title: Melancholia (2011 film)

text: On 18 May 2011, "Melancholia" premiered at the 64th Cannes Film Festival, where it was received with critical acclaim and Dunst received the festival's Best Actress Award for her performance, which was a common area of praise among critics. Although it has detractors, many critics and film scholars have considered the film to be a personal masterpiece; claiming that the film considered to be the best of the trilogy and one of the von Trier's best works. Along with von Trier's previous film "Dogville" (2003), it was later included in the 2016 poll of the greatest films since 2000 conducted by BBC.


title: Melancholia (2011 film)

text: It has since been featured in various listings of the best films of 2011, the best films of the 2010s, and the best films of the 21st century.


title: Melancholia (2011 film)

text: A dream sequence showcases slow-motion shots of the main characters, a collapsing horse, falling birds, butterflies, different planets, and images of the Earth colliding with a rogue planet.


title: Melancholia (2011 film)

text: The dream belongs to Justine, who weds Michael in a castle owned by her brother-in-law John and her sister Claire. Justine and Michael are late for the reception due to their stretch limousine's difficulty traversing the narrow and winding rural road. Upon their arrival, Justine sees a star in the sky shining brightly. John, an astronomy enthusiast, explains it is the star Antares. The festivities are less than harmonious; Justine's divorced parents Gaby and Dexter verbally abuse each other in front of the guests. Justine, to John and Claire's annoyance, keeps wandering away. Justine's employer Jack, who announces her promotion to art director of his advertising firm, expects her to write a slogan for a new campaign during the celebration. Justine finds herself pushed into a role that others have chosen for her and falls back into depression, from which she has been suffering for a long time. Toward the end of the party, which goes on until the early hours of the morning, she quits her job in an argument and calls off her marriage to Michael after cheating on him. Early the following morning, while horseriding with Claire, Justine notices Antares is no longer visible in the sky.


title: Melancholia (2011 film)

text: Justine returns home with Claire, but sinks even further into depression, and is welcomed back to John and Claire's estate, where she struggles to leave her bed and is unable to eat. According to John, Antares's absence is due to the rogue planet "Melancholia". The planet appeared from behind the Sun and passed in front of Antares. John announces that according to the scientists' calculations, Melancholia will pass in close proximity to Earth, but will not collide with it. Claire looks anxiously at Melancholia's path on the Internet, learning of a predicted collision with Earth. John tries to calm her down but secretly secures food and gasoline. In view of the approaching planet, Claire increasingly loses her composure, while Justine longs for the end of the world and "sunbathes" naked in the planet's glow at night.


title: Melancholia (2011 film)

text: Strange omens pile up in the days that follow. The electricity in the castle goes out, the butler does not come to work, the horses in the stable are restless, St. Elmo's fires emerge at various times, and the weather changes erratically. Melancholia initially flies past Earth, seemingly vindicating John. Melancholia then crosses Earth's orbit a second time, however, now moving directly toward Earth. Upon this discovery, John commits suicide by overdosing on pills. Claire hides his death from the family and attempts to flee with her son Leo, but the cars will not start. Justine declines to spend her final moments with Claire on the terrace by candlelight and wine. Instead, Justine calms Leo down by suggesting that they build a "magic cave" out of branches. Shortly before the collision, Justine, Claire, and Leo sit under the "cave" and hold hands. While Justine and Leo seem apathetic to, or at peace with their impending doom, Claire panics and despairs. Melancholia finally collides with Earth, engulfing them in a sea of flames as both planets shatter against each other.


title: Melancholia (2011 film)

text: Von Trier's initial inspiration for the film came from a depressive episode he suffered. The film is a Danish production by Zentropa, with international co-producers in Denmark, Sweden, France, and Germany.


title: Melancholia (2011 film)

text: Filming took place in Sweden. "Melancholia" prominently features music from the prelude to Richard Wagner's opera "Tristan und Isolde" (1857–1859). It is the second entry in von Trier's unofficially titled "Depression Trilogy", preceded by "Antichrist" and followed by "Nymphomaniac".


title: Melancholia (2011 film)

text: The idea for the film originated during a therapy session Lars von Trier attended during treatments for his depression. A therapist had told von Trier that depressive people tend to act more calmly than others under heavy pressure, because they already expect bad things to happen. Von Trier then developed the story not primarily as a disaster film, and without any ambition to portray astrophysics realistically, but as a way to examine the human psyche during a disaster.


title: Melancholia (2011 film)

text: The idea of a planetary collision was inspired by websites with theories about such events. Von Trier decided from the outset that it would be clear from the beginning that the world would actually end in the film, so audiences would not be distracted by the suspense of not knowing. The concept of the two sisters as main characters developed via an exchange of letters between von Trier and the Spanish actress Penélope Cruz. Cruz wrote that she would like to work with von Trier, and spoke enthusiastically about the play "The Maids" by Jean Genet. As von Trier subsequently tried to write a role for the actress, the two maids from the play evolved into the sisters Justine and Claire in "Melancholia". Much of the personality of the character Justine was based on von Trier himself. The name was inspired by the Marquis de Sade novel "Justine" (1791).


title: Melancholia (2011 film)

text: "Melancholia" was produced by Denmark's Zentropa, with co-production support from its subsidiary in Germany, Sweden's Memfis Film, France's Slot Machine, and Liberator Productions. The production received 7.9 million Danish kroner from the Danish Film Institute, 600,000 euro from Eurimages,and 3 million Swedish kronor from the Swedish Film Institute. Additional funding was provided by Film i Väst, DR, Arte France, CNC, Canal+, BIM Italy, Filmstiftung Nordrhein-Westfalen, Sveriges Television, and Nordisk Film & TV-Fond. The total budget was 52.5 million Danish kroner.


title: Melancholia (2011 film)

text: Cruz was initially expected to play the lead role, but dropped out when the filming schedule of another project was changed. Von Trier then offered the role to Kirsten Dunst, who accepted it. Dunst had been suggested for the role by the American filmmaker Paul Thomas Anderson in a discussion about the film between him and von Trier.


title: Melancholia (2011 film)

text: Principal photography began 22 July and ended 8 September 2010. Interior scenes were shot at Film i Väst's studios in Trollhättan, Sweden. It was the fourth time von Trier made a film in Trollhättan. Exteriors included the area surrounding the Tjolöholm Castle. The film was recorded digitally with Arri Alexa and Phantom cameras. Von Trier employed his usual directing style with no rehearsals; instead the actors improvised and received instructions between the takes. The camera was initially operated by von Trier, and then left to cinematographer Manuel Alberto Claro who repeated von Trier's movements. Claro said about the method: "[von Trier] wants to experience the situations the first time. He finds an energy in the scenes, presence, and makes up with the photographic aesthetics." Von Trier explained that the visual style he aimed at in "Melancholia" was "a clash between what is romantic and grand and stylized and then some form of reality", which he hoped to achieve through the hand-held camerawork. He feared, however, that it would tilt too much toward the romantic, because of the setting at the upscale wedding, and the castle, which he called "super kitschy".


title: Melancholia (2011 film)

text: The prelude to Richard Wagner's "Tristan und Isolde" supplies the main musical theme of the film, and von Trier's use of an overture-like opening sequence before the first act is a technique closely associated with Wagner. This choice was inspired by a 30-page section of Marcel Proust's "In Search of Lost Time", where Proust concludes that Wagner's prelude is the greatest work of art of all time. "Melancholia" uses music more than any film by von Trier since "The Element of Crime" from 1984. In some scenes, the film was edited in the same pace as the music. Von Trier said: "It's kind of like a music video that way. It's supposed to be vulgar." Von Trier also pointed out parallels between both the film's usage of Wagner and the film's editing to the music and the aesthetics of Nazi Germany.


title: Melancholia (2011 film)

text: Visual effects were provided by companies in Poland, Germany, and Sweden under visual effects supervisor Peter Hjorth. Poland's Platige Image, which previously had worked with von Trier on "Antichrist", created most of the effects seen in the film's opening sequence; the earliest instructions were provided by von Trier in the summer 2010, after which a team of 19 visual effects artists worked on the project for three months.


title: Melancholia (2011 film)

text: In his director's statement, von Trier wrote that he had started to regret having made such a polished film, but that he hoped it would contain some flaws which would make it interesting: "I desired to dive headlong into the abyss of German romanticism ... But is that not just another way of expressing defeat? Defeat to the lowest of cinematic common denominators? Romance is abused in all sorts of endlessly dull ways in mainstream products."


