clozapine continued in an investigational capacity in the United States because, even in the 1980s, the duration of hospitalisation, especially in State Hospitals for those with treatment resistant schizophrenia might often be measured in years rather than days. The role of clozapine in treatment resistant schizophrenia was established by the landmark Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double-blind design with the power to demonstrate superiority over standard antipsychotic treatment. The inclusion criteria were patients who had failed to respond to at least three previous antipsychotics and had then not responded to a single blind treatment with haloperidol (mean dose 61 mg +/- 14 mg/d). Two hundred and sixty-eight were randomised were to double blind trials of clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d). 30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.


title: Clozapine

text: In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective judged to be at chronic risk for suicidal behavior. In 2005, the FDA approved criteria to allow reduced blood monitoring frequency. In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry. Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised.


title: Clozapine

text: Clozapine is a dibenzodiazepine that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C). Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).


title: Clozapine

text: Clozapine is usually used for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson's Disease. It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by systematic reviews and meta-analysis. Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug. Clozapine treatment has been demonstrated to produced improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics. Very long term follow-up studies reveal multiple benefits in terms of reduced mortality, with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of suicide or attempted suicide. Clozapine has a significant anti-aggressive effect. Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found. In secure hospitals and other settings clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm. Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the approximately 100 reported cases patients agreed to take oral medication prior to the use of a coercive intervention. Clozapine has also been used off-label to treat catatonia with success in over 80% of cases.


title: Clozapine

text: On the basis of systematic reviews clozapine is recommended in some treatment guidelines as a third or fourth line treatment for bipolar disorder. Bipolar disorder is an unlicensed indication for clozapine.


title: Clozapine

text: Clozapine is also used in emotionally unstable personality disorder and a randomised controlled trial is currently underway. The use of clozapine to treat personality disorder is uncommon and unlicensed.


title: Clozapine

text: Whilst clozapine is usually initiated in hospital setting community initiation is also available. Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to extrapyramidal symptoms of other antipsychotics or psychosis in Parkinson's disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.


title: Clozapine

text: Baseline tests usually also include; a physical examination including baseline weight, waist circumference and BMI, assessments of renal function and liver function, an ECG and other baseline bloods may also be taken to facilitate monitoring of possible myocarditis, these might include C reactive protein (CRP) and troponin. In Australia and New Zealand pre-clozapine echocardiograms are also commonly performed. A number of service protocols are available and there are variations in the extent of preclozapine work ups. Some might also include fasting lipids, HbA1c and prolactin. At the Maudsley Hospital in the UK the Treat service also routinely performs a wide variety of other investigations including multiple investigations for other causes of psychosis and comorbidities including; MRI brain imaging, thyroid function tests, B12, folate and serum calcium levels, infection screening for blood borne viruses including Hepatitis B and C, HIV and syphilis as well as screening for autoimmune psychosis by anti-NMDA, anti-VGKC and Anti-nuclear Antibody screening. Investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, CRP and BNP and for neuroleptic malignant syndrome CK.


title: Clozapine

text: The dose of clozapine is initially low and gradually increased over a number of weeks. Initial doses may range from 6.5 to 12.5 mg/d increasing stepwise typically to doses in the range of 250–350 mg per day at which point an assessment of response will be performed. In the UK the average clozapine dose is 450 mg/d. But response is highly variable and some patients respond at much lower doses and vice versa.


title: Clozapine

text: During the initial dose titration phase the following are typically monitored; usually daily at first; pulse, blood pressure and since orthostatic hypotension can be problematic this should be monitored both sitting and standing. If there is a significant drop then the rate of the dose increase may be slowed, temperature.


title: Clozapine

text: Weekly tests include; Mandatory full blood counts are performed weekly for the first 18 weeks. In some services there will also be monitoring of markers that might indicate myocarditis; troponin, CRP and BNP although the exact tests and frequency vary between services. Weight is usually measured weekly.


title: Clozapine

text: Thereon other investigations and monitoring will always include full blood counts (fortnightly for 1 year then monthly). Weight, waist circumference, lipids and glucose or HbA1c may also be monitored.


title: Clozapine

text: As with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week. That said responses, especially those which are partial, can be delayed. Quite what an adequate trial of clozapine is, is uncertain but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/L. There is considerable inter-individual variation. A significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900 mg/day. Options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. Avoiding unnecessary polypharmacy is a general principle in drug treatment.


title: Clozapine

text: The neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. There is a significant margin of safety. Some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. A knowledge of neutrophil biology allows blood sampling optimisation. Neutrophils show a diurnal variation in response to the natural cycle of G-CSF production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. Simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. However this is a disruption to usual hospital practice. Other practical steps are to ensure that blood results become available in hours and when senior staff are available.


title: Clozapine

text: Clozapine is widely recognised as being underused with wide variation in prescribing, especially in patients with African heritage.