title: Melancholia (2011 film)

text: The premiere took place at the 2011 Cannes Film Festival, where "Melancholia" was screened in competition on 18 May. The press conference after the screening gained considerable publicity. "The Hollywood Reporter"'s Scott Roxborough wrote that "Von Trier has never been very P.C. and his Cannes press conferences always play like a dark stand-up routine, but at the "Melancholia" press conference he took it to another level, tossing a grenade into any sense of public decorum." Von Trier first joked about working on a hardcore pornographic film that would star Dunst and Gainsbourg. When asked about the relation between the influences of German Romanticism in "Melancholia" and von Trier's own German heritage, the director brought up that he had been raised believing his biological father was a Jew, only to learn as an adult that his actual father was a German. He then made jokes about Jews and Nazis, said he understood Adolf Hitler and admired the work of architect Albert Speer, and jokingly announced that he was a Nazi. The Cannes Film Festival issued an official apology for the remarks the same day and clarified that von Trier is not a Nazi or an anti-Semite, then declared the director "persona non grata" the following day. This meant he was not allowed to go within 100 meters of the Festival Palace, but he did remain in Cannes and continued to give promotional interviews.


title: Melancholia (2011 film)

text: On 26 May 2011, the film was released in Denmark through Nordisk Film. Launched on 57 screens, the film entered the box-office chart as number three. A total of 50,000 tickets were eventually sold in Denmark. It was released in the United Kingdom and Ireland on 30 September, in Germany on 6 October and in Italy on 21 October. Magnolia Pictures acquired the distribution rights for North America and it was released on 11 November, with a pre-theatrical release on 13 October as a rental through such Direct TV vendors as Vudu and Amazon.com. Madman Entertainment bought the rights for Australia and New Zealand.


title: Melancholia (2011 film)

text: On review aggregator Rotten Tomatoes, 80% of 206 critic reviews are positive, and the average rating is 7.5/10. The website's critical consensus states, ""Melancholia"s dramatic tricks are more obvious than they should be, but this is otherwise a showcase for Kirsten Dunst's acting and for Lars von Trier's profound, visceral vision of depression and destruction." According to Metacritic, the film received "generally favorable reviews", based on an average score of 80/100 from 40 critics. A 2017 data analysis of Metacritic reviews by "Gizmodo UK" found the film to be the most critically divisive film of recent years.


title: Melancholia (2011 film)

text: Kim Skotte of "Politiken" compared the film with the director's previous work: "There are images—many images—in "Melancholia" which underline that Lars von Trier is a unique film storyteller... The choice of material and treatment of it underlines Lars von Trier's originality... Through its material and look, "Melancholia" creates rifts, but unlike "Antichrist" I don't feel that there is a fence pole in the rift which is smashed directly down into the meat. You sit on your seat in the cinema and mildly marveled go along in the end of the world."


title: Melancholia (2011 film)

text: "Berlingske"'s Ebbe Iversen wrote about the film: "It is big, it is enigmatic, and now and then rather irritating. But it is also a visionary work, which makes a gigantic impression. From time to time the film moves on the edge of kitsch, but with Justine played by Kirsten Dunst and Claire played by Charlotte Gainsbourg as the leading characters, "Melancholia" is a bold, uneven, unruly and completely unforgettable film."


title: Melancholia (2011 film)

text: Steven Loeb of "Southampton Patch" wrote: "This film has brought the best out of von Trier, as well as his star. Dunst is so good in this film, playing a character unlike any other she has ever attempted, that she won the award for Best Actress at the Cannes Film Festival this past May. Even if the film itself were not the incredible work of art that it is, Dunst's performance alone would be incentive enough to recommend it."


title: Melancholia (2011 film)

text: Sukhdev Sandhu wrote from Cannes in "The Daily Telegraph" that the film "at times comes close to being a tragi-comic opera about the end of the world," and that, "the apocalypse, when it comes, is so beautifully rendered that the film cements the quality of fairy tale that its palatial setting suggests." About the actors' performances, Sandhu wrote: "all of them are excellent here, but Dunst is exceptional, so utterly convincing in the lead role—troubled, serene, a fierce savant—that it feels like a career breakthrough. Meanwhile, Gainsbourg, for whom the end of the world must seem positively pastoral after the horrors she went through in "Antichrist", locates in Claire a fragility that ensures she's more than a whipping girl for social satire." Sandhu brought up one reservation in the review, in which he gave the film the highest possible rating of five stars: "there is, as always with Von Trier's work, a degree of intellectual determinism that can be off-putting; he illustrates rather than truly explore ideas." Peter Bradshaw, writing for "The Guardian", stated "Windup merchant Lars von Trier is back with a film about the end of the world – but it's not to be taken entirely seriously", and gave it three stars out of a possible five.


title: Melancholia (2011 film)

text: In 2020, amid the COVID-19 pandemic, an "Atlantic" culture writer found "the perspective of a catastrophe-minded person thrust into a state of actual catastrophe finds perhaps no better creative expression" than in the film. "BBC Culture" stated that "arguably no film has been more profoundly compassionate in its depiction of a mental crisis".


title: Melancholia (2011 film)

text: Dunst received the Best Actress Award at the closing ceremony of the Cannes Film Festival. The film won three awards at the European Film Awards for Best Film, Best Cinematographer (Manuel Alberto Claro), and Best Designer (Jette Lehmann).


title: Melancholia (2011 film)

text: The U.S. National Society of Film Critics selected "Melancholia" as the best picture of 2011 and named Kirsten Dunst best actress. The film was also nominated for four Australian Academy of Cinema and Television Arts Awards: Best Film – International; Best Direction – International for von Trier, Best Screenplay – International also for von Trier, and Best Actress – International for Dunst.


title: Melancholia (2011 film)

text: "Film Comment" magazine listed "Melancholia" third on its Best Films of 2011 list. The film also received 12 votes—seven from critics and five from directors—in the British Film Institute's 2012 "Sight & Sound" poll of the greatest movies ever made, making it one of the few films of the 21st century to appear within the top 250. In 2016, the film was named as the 43rd best film of the 21st century, from a poll of 177 film critics from around the world. In 2019, "Time" listed it as one of the best films of the 2010s decade, while "Cahiers du cinéma" named it the eighth best film of the 2010s. That same year, "Vulture" named "Melancholia" the best film of the 2010s.


title: Melancholia (2011 film)

text: In 2018, playwright Declan Greene adapted the film into a stage play for Malthouse Theatre in Melbourne, Australia. The cast featured Eryn Jean Norvill as Justine, Leeanna Walsman as Claire, Gareth Yuen as Michael, Steve Mouzakis as John, and Maude Davey as Gaby, while child actors Liam Smith and Alexander Artemov shared the role of Leo. In the adaptation, the character of Dexter, Justine's father is omitted, while Justine's boss, Jack, is combined with John.


title: Dominic Raab

text: Dominic Rennie Raab (; born 25 February 1974) is a British politician who has served as Deputy Prime Minister of the United Kingdom, Secretary of State for Justice, and Lord Chancellor since October 2022, having previously served from 2021 to September 2022. He has been Member of Parliament (MP) for Esher and Walton since 2010. A member of the Conservative Party, he served as Brexit Secretary in 2018 and as both First Secretary of State and Foreign Secretary from 2019 to 2021.


title: Dominic Raab

text: Born in Buckinghamshire, Raab attended Dr Challoner's Grammar School. He studied law at Lady Margaret Hall, Oxford, switching to Jesus College, Cambridge to study for a master's degree. He began his career as a solicitor at Linklaters, before working at the Foreign and Commonwealth Office and as a political aide. He was elected for Esher and Walton at the 2010 general election. As a backbencher, Raab co-wrote a number of papers and books, including "After the Coalition" (2011) and "Britannia Unchained" (2012). He served as Parliamentary Under-Secretary of State for Justice from 2015 to 2016. Following Theresa May's appointment as Prime Minister, Raab returned to the backbenches but was appointed to the second May government as Minister of State for Courts and Justice following the 2017 general election. In the 2018 cabinet reshuffle, he was moved to the post of Minister of State for Housing and Planning.