title: Clozapine

text: Psychiatrists prescribing practices have been found to be the most significant variable regarding variance in its use. Surveys of psychiatrists attitudes to clozapine have found that many had little experience in its use, over estimated the incidence and were fearful of side effects, and did not appreciate that many patients prefer to take clozapine than other antipsychotics, are reluctant to prescribe clozapine, had little experience in its use and believed that patients treated with clozapine were less satisfied than those treated with other antipsychotics. In contrast to many psychiatrists expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive. Whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation. Clozapine is no longer actively marketed and this may also be one of the explanations for its underuse.


title: Clozapine

text: Despite the strong evidence and universal endorsement by national and international treatment guidelines and the experiences of patients themselves, most people eligible for clozapine are not treated with it. A large study in England found that approximately 30% of those eligible for clozapine were being treated with it. Those patients that do start clozapine usually face prolonged delay, multiple episodes of psychosis and treatments such as high dose antipsychotics or polypharmacy. Instead of two previous antipsychotics many will have been exposed to ten or more drugs which were not effective. In a study of 120 patients conducted in four hospitals in South-East London, found a mean of 9.2 episodes of antipsychotic prescription before clozapine was initiated and the mean delay in using clozapine was 5 years. Treatments that have no evidence base or are regarded as actively harmful are used instead multiple and or high-dose treatment.


title: Clozapine

text: A general finding in healthcare provision is that minority groups receive inferior treatment; this is a particular finding in the US. In the US a general finding is that compared to their white peers African American people are less likely to be prescribed the second generation antipsychotics, which are more expensive than alternatives and this was even apparent and especially so for clozapine when comparison was made in the Veterans Affairs medical system and when differences regarding socioeconomic factors were taken into account. As well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia.


title: Clozapine

text: Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry. A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations. For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 10/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima. But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The Duffy–Null polymorphism, which protects against some types of malaria, is predictive of BEN.


title: Clozapine

text: Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including (1) severe neutropenia (low levels of neutrophils), (2) orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting, (3) seizures, (4) myocarditis (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis. Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.


title: Clozapine

text: Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. Sexual problems, like retrograde ejaculation, have been reported while taking clozapine. Rare adverse effects include periorbital edema. Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.


title: Clozapine

text: Clozapine Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and Clozapine Induced Agranulocytosis (CIA) in 0.4%. These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS). The exact schedules and blood count thresholds vary internationally and the thresholds at which clozapine can be used in the U.S. has been lower than those currently used in the U.K. and Australasia for some time. The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7700 patients treated. Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks. After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still. When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then clozapine is stopped immediately and can then no longer be used within the medicinal licence. Stopping clozapine almost always results in resolution of the neutrophil reduction. However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis. Rapid point-of-care tests may simplify the monitoring for agranulocytosis.


title: Clozapine

text: A clozapine "rechallenge" is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off. Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited.


title: Clozapine

text: Clozapine can rarely cause myocarditis and cardiomyopathy. A large meta-analysis of clozapine exposure to over 250,000 people revealed that these occurred in approximately 7 in 1000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness. Signs of heart failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate. A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives. Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published. A systematic review of rechallenge after myocarditis has show success in over 60% of reported cases.


title: Clozapine

text: Another underrecognized and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers. Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis. A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication. Monitoring bowel function and the preemptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae.


title: Clozapine

text: Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%). The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day. While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for hypersalivation. Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication. Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine, diphenhydramine and topical anticholinergic medications like ipratropium bromide. Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.


title: Clozapine

text: CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paresthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome.


title: Clozapine

text: Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation. Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis. Doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.


title: Clozapine

text: In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. For people who gain weight because of clozapine, taking metformin may reportedly improve three of the five components of the metabolic syndrome: waist circumference, fasting glucose, and fasting triglycerides.


title: Clozapine

text: International adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events. The mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation, immune effects of clozapine's effects on the resolution of inflammation.


title: Clozapine

text: Symptoms of overdose can be variable, but often include; sedation, confusion, tachycardia, seizures and ataxia. Fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000 mg have been survived.


title: Clozapine

text: Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.


title: Clozapine

text: When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine. Patients should be monitored for "decreased therapeutic effects of clozapine if carbamazepine" is started or increased. If carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. The study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis.


title: Clozapine

text: Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in subjects concurrently taking ciprofloxacin. Thus, the prescribing information for clozapine recommends "reducing the dose of clozapine by one-third of original dose" when ciprofloxacin and other CYP1A2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose.


title: Clozapine

text: Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.


title: Clozapine

text: Clozapine is an antagonist at the 5-HT subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.


title: Clozapine

text: A direct interaction of clozapine with the GABA receptor has also been shown. GABA receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABA receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.


title: Clozapine

text: Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.