title: Dominic Raab

text: In 2018, Raab was promoted to Secretary of State for Exiting the European Union following the resignation of David Davis. Two weeks later, Raab was deputised by May to negotiate Britain's departure from the European Union, leaving him to oversee domestic preparations instead. Four months later, Raab resigned as Brexit Secretary in opposition to May's draft Brexit withdrawal agreement.


title: Dominic Raab

text: Following May's resignation in 2019, Raab ran to succeed her in the 2019 Conservative Party leadership election, eliminated in the second ballot of Conservative MPs. Following Boris Johnson's appointment as Prime Minister, Raab was appointed First Secretary of State and Secretary of State for Foreign and Commonwealth Affairs. In 2020, when the Department for International Development was merged with the Foreign and Commonwealth Office, Raab's post was retitled Secretary of State for Foreign, Commonwealth and Development Affairs. In the 2021 cabinet reshuffle, he was moved to the posts of Deputy Prime Minister, Secretary of State for Justice and Lord Chancellor. Following a stint on the backbenches during the premiership of Liz Truss, he was re-appointed to the posts in Rishi Sunak's ministry.


title: Dominic Raab

text: Dominic Rennie Raab was born on 25 February 1974 in Buckinghamshire. He is the son of Jean, a clothes buyer, and Peter Raab, a food manager for Marks & Spencer. His father, who was Jewish, came to Britain from Czechoslovakia in 1938 at age six, when his family decided to flee because the Munich Agreement gave the Sudetenland to Nazi Germany. Raab was brought up in his English mother's faith, in the Church of England. He grew up in Gerrards Cross, Buckinghamshire. Raab was 12 years old when his father died of cancer.


title: Dominic Raab

text: Raab attended Dr Challoner's Grammar School, Amersham and spent a brief period as a volunteer on Kibbutz Sarid before studying law at Lady Margaret Hall, Oxford, where he had a room on the same corridor as future "Channel 4 News" presenter Cathy Newman. Raab spent his time at Oxford "doing a lot of karate" and captained the university karate team, and graduated with a Bachelor of Arts degree in Jurisprudence. He then pursued further studies at Jesus College, Cambridge, where he won the Clive Parry Prize for International Law, and obtained a Master of Laws degree.


title: Dominic Raab

text: After leaving Cambridge, Raab trained professionally at the major City of London law firm Linklaters, completing his mandatory two-year training contract at the firm. Raab qualified as a solicitor in the UK under Linklaters in the year 2000, leaving the firm shortly after qualifying, also in 2000. At Linklaters, Raab worked on project finance, international litigation and competition law. This included time on secondments at Liberty (the human rights NGO) and in Brussels advising on EU and WTO law.


title: Dominic Raab

text: In total Raab worked for six years professionally as a solicitor after qualifying, in both commercial work and Civil service positions for the government in the Foreign Office, before leaving the legal profession to pursue politics in 2006.


title: Dominic Raab

text: During his time as a lawyer in the Civil Service under the Labour Government until 2006, Raab's briefs included leading a team at the British Embassy in The Hague, dedicated to bringing war criminals to justice in a position closely linked to Tony Blair. After returning to London, he advised on the Arab–Israeli conflict, the European Union and Gibraltar. He defended Tony Blair against a subpoena from former Yugoslav President Slobodan Milošević.


title: Dominic Raab

text: On moving from the legal profession to politics in 2006, Raab's first political roles as part of the Conservative Party were as an aide to MP David Davis, and then to Dominic Grieve. When, most of two decades later in 2021 in his ministerial political career Raab was appointed Justice Secretary, he was described within the legal press as an "ex-rookie" solicitor of a major law firm.


title: Dominic Raab

text: Raab was elected to Parliament at the 2010 election to represent Esher and Walton, a then-safe Conservative seat in Surrey, with a total of 32,134 votes (58.9% of the vote) and a majority of 18,593 over his nearest rival.


title: Dominic Raab

text: He lives in and commutes from Thames Ditton, in his constituency. Since being elected he has campaigned for fairer funding for local services in Elmbridge, stronger local democracy in the running of community hospitals in Cobham, Walton and Molesey, more visible and responsive policing, and against the construction of an M25 service station at Downside.


title: Dominic Raab

text: In the House of Commons, Raab spoke in support of the coalition government's plans to cut the budget deficit, expand academy schools, repeal the Identity Cards Act 2006, and enact a Freedom Bill. He criticised the government for opting into the EU directive on the European Investigation Order, arguing it would strain operational policing resources, and would dilute safeguards protecting British citizens from misuse of personal data and guaranteeing a fair trial.


title: Dominic Raab

text: He came to media attention in August 2010, after requesting that the pressure group 38 Degrees remove his parliamentary email address from their website, arguing that lobby groups sending or coordinating 'clone emails' designed to deluge MPs' inboxes detracted from their ability to correspond with constituents and help those in real need. 38 Degrees said that the email address is paid for by taxpayers' money and is in the public domain, thus they have every right to host it on their website and use it for campaigning.


title: Dominic Raab

text: Raab has participated in debates on giving prisoners the vote and extradition. In April 2011, he also presented an ultimately unsuccessful Ten Minute Rule Bill proposing that emergency service and transport unions should be required by law to ensure that strike votes receive 50% support of union members. Raab argued that reform was needed to prevent "militant union bosses" holding the "hard working majority" to ransom.


title: Dominic Raab

text: On 7 March 2012, Raab opened a debate in the House of Commons on Sergei Magnitsky and Impunity for Gross Human Rights Abuses, calling on the UK government to bring forward legislative proposals that would allow it to impose visa bans and asset freezes on state officials responsible for gross human rights abuses against individuals. The motion was supported by three former Foreign Secretaries and two former Foreign Ministers and had cross-party support and was passed unanimously by MPs.


title: Dominic Raab

text: On 30 January 2014, Raab proposed an amendment to the Immigration Bill to deport all prisoners given a sentence of a year or more. It was defeated, but allowed 99 members to voice that change was necessary to prevent immigrants convicted of crimes from using the ECHR as support to remain in the UK.


title: Dominic Raab

text: In the 2015 general election on 7 May, Raab retained his Esher and Walton seat with a majority of 28,000 votes over his nearest rival. On 12 May, he was appointed Parliamentary Under-Secretary of State at the Ministry of Justice under Michael Gove, with responsibility for human rights questions. In September 2015, in this capacity, he addressed representatives of the 46 other member states of the Council of Europe on the question of the UK's blanket ban on prisoner voting.


title: Dominic Raab

text: In the 2017 general election, Raab was elected with a reduced majority of 23,000. In the 2019 general election, he was reelected with a significantly reduced majority of 2,743.


title: Dominic Raab

text: In February 2018, Raab advertised for an unpaid intern just ahead of a Department for Business, Energy and Industrial Strategy (BEIS) publication responding to the Taylor review on insecure work. The BEIS report criticised "exploitative unpaid internships", saying "an employer cannot avoid paying someone the minimum wage simply by calling them an 'intern' or saying that they are doing an internship."


title: Dominic Raab

text: On 30 January 2011, "The Mail on Sunday" published an article alleging – falsely – that Raab, in his previous role as Chief of Staff to David Davis in 2007, had paid a female employee £20,000 in an out-of-court settlement as part of a confidentiality agreement to drop a claim of workplace bullying. Raab responded by stating: "This is a smear and any insinuation that I have behaved improperly is false and malicious". He subsequently sued the newspaper for libel. "The Mail on Sunday"s publisher Associated Newspapers' attempt to stop the action was denied by the High Court in December 2011.


title: Dominic Raab

text: During these proceedings, it was disclosed that the employee had taken a claim against Raab to an employment tribunal, where it was settled with a compromise agreement which included monetary compensation and a confidentiality clause for both parties. The newspaper issued an apology on 18 March 2012, stating: "We accept that our allegations were unfounded and we apologise to Mr Raab for the damage, embarrassment and offence caused".


title: Dominic Raab

text: In late October 2017, a dossier listing allegations of a mainly sexual nature against several dozen Conservative MPs made internally by party researchers was circulated at Westminster and amongst journalists. Raab wrote on his website at the beginning of November that his entry made a false accusation of an "Injunction for inappropriate behaviour with a woman". He commented: "I have never been served with any injunction for anything. Nor have I ever sought one". It was "false and malicious" to make "any insinuation that I have engaged in anything resembling sexual harassment, sexually abusive behaviour or lewd remarks". He believed the dossier itself was a "form of harassment and intimidation". Raab said he was taking legal advice.


title: Dominic Raab

text: In April 2018, as Minister of State for Housing and Planning Raab said in an interview that immigration had "put house prices up by something like 20%" over the past 25 years. The UK Statistics Authority asked Raab to publish the evidence for his claim. A document published by the Ministry of Housing, Communities and Local Government shows that the finding was based on an out-of-date model that had never been intended for this kind of analysis. Raab defended the model and said: "I did indeed say care was needed with the data, and I was right that immigration put average prices up by 20%. We need a balanced approach."


title: Dominic Raab

text: Raab was an active campaigner in the 2016 EU membership referendum, advocating that Britain should leave the European Union. He said in an interview that it would be better for the British economy to leave: "We'll be better off if we're freed up to trade more energetically with the growth markets like Latin America and Asia. I think it will be good for job creation and also cut prices in the stores." He also argued that there was too much waste and corruption in the EU. During the Brexit campaign, Raab repeatedly argued that there was no doubt that the UK would get a trade deal with the EU.


title: Dominic Raab

text: On 9 July 2018, following the resignation of David Davis, Raab was appointed Secretary of State for Exiting the European Union, and was later deputised by Theresa May after just two weeks to oversee domestic preparations while May would be in charge of actually meeting with EU Officials.


title: Dominic Raab

text: In November 2018, Raab was criticised by Labour's shadow Brexit minister, Jenny Chapman, after Raab said that he "hadn't quite understood the full extent" of how much UK trade relies on the Dover–Calais crossing.


title: Dominic Raab

text: On 15 November 2018, Raab announced his resignation as Brexit Secretary, citing his disapproval over the Cabinet position on the draft Brexit withdrawal agreement. According to a BBC News report, Raab was concerned with "two major and fatal flaws" in the draft agreement, namely that the proposed terms "threaten the integrity of the United Kingdom" and that "they would lead to an indefinite if not permanent situation where [the UK is] locked into a regime with no say over the rules being applied, with no exit mechanism", flaws which would prove "damaging for the economy but devastating for public trust in our democracy". While subsequently describing May's deal as worse than remaining in the EU, he voted in favour of it at the occasion of the third vote on the withdrawal agreement on 29 March 2019. He described the Irish backstop as "undemocratic and [...] something that will have to be removed."


title: Dominic Raab

text: Following his resignation, Raab defended the position that the UK should not pay the so-called Brexit divorce bill (amounting to around £39 billion) in the event of a no-deal Brexit. This bill reflects commitments which the UK entered into for the EU's Multiannual Financial Framework for the years 2014–2020 and so according to some interpretations is not linked to Britain's exit from the European Union. The House of Lords alternatively found that the UK would not be liable for such payments.


title: Dominic Raab

text: In June 2019, unnamed EU sources claimed that Raab had been nicknamed "The Turnip" in Brussels, a play on "raap", the Dutch word for the vegetable, suggesting EU dissatisfaction with his negotiation strategy.


title: Dominic Raab

text: On 25 May 2019, Raab announced he was standing in the Conservative Party leadership election after Theresa May announced her resignation. In the second round of voting, on 18 June, Raab failed to obtain the required minimum number of 33 votes, winning 30 and finishing in sixth place, behind Sajid Javid. After being eliminated, he endorsed the frontrunner Boris Johnson, who subsequently won the contest.


title: Dominic Raab

text: On 24 July 2019, Boris Johnson appointed Raab Foreign Secretary, succeeding Jeremy Hunt, and handed him the additional title First Secretary of State. On arrival at the Foreign Office, Raab said: "I'm hugely humbled to take on this role at this time and excited about the opportunities that lie ahead."


title: Dominic Raab

text: In 2019, the International Court of Justice in The Hague ruled that the United Kingdom must transfer the Chagos Archipelago to Mauritius as they were not legally separated from the latter in 1965. In its statement rejecting the ruling, the Foreign Office said: "The United Kingdom has no doubt about its sovereignty over the Chagos Archipelago, which has been under continuous British sovereignty since 1814." The shadow foreign secretary, Lisa Nandy, in a letter to Raab said the UK position "is damaging to Britain's reputation, undermines your credibility and moral authority".


title: Dominic Raab

text: Raab stood in for Johnson at Prime Minister's Questions on 2 October 2019, as First Secretary of State.


title: Dominic Raab

text: On 3 January 2020, the high-level Iranian General, Qasem Soleimani, was assassinated by the United States, which considerably heightened the existing tensions between the two countries. Raab backed the strike, describing the American action as self-defence. He said that his government had "always recognised the aggressive threat posed by the Iranian Quds force".


title: Dominic Raab

text: Raab supported Johnson's decision to allow China's Huawei to build part of UK's 5G network despite U.S. and Australian opposition.


title: Dominic Raab

text: On 23 March, during the coronavirus pandemic, the government confirmed that Raab, as First Secretary of State, was to deputise for Johnson if he became "incapacitated" due to COVID-19. On 6 April, after Johnson was admitted to an intensive care unit due to his illness with COVID-19, Raab was asked to deputise for Johnson. In April 2020, Raab was questioned in the first two sessions of virtual Prime Minister's Questions (PMQs) by new Labour Leader Keir Starmer.


title: Dominic Raab

text: In April 2020, Raab warned that the UK cannot go back to "business as usual" with China after the end of the COVID-19 pandemic.


title: Dominic Raab

text: On 16 June, it was announced by the Prime Minister that Raab would absorb the responsibilities of the Secretary of State for International Development in September 2020 upon the formation of a joint department called the Foreign, Commonwealth and Development Office. His brief changed to Secretary of State for Foreign, Commonwealth and Development Affairs on 2 September, and he said that the UK would continue to spend 0.7% of its national income on foreign aid.


title: Dominic Raab

text: After the 30 June 2020 imposition by the Xi Jinping regime of the national security law in Hong Kong, Raab described the following day in the Commons what he saw as a "grave and deeply disturbing" event, dissected the affront to the Sino-British Joint Declaration in the Commons, and announced a new chapter in Hong Kong–United Kingdom relations with substantial changes to the idea of British National (Overseas) permits. Raab did not rule out boycotting the 2022 Winter Olympics over the treatment of the Uyghur Muslims by the Chinese government.


title: Dominic Raab

text: Raab welcomed the peace agreement between Israel and the United Arab Emirates, saying he was gladdened by suspension of Israel's plans to annex parts of the occupied Palestinian territories in the West Bank. Raab also welcomed the normalization of relations between Israel and Sudan saying that it is "a positive step between two valued friends."


title: Dominic Raab

text: In March 2020, Raab visited the mausoleum of the Turkish leader Mustafa Kemal Atatürk and called Turkey a "staunch ally in NATO and one of its largest contributors of military personnel." Raab said, "The UK stands with Turkey in the fight against terrorism, and recognises the serious threat posed" by the Kurdish separatist movement PKK. On 6 October, Raab warned that the result of the 2020 Nagorno-Karabakh conflict between Armenia and Azerbaijan may be the strengthening of relations between Russia and Turkey, saying that a "battle for geopolitical stances is in progress. I believe that even though the behavior of our Turkish partners in NATO is sometimes disappointing, we need to be very careful with the risk that Turkey is falling into Russia's arms."


title: Dominic Raab

text: On 10 May 2021, Raab condemned rocket attacks on Israel and called for "immediate de-escalation on all sides" and an "end to targeting of civilian populations".


title: Dominic Raab

text: On 15 August 2021, as the Taliban militant group once again controlled a vast majority of Afghan territory, the Taliban began capturing the capital city of Kabul. Raab was abroad on holiday when Kabul fell to the Taliban. He returned to the UK on 16 August and said the UK government was surprised by the "scale and pace" of the Taliban's takeover of Afghanistan. Defence secretary, Ben Wallace admitted all remaining UK nationals and Afghan allies might not get away and said "Some people won't get back". Unnamed sources told "The Guardian" Raab refused to talk to some Foreign Office staff and this allegedly caused problems during the Afghanistan evacuation. Raab denies the claims. The Foreign Affairs Select Committee said the government was "missing in action" after examining the episode. Unnamed insiders told "The Guardian" in November 2022 that Raab limited the number of senior staff he dealt with. Unnamed sources said "Decisions that should have taken hours took days or simply did not happen." Raab allegedly avoided communicating with "those he found to be challenging voices".