title: Clozapine

text: The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. However, it was shown that co-administration of food decreases the rate of absorption. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).


title: Clozapine

text: Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and feces. The major metabolite, "norclozapine" (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.


title: Clozapine

text: Clozapine and norclozapine (desmethyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimisation.


title: Clozapine

text: Despite the expense of the risk monitoring and management systems required, clozapine use is highly cost effective; with a number of studies suggesting savings of tens of thousands of dollars per patient per year compared to other antipsychotics as well as advantages regarding improvements in quality of life. Clozapine is available as a generic medication.


title: Celia Cruz

text: Úrsula Hilaria Celia de la Caridad Cruz Alfonso (21 October 1925 – 16 July 2003), known as Celia Cruz, was a naturalized Cuban-American singer and one of the most popular Latin artists of the 20th century. Cruz rose to fame in Cuba during the 1950s as a singer of guarachas, earning the nickname "La Guarachera de Cuba". In the following decades, she became known internationally as the "Queen of Salsa" due to her contributions to Latin music.


title: Celia Cruz

text: She began her career in her native Cuba, earning recognition as a vocalist of the popular musical group Sonora Matancera, a musical association that lasted fifteen years (1950-1965). Cruz mastered a wide variety of Afro-Cuban music styles including guaracha, rumba, afro, son and bolero, recording numerous singles in these styles for Seeco Records. In 1960, after the Cuban Revolution caused the nationalization of the music industry, Cruz left her native country, becoming one of the symbols and spokespersons of the Cuban community in exile. Cruz continued her career, first in Mexico, and then in the United States, the country that she took as her definitive residence. In the 1960s, she collaborated with Tito Puente, recording her signature tune "Bemba colorá". In the 1970s, she signed for Fania Records and became strongly associated with the salsa genre, releasing hits such as "Quimbara". She often appeared live with Fania All-Stars and collaborated with Johnny Pacheco and Willie Colón. During the last years of her career, Cruz continued to release successful songs such as "La vida es un carnaval" and "La negra tiene tumbao".


title: Celia Cruz

text: Her musical legacy is made up of a total of 37 studio albums, as well as numerous live albums and collaborations. Throughout her career, she was awarded numerous prizes and distinctions, including two Grammy Awards and three Latin Grammy Awards. In addition to her prolific career in music, Cruz also made several appearances as an actress in movies and telenovelas. Her catchphrase ""¡Azúcar!"" ("Sugar!") has become one of the most recognizable symbols of salsa music.


title: Celia Cruz

text: Úrsula Hilaria Celia de la Caridad Cruz Alfonso was born on 21 October 1925, at 47 Serrano Street in the Santos Suárez neighborhood of Havana, Cuba. Her father, Simón Cruz, was a railway stoker, and her mother, Catalina Alfonso Ramos, a housewife who took care of an extended family. Celia was one of the eldest among fourteen children living in the house, including cousins and her three siblings, Dolores, Gladys, and Bárbaro, and she used to sing cradle songs to put them to sleep. According to her mother, she began singing as a child at 9 or 10 months of age, often in the middle of the night. She also sang in school during the Fridays' "actos cívicos" and in her neighborhood ensemble, Botón de oro.


title: Celia Cruz

text: While growing up in Cuba's diverse 1930s musical climate, Cruz listened to many musicians who influenced her adult career, including Fernando Collazo, Abelardo Barroso, Pablo Quevedo, Antonio Arcaño and Arsenio Rodríguez. Despite her father's opposition and the fact that she was Catholic, as a child Cruz learned Santería songs from her neighbor who practiced Santería. Cruz also studied the words to Yoruba songs with colleague Merceditas Valdés (an "akpwon", a santería singer) from Cuba and later made various recordings of this religious genre, even singing backup for other female akpwons like Candita Batista.


title: Celia Cruz

text: As a teenager, her aunt took her and her cousin to cabarets to sing, but her father encouraged her to attend school in the hope she would become a teacher. After high school, she attended the Normal School for Teachers in Havana with the intent of becoming a literature teacher. At the time being a singer was not viewed as an entirely respectable career. However, one of her teachers told her that, as an entertainer, she could earn in one day what most Cuban teachers earned in a month. From 1947, Cruz studied music theory, voice, and piano at Havana's National Conservatory of Music.


title: Celia Cruz

text: One day, her cousin took her to Havana's radio station Radio García-Serra, where she became a contestant in the "Hora del té" amateur radio program. It was her first time using a microphone and she sang the tango "Nostalgia" (as a tribute to Paulina Álvarez), winning a cake as the first prize for her performance. On other occasions she won silver chains, as well as opportunities to participate in more contests. She also sang in other amateur radio programs such as "La suprema corte del arte", broadcast by CMQ, always winning first prize. The only exception was when she competed against Vilma Valle, having to split their earnings: 25 dollars each.