title: Dominic Raab

text: In a cabinet reshuffle on 15 September 2021, Raab was appointed Secretary of State for Justice and Lord Chancellor. He was also given the title of Deputy Prime Minister, a post unused since the Cameron–Clegg coalition.


title: Dominic Raab

text: Raab declined to run in the July–September 2022 Conservative Party leadership election. He endorsed Rishi Sunak's leadership bid.


title: Dominic Raab

text: In August 2022, Raab moved to block the release of the parents of now seven year old Tony Hudgell, who had been abused by them and had to have his legs amputated.


title: Dominic Raab

text: "The Guardian" reported in December 2022 that Raab prevented the victims' commissioner for England and Wales being reappointed and is not expected to replace her for months. According to Victims' groups, critical legislation was going through parliament without an independent reviewer. Unnamed sources stated Raab intervened to stop Vera Baird staying as victims' commissioner.


title: Dominic Raab

text: Raab was reappointed by Rishi Sunak as Deputy Prime Minister, Justice Secretary and Lord Chancellor on 25 October 2022. In November 2022, Raab said that terrorist offenders will face longer sentences if they commit crime, such as vandalising cells, while in prison.


title: Dominic Raab

text: On 16 November 2022, two formal complaints were made about Raab's behaviour during his time as Justice Secretary and Foreign Secretary in Boris Johnson's government. Allegations against Raab included that he lost his temper during work and that staff were "scared" to enter his office. After Raab had been notified about the two formal complaints, Rishi Sunak agreed to Raab's request for an independent inquiry into the complaints. Raab said he would "co-operate fully" and that he would "thoroughly rebut and refute" the claims against him. He said he had "never tolerated bullying" and was confident that he had behaved professionally. Adam Tolley KC was appointed to undertake the investigation. "The prime minister will remain the arbiter of the code," the PM's official spokesman stated.


title: Dominic Raab

text: "The Observer" was told in November 2022 there were concerns about the way Raab treated officials while he was Brexit secretary in 2018. An unnamed senior source said that a prominent official in the Brexit department sent a document stating a "formal expression of concern" to the Cabinet Office. "The Observer" understands the document claimed "unprofessional, even bullying, conduct of the minister towards his private office". A source who knew the complaint said that no action was taken. Sources close to Raab denied the complaint. A formal investigation will include looking at what Raab did in 2018 as Brexit secretary.


title: Dominic Raab

text: "The Guardian" reported in November 2022 that unnamed Ministry of Justice sources said that senior civil servants, who directly experienced Raab's alleged aggressive behaviour and bullying had made "a handful" of formal complaints. An unnamed MoJ insider told "The Guardian" that the new allegations were "more serious and more specific" than previous claims over Raab's abrasive management style. Raab was allegedly "demeaning and aggressive" to staff. Unnamed Whitehall sources earlier complained Raab had behaved "so badly and inappropriately" at an earlier high-level meeting that Antonia Romeo had to contact senior officials of the home secretary to express regret.


title: Dominic Raab

text: Simon McDonald said in November 2022 that staff were "scared to go into his [Raab's] office" due to his "controlling" manner. McDonald, who was with Raab at the Foreign Office said: "It was language, it was tone, he would be very curt with people. And he did this in front of a lot of other people." McDonald said that people felt demeaned, that Raab "was not aware of the impact of his behaviour (...) and couldn't be made to see that impact." A spokesman for Raab denied the allegations. Helen Grant, who worked with Raab as a minister at the Foreign Office, said Raab had been "very decent", with "high professional standards".


title: Dominic Raab

text: In November 2022 it was reported in "The Guardian" that senior civil servants in the Ministry of Justice were offered "respite or a route out" of the department after Raab was reappointed due to fears that some were traumatised by his behaviour when he was there before. Antonia Romeo allegedly spoke to Raab to warn him to treat staff professionally and with respect. Multiple unnamed sources within the Ministry of Justice told "The Guardian" that Raab created a "culture of fear" in the department. The unnamed sources said that Raab was "demeaning rather than demanding", was "very rude and aggressive" and "wasn't just unprofessional, he was a bully". Raab's spokesman said he "holds himself to the highest standards of professionalism". "The Sun" suggested Raab had once hurled tomatoes from a salad across a room in a fit of anger. Raab's spokesman said the claim was "nonsense".


title: Dominic Raab

text: "The Times" reported a formal complaint that civil servants were "signed off work for extended periods of time" when Raab was Justice secretary. Some civil servants were allegedly left in tears after speaking to Raab or his senior team according to "The Times". The newspaper further suggested that work pressure and unreasonable deadlines impacted some colleagues' mental and physical health to the point where they saw their GPs. A group of mid-ranking officials reportedly submitted the complaint against Raab in March 2022. The report was allegedly resubmitted in the week to 17 November 2022 after the government stated that no formal complaints had been made against Raab. It was further reported that the complaint also alleged there was a "tangible shift towards a dysfunctional working culture is starting to hinder" effective work in the department.


title: Dominic Raab

text: On 24 November 2022 "The Guardian" reported that "BBC" "Newsnight" alleged that some of Raab's unnamed former private secretaries were preparing formal complaints. Dave Penman of the civil service’s FDA alleged there were many allegations apparently from various departments where Raab had worked. Penman wants Sunak to approve investigating every complaint. When asked by "Newsnight" whether the complaints could appear like a "witch-hunt", Penman said it "demonstrated a level of concern about the deputy prime minister's behaviour." Penman added that the large number of complaints about a minister's behaviour were unprecedented. Penman alleged Sunak must decide if it is "safe" for civil servants to work with Raab despite serious allegations about his behaviour. Raab has previously denied any wrongdoing and expressed support for the review. Labour wants Sunak to enlarge the inquiry and enable the independent investigation of formal and informal complaints. On 14 December 2022, Sunak's spokesman said that five more complaints over Raab's alleged behaviour as justice secretary were being investigated.


title: Dominic Raab

text: In 2009, prior to becoming an MP, Raab said he did not support the Human Rights Act, stating that "The very enactment of the Human Rights Act has served as a trigger for the formulation of claims by lawyers and judicial reasoning by courts, using human rights arguments that would never have been dared before. The spread of rights has become contagious and, since the Human Rights Act, opened the door to vast new categories of claims, which can be judicially enforced against the government through the courts."


title: Dominic Raab

text: In July 2010, he secured a review of positive discrimination rules being applied to Foreign and Commonwealth Office work experience schemes, having been contacted by a constituent who had been rejected from the scheme for failing to meet "the social criteria". The two programmes at the organisation barred white males from applying, other than those from low-income backgrounds; Raab argued they re-introduced discrimination 'via the backdoor'. The MP welcomed the review, blaming the situation on the previous Labour government. He stated "positive discrimination is wrong in the same way as negative discrimination. It means people are thinking in terms of social criteria and it is anti-meritocratic."


title: Dominic Raab

text: In August 2020, Raab visited Israel and the West Bank to "press for renewed dialogue" between the two sides.


title: Dominic Raab

text: In 2011, Raab wrote that "Peace must precede Palestinian statehood", and criticised the Israeli settlements as undermining "the prospects for a continuous Palestinian state."


title: Dominic Raab

text: On 10 February 2011, Raab gave the winding-up speech in the debate on whether to give prisoners the vote, arguing that freedom entails responsibility and that elected lawmakers in the House of Commons rather than "unaccountable" judges in Strasbourg should decide the matter.


title: Dominic Raab

text: On 22 June 2011, the Joint Committee on Human Rights (JCHR) published a report on The Human Rights Implications of British extradition. As a member of the JCHR, Raab proposed that the committee looks into the issue of fast-track extradition of British citizens following several instances of miscarriages of justice. In an article for "The Times", Raab argued that more needed to be done to protect British citizens subject to European Arrest Warrants. The JCHR has called for safeguards to ensure warrants are not issued for minor offences and when there is minimal evidence, and for checks to prevent extradition for investigation rather than prosecution. On 24 November 2011, Raab led a debate in the House of Commons calling for extradition reform. His motion had cross-party support, and was backed by Gary McKinnon's mother, Janis Sharpe.


title: Dominic Raab

text: On 3 November 2016, and in response to the decision of the High Court in "R (Miller) v Secretary of State for Exiting the European Union" on whether the government was entitled to notify an intention to leave the European Union under Article 50 of the Treaty on European Union without a vote in Parliament, Raab stated that in the 2016 EU membership referendum "the British people gave a clear mandate for the UK Government to leave the EU and take back control of our borders, laws, money and trade. It is disappointing that today the court has chosen to ignore their decision". He went on to state that the decision was "a plain attempt to block Brexit by people who are out of touch with the country and refuse to accept the result. However, the vote to leave the EU was clear and they should not seek to obstruct it".


title: Dominic Raab

text: In October 2018, Raab told BBC One's "The Andrew Marr Show" that the assassination of Jamal Khashoggi was a "terrible case" but the UK government was "not throwing our hands in the air and terminating the relationship with Saudi Arabia, not just because of the huge number of British jobs that depend on it but also because if you exert influence over your partners you need to be able to talk to them... The problem with Labour's position is it would cost thousands of British jobs."


title: Dominic Raab

text: In 2009, Raab published his first book, "The Assault on Liberty – What Went Wrong with Rights". In October 2010, he published "Fight Terror, Defend Freedom", a pamphlet on the Home Office counter-terrorism review.


title: Dominic Raab

text: In January 2011, Raab wrote an article on the use of control orders in counter-terrorism cases in which he contended that they are ineffective and should be scrapped with a greater focus on prosecutions.


title: Dominic Raab

text: Raab published a pamphlet with the think tank Civitas entitled "Strasbourg in the Dock" in April 2011. The pamphlet followed Parliament's recent rejection of a European Court of Human Rights ruling (the "Hirst" case) that at least some prisoners should have the right to vote. Raab argued that judges had overstepped the mark in relation to the case because they were not elected. The Strasbourg judges are elected by the 324 members of the


title: Dominic Raab

text: Parliamentary Assembly of the Council of Europe; members are drawn from the national parliaments of the Council of Europe's member states. Raab contended that many of the judges were lacking experience and as a result "are undermining the credibility and value of the Court". Raab made a range of proposals to strengthen the authority of Britain's Supreme Court, give elected lawmakers the last word on the creation of new rights, and reform the Strasbourg Court.


title: Dominic Raab

text: In July 2011, Raab called for reform of the UK Borders Act 2007 which allows foreign criminals to avoid deportation by claiming a "right to family life" under Article 8 of the European Convention on Human Rights. He proposed that the reference to the Human Rights Act be removed. He argued this could be done in a way that ensures foreign criminals could avoid deportation only if there is a "serious risk" they will be tortured on their return.


title: Dominic Raab

text: On 30 January 2011, he wrote a comment piece for "The Sunday Times" on implementation of the Equality Act 2010. Raab argued for a meritocratic approach against positive discrimination and highlighted the lower standard of human rights protections in extradition cases compared with deportation cases.


title: Dominic Raab

text: In an article in January 2011 on the Politics Home website, Raab argued in favour of transferable paternity leave and against "the equality bandwagon" "pitting men and women against each other". He argued in favour of a consistent approach to sexism against men and women commenting that some feminists were "now amongst the most obnoxious bigots" and it was sexist to blame men for the recession.


title: Dominic Raab

text: Raab highlighted the wide range of sex discrimination he said was faced by males including "anti-male discrimination in rights of maternity/paternity leave", young boys being "educationally disadvantaged compared to girls", and how "divorced or separated fathers are systematically ignored by the courts". Raab stated "from the cradle to the grave, men are getting a raw deal. Men work longer hours, die earlier, but retire later than women", noting that the pensions inequalities were still not going to be rectified for another seven years.


title: Dominic Raab

text: He was subsequently interviewed on the piece by the "London Evening Standard", as well as BBC Radio 4. Theresa May, who was Minister for Women and Equalities at the time, criticised Raab's "obnoxious bigots" comment but agreed with his suggestions on paternity leave and ending gender warfare. Her remarks took place during a debate on employment law in the House of Commons.


title: Dominic Raab

text: Raab's remarks were criticised by some Labour MPs, including Harriet Harman and Nia Griffith, who said Raab should "stop being so self-pitying. The reality is that women with very good qualifications time and time again do not get the top jobs and opportunities." Raab stood by his comments in a comment piece for "The Daily Telegraph", highlighting the various statements Harman had made about men, contrasting them with similar comments about women by the likes of Andy Gray. Raab also stated he had received an "overwhelmingly positive" reaction to his comments "from both men and women".


title: Dominic Raab

text: In July 2012, Raab published a pamphlet with the Centre for Policy Studies entitled "Unleashing the British Underdog: 10 Bets on the Little Guy". In the report, Raab outlines 10 policies to improve social mobility and provide opportunities for those from non-traditional backgrounds to succeed.


title: Dominic Raab

text: In October 2011, Dominic Raab and four other MPs of the 2010 intake published "After the Coalition", an argument that Conservative principles adapted to the modern world would be essential for the future national success of the party. The book was serialised in "The Daily Telegraph". Raab wrote his piece for the paper on British foreign policy, arguing it should reflect the national interest: Britain should not overextend itself in foreign conflicts, aid should be focused on the poorest countries and Britain should champion free trade abroad.


title: Dominic Raab

text: In November 2011, Raab wrote a pamphlet published by the Centre for Policy Studies, "Escaping the Strait Jacket – Ten Regulatory Reforms to Create Jobs". The paper makes the case for reforming red tape to boost job creation on grounds of economic competitiveness and social fairness.


title: Dominic Raab

text: In September 2012 Raab co-authored the book "Britannia Unchained". The book addressed issues of the national debt, state education, innovation and work ethic.


title: Dominic Raab

text: Raab called for measures to cut regulation on start-up companies, expand vocational training, reduce childcare costs and lower marginal (income-focused) rates of taxation to "rediscover and reward the lost virtue of hard-work – a tried and tested route to individual success, a more prosperous economy and a fairer society."


title: Dominic Raab

text: Writing on work ethic in "The Daily Telegraph", Raab said that longer periods in education, earlier retirement, welfare dependency and high marginal rates of taxation had led to a situation where "(w)e have a smaller proportion of the workforce pedalling harder to sustain the rest – which is economically debilitating and socially divisive."


title: Dominic Raab

text: Raab is married to Erika Rey, a Brazilian marketing executive who until 2020 worked for Google. They have two children, and live in Thames Ditton, Surrey.


title: Dominic Raab

text: In October 2021, following the murder of Sir David Amess, Raab told ITV News that he had received three death threats in the previous two years.


title: Dominic Raab

text: In 2019, LBC's Iain Dale and a panel placed Raab fourth in a list of that year's "Top 100 Most Influential Conservatives".


title: Angus Cloud

text: Conor Angus Cloud Hickey (born July 10, 1998) is an American actor best known for his portrayal of Fezco in the HBO television series "Euphoria".


title: Angus Cloud

text: Angus Cloud originates from Oakland, California, although much of his family resides in Ireland. Cloud is the eldest of his siblings, and has two younger twin sisters. He attended the School of Production Design at Oakland School for the Arts, where he was a classmate of his "Euphoria" co-star Zendaya. While working at Woodland restaurant close to Barclays Center in Brooklyn, he was scouted by "Euphoria" casting director Jennifer Venditti. Cloud also premiered in the skate movie, "North Hollywood" as the character Walker.


title: Spironolactone

text: Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of transgender hormone therapy in transfeminine people. Spironolactone is taken by mouth.


title: Spironolactone

text: Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex. In those with liver or kidney problems, extra care should be taken. Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy. It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen-like effects. Spironolactone belongs to a class of medications known as potassium-sparing diuretics.


title: Spironolactone

text: Spironolactone was discovered in 1957, and was introduced in 1959. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2020, it was the 51st most commonly prescribed medication in the United States, with more than 13million prescriptions.


title: Spironolactone

text: Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, low blood levels of potassium, secondary hyperaldosteronism (such as occurs with liver cirrhosis), and Conn's syndrome (primary hyperaldosteronism). The most common use of spironolactone is in the treatment of heart failure. On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy. The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete. Spironolactone is also used to treat Bartter's syndrome due to its ability to raise potassium levels.


title: Spironolactone

text: Spironolactone has antiandrogenic activity. For this reason, it is frequently used to treat a variety of dermatological conditions in which androgens play a role. Some of these uses include acne, seborrhea, hirsutism, and pattern hair loss in women. Spironolactone is the most commonly used medication in the treatment of hirsutism in the United States. High doses of spironolactone, which are needed for considerable antiandrogenic effects, are not recommended for men due to the high risk of feminization and other side effects. Spironolactone can be used to treat symptoms of hyperandrogenism, such as due to polycystic ovary syndrome, in women, dose of 50-100mg in 1 or 2 doses.


title: Spironolactone

text: While loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of less than 35%.


title: Spironolactone

text: In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant death and morbidity benefit of the medication. People in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently. Likewise, it has shown benefit for and is recommended in patients who recently had a heart attack and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers. Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo.


title: Spironolactone

text: It is recommended that alternatives to spironolactone be considered if serum creatinine is greater than 2.5 mg/dL (221 μmol/L) in males or greater than 2 mg/dL (176.8 μmol/L) in females, if glomerular filtration rate is below 30 mL/min or with a serum potassium of greater than 5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of kidney function as well.


title: Spironolactone

text: According to a systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone. When blood samples from 366 participants in the TOPCAT study were analyzed for presence of canrenone (an active metabolite of spironolactone), 30% of blood samples from Russia lacked detectable residues of canrenone. This led to the conclusion that the TOPCAT trial results in Russia do not reflect actual clinical experience with spironolactone in patients with preserved ejection fraction. The TOPCAT study results are now considered to have been invalidated. The study's prime investigator and other prominent research cardiologists are now advising physicians treating heart failure with preserved ejection fraction to consider prescribing spironolactone pending outcome of two multicenter trials of newer medications.


title: Spironolactone

text: Due to its antiandrogenic properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer medication, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogenic effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related medication canrenone in reducing mortality from heart failure.


title: Spironolactone

text: The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks.


title: Spironolactone

text: Unlike with some other diuretics, potassium supplementation should "not" be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms.


title: Spironolactone

text: About 1 in 100 people with hypertension have elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure. There is no evidence of person-oriented outcome at any dose in this group.


title: Spironolactone

text: Spironolactone is used in the treatment of hyperaldosteronism (high aldosterone levels or mineralocorticoid excess), for instance primary aldosteronism (Conn's syndrome). Antimineralocorticoids like spironolactone and eplerenone are first-line treatments for hyperaldosteronism. They improve blood pressure and potassium levels, as well as left ventricular hypertrophy, albuminuria, and carotid intima-media thickness, in people with primary aldosteronism. In people with hyperaldosteronism due to unilateral aldosterone-producing adrenocortical adenoma, adrenalectomy should be preferred instead of antimineralocorticoids. Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of teratogenicity in male fetuses.


title: Spironolactone

text: Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including oily skin, acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and male pattern hair loss (androgenic alopecia). In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair. Moreover, men with congenital 5α-reductase type II deficiency, 5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male-pattern hair loss. Conversely, hyperandrogenism in women, for instance due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general. In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.


title: Spironolactone

text: Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women. In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin. Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful. Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill. Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months. Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses. Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism. Ongoing therapy is generally required to avoid relapse of symptoms. Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication. Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women). There is tentative low quality evidence supporting its use for this indication. Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.


title: Spironolactone

text: Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects. For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception. Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose. Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.


title: Spironolactone

text: Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly. As an example, spironolactone has been reported to reduce symptoms of acne in males. An additional example is the usefulness of spironolactone as an antiandrogen in transgender women.


title: Spironolactone

text: Topical spironolactone has been found to be effective in the treatment of acne as well. As a result, topical pharmaceutical formulations containing 2% or 5% spironolactone cream became available in Italy for the treatment of acne and hirsutism in the early 1990s. The products were discontinued in 2006 when the creams were added to the list of doping substances with a decree of the Ministry of Health that year.


title: Spironolactone

text: Spironolactone, the 5α-reductase inhibitor finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism. However, some clinical research has found that the effectiveness of spironolactone for hirsutism is greater than that of finasteride but is less than that of flutamide. The combination of spironolactone with finasteride is more effective than either alone for hirsutism and the combination of spironolactone with a birth control pill is more effective than a birth control pill alone. One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism. Spironolactone is considered to be a first-line treatment for hirsutism, finasteride and the steroidal antiandrogen cyproterone acetate are considered to be second-line treatments, and flutamide is no longer recommended for hirsutism due to liver toxicity concerns. The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety.


title: Spironolactone

text: The combination of spironolactone with a birth control pill in the treatment of acne appears to have similar effectiveness to a birth control pill alone and the combination of a birth control pill with cyproterone acetate, flutamide, or finasteride. However, this was based on low- to very-low-quality evidence. Spironolactone may be more effective than birth control pills in the treatment of acne, and the combination of spironolactone with a birth control pill may have greater effectiveness for acne than either alone. In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne. In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same time period. However, the use of flutamide for acne is limited by its liver toxicity. Bicalutamide is a potential alternative to flutamide for acne as well. Spironolactone can be considered as a first-line treatment for acne in those who have failed other standard treatments such as topical therapies and under certain other circumstances, although this is controversial due to the side effects of spironolactone and its teratogenicity.


title: Spironolactone

text: There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss. The effectiveness of spironolactone in the treatment of both acne and hirsutism appears to be dose-dependent, with higher doses being more effective than lower doses. However, higher doses also have greater side effects, such as menstrual irregularities.


title: Spironolactone

text: Spironolactone medication is not approved for use as an antiandrogen by the Food and Drug Administration; instead, it is used off-label for such purposes.


title: Spironolactone

text: Spironolactone is typically used at a low dosage of 25 to 50 mg/day in the treatment of heart failure, while it is used at low to high dosages of 25 to 200 mg/day in the treatment of essential hypertension, and at high dosages of 100 to 400 mg/day for hyperaldosteronism and ascites due to cirrhosis. The medication is typically used at high dosages of 100 to 200 mg/day in the treatment of skin and hair conditions in women, and at high dosages of 100 to 400 mg/day in feminizing hormone therapy for transgender women.


title: Spironolactone

text: Spironolactone can be used to treat symptoms of hyperandrogenism, such as polycystic ovary syndrome, in women, dose of 50-100mg in 1 or 2 doses.


title: Spironolactone

text: Spironolactone is available in the form of tablets (25 mg, 50 mg, 100 mg; brand name Aldactone, others) and suspensions (25 mg/5 mL; brand name CaroSpir) for use by mouth. It has also been marketed in the form of 2% and 5% topical cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, but this product is no longer available. The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others). Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed; other routes of administration such as intravenous injection are not used. The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate.


title: Spironolactone

text: Contraindications of spironolactone include hyperkalemia (high potassium levels), severe and end-stage kidney disease (due to high hyperkalemia risk, except possibly in those on dialysis), Addison's disease (adrenal insufficiency and low aldosterone levels), and concomitant use of eplerenone. It should also be used with caution in people with some neurological disorders, no urine production, acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia.


title: Spironolactone

text: One of the most common side effects of spironolactone is frequent urination. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure), ataxia (muscle incoordination), drowsiness, dizziness, dry skin, and rashes. Because of its antiandrogenic activity, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), feminization in general, and demasculinization, as well as sexual dysfunction including loss of libido and erectile dysfunction, although these side effects are usually confined to high doses of spironolactone. At very high doses (400 mg/day), spironolactone has also been associated with testicular atrophy and reversibly reduced fertility, including semen abnormalities such as decreased sperm count and motility in men. However, such doses of spironolactone are rarely used clinically. In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement. Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.


title: Spironolactone

text: The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia in these people can present as a normal anion-gap metabolic acidosis. It has been reported that the addition of spironolactone to loop diuretics in patients with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury (AKI). Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established. Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.


title: Spironolactone

text: Most of the side effects of spironolactone are dose-dependent. Low-dose spironolactone is generally very well tolerated. Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals. Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia. The side effects of spironolactone are usually mild and rarely result in discontinuation.


title: Spironolactone

text: Spironolactone can cause hyperkalemia, or high blood potassium levels. Rarely, this can be fatal. Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia. At a higher dosage, a rate of hyperkalemia of 24% has been observed. An abrupt and major increase in the rate of hospitalization due to hyperkalemia from 0.2% to 11% and in the rate of death due to hyperkalemia from 0.3 per 1,000 to 2.0 per 1,000 between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999. However, another population-based study in Scotland failed to replicate these findings. The risk of hyperkalemia with spironolactone is greatest in the elderly, in people with renal impairment (e.g., due to chronic kidney disease or diabetic nephropathy), in people taking certain other medications (including inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, the antibiotic trimethoprim, and potassium supplements), and at higher dosages of spironolactone.


title: Spironolactone

text: Although spironolactone poses an important risk of hyperkalemia in the elderly, in those with kidney or cardiovascular disease, and/or in those taking medications or supplements which increase circulating potassium levels, a large retrospective study found that the rate of hyperkalemia in young women without such characteristics who had been treated with high doses of spironolactone for dermatological conditions did not differ from that of controls. This was the conclusion of a 2017 hybrid systematic review of studies of spironolactone for acne in women as well, which found that hyperkalemia was rare and was invariably mild and clinically insignificant. These findings suggest that hyperkalemia may not be a significant risk in such individuals, and that routine monitoring of circulating potassium levels may be unnecessary in this population. However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors. Occasional testing on a case-by-case basis in those with known risk factors may be justified. Side effects of spironolactone which may be indicative of hyperkalemia and if persistent could justify serum potassium testing include nausea, fatigue, and particularly muscle weakness. Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.


title: Spironolactone

text: Spironolactone frequently causes breast pain and breast enlargement in women. This is "probably because of estrogenic effects on target tissue." At low doses, breast tenderness has been reported in only 5% of women, but at high doses, it has been reported in up to 40% of women. Breast enlargement and tenderness may occur in 26% of women at high doses. Some women regard spironolactone-induced breast enlargement as a positive effect.


title: Spironolactone

text: Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men. At low doses, the rate is only 5 to 10%, but at high doses, up to or exceeding 50% of men may develop gynecomastia. In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls. Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100 mg/day, in 5 of 8 (62.5%) at 200 mg/day, and in 6 of 9 (66.7%) at 400 mg/day, relative to none of 12 controls. The severity of gynecomastia with spironolactone varies considerably, but is usually mild. As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness. In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.


title: Spironolactone

text: The time to onset of spironolactone-induced gynecomastia has been found to be 27 ± 20 months at low doses and 9 ± 12 months at high doses. Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication. However, after a sufficient duration of gynecomastia being present (e.g., one year), hyalinization and fibrosis of the tissue occurs and drug-induced gynecomastia may become irreversible.


title: Spironolactone

text: Spironolactone at higher doses can cause menstrual irregularities as a side effect in women. These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding. They are common during spironolactone therapy, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses. For example, about 20% of women experienced menstrual irregularities with 50 to 100 mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200 mg/day. Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation. Spironolactone produces an irregular and anovulatory pattern of menstrual cycles. It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women, as well as with polymenorrhea (short menstrual cycles). The medication reportedly has no birth control effect.


title: Spironolactone

text: It has been suggested that the weak progestogenic activity of spironolactone is responsible for these effects, although this has not been established and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women. An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels. Indeed, CYP17A1 genotype is associated with polymenorrhea. Regardless of their mechanism, the menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with a birth control pill, due to the progestin component.


title: Spironolactone

text: Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood. In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms. However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%. Likewise, a 10-year observational study found that the incidence of depression in 196 transgender women taking high-dose spironolactone in combination with an estrogen was less than 1%.


title: Spironolactone

text: Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as anaphylaxis, kidney failure, hepatitis (two reported cases, neither serious), agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis. Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.


title: Spironolactone

text: Long-term administration of spironolactone gives the histologic characteristic of "spironolactone bodies" in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin.


title: Spironolactone

text: In the United States, spironolactone is considered pregnancy category C meaning that it is unclear if it is safe for use during pregnancy. It is able to cross the placenta. Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the medication while nursing. However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant.


title: Spironolactone

text: A study found that spironolactone was not associated with teratogenicity in the offspring of rats. Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses. In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200 mg/kg per day). Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).


title: Spironolactone

text: In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans. Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects. A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy. In addition, spironolactone has been used at high doses to treat pregnant women with Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants. There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2 mg/day or high doses of 50 to 100 mg/day). In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.


title: Spironolactone

text: A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans. However, there was also insufficient evidence to be certain that it does not.


title: Spironolactone

text: Spironolactone is relatively safe in acute overdose. Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea. In rare cases, hyponatremia, hyperkalemia, or hepatic coma may occur in individuals with severe liver disease. However, these adverse reactions are unlikely in the event of an acute overdose. Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function. Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in clinical trials. Its oral median lethal dose (LD) is more than 1,000 mg/kg in mice, rats, and rabbits.


title: Spironolactone

text: There is no specific antidote for overdose of spironolactone. Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage. The treatment of spironolactone overdose is supportive, with the purpose of maintaining hydration, electrolyte balance, and vital functions. Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.


title: Spironolactone

text: Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium. Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne. Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.


title: Spironolactone

text: Spironolactone has been reported to induce the enzymes CYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in interactions with various medications. However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4. In any case, spironolactone has been found to reduce the bioavailability of oral estradiol, which could be due to induction of estradiol metabolism via CYP3A4. Spironolactone has also been found to inhibit UGT2B7. Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin.


title: Spironolactone

text: Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone. Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with it for hyperandrogenism, and licorice hence may be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them. On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to attenuate the diuresis and natriuresis induced by spironolactone, but, not to affect its antihypertensive effect.


title: Spironolactone

text: Some research has suggested that spironolactone might be able to interfere with the effectiveness of antidepressant treatment. As the medication acts as an antimineralocorticoid, it is thought that it might be able to reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic–pituitary–adrenal axis and by increasing levels of glucocorticoids such as cortisol. However, other research contradicts this hypothesis and has suggested that spironolactone might actually produce antidepressant effects, for instance studies showing antidepressant-like effects of spironolactone in animals.


title: Spironolactone

text: The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities. Spironolactone is a prodrug, so most of its actions are actually mediated by its various active metabolites. The major active forms of spironolactone are 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ-spironolactone).


title: Spironolactone

text: Spironolactone is a potent antimineralocorticoid. That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone. By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body. The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to cirrhosis. It is also responsible for many of the side effects of spironolactone, such as urinary frequency, dehydration, hyponatremia, low blood pressure, fatigue, dizziness, metabolic acidosis, decreased kidney function, and its risk of hyperkalemia. Due to the antimineralocorticoid activity of spironolactone, levels of aldosterone are significantly increased by the medication, probably reflecting an attempt of the body to maintain homeostasis.


title: Spironolactone

text: Spironolactone is a moderate antiandrogen. That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). By blocking the AR, spironolactone inhibits the effects of androgens in the body. The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like acne, seborrhea, hirsutism, and pattern hair loss and hyperandrogenism in women, precocious puberty in boys with testotoxicosis, and as a component of feminizing hormone therapy for transgender women. It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men. Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue. Although useful as an antiandrogen in women, who have low testosterone levels compared to men, spironolactone is described as having relatively weak antiandrogenic activity.


title: Spironolactone

text: Spironolactone is a weak steroidogenesis inhibitor. That is, it inhibits steroidogenic enzymes, or enzymes involved in the production of steroid hormones. Spironolactone and/or its metabolites have been found "in vitro" to weakly inhibit a broad array of steroidogenic enzymes including cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, 5α-reductase, 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 21-hydroxylase, and aldosterone synthase (18-hydroxylase). However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses. In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis. The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women. However, its androgen synthesis inhibition is probably clinically insignificant.


title: Spironolactone

text: Spironolactone has been found in some studies to increase levels of estradiol, an estrogen, although many other studies have found no changes in estradiol levels. The mechanism of how spironolactone increases estradiol levels is unclear, but it may involve inhibition of the inactivation of estradiol into estrone and enhancement of the peripheral conversion of testosterone into estradiol. It is notable that spironolactone has been found "in vitro" to act as a weak inhibitor of 17β-hydroxysteroid dehydrogenase 2, an enzyme that is involved in the conversion of estradiol into estrone. Increased levels of estradiol with spironolactone may be involved in its preservation of bone density and in its side effects such as breast tenderness, breast enlargement, and gynecomastia in women and men.


title: Spironolactone

text: In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex. Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well. However, other clinical studies have found no change in cortisol levels with spironolactone, and those that have found increases often have observed only small changes. In accordance, spironolactone has not been associated with conventional glucocorticoid medication effects or side effects.


title: Spironolactone

text: Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor. These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its drug interactions, respectively.