Mipomersen

Mipomersen
Clinical data
Trade namesKynamro
Other namesISIS 301012
AHFS/Drugs.comMultum Consumer Information
Routes of
administration		Subcutaneous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding≥90%
MetabolismNucleases
Elimination half-life1–2 months
Excretion<4% in urine in 24 hours
Identifiers
  • 2’-O-(2-Methoxyethyl)-P-thioguanylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-deoxy-P-thioadenylyl-(3’→5’)-2’-deoxy-P-thioguanylyl-(3’→5’)-P- thiothymidylyl-(3’→5’)-2’-deoxy-5-methyl-P-thiocytidylyl-(3’→5’)-P-thiothymidylyl-(3’→5’)-2’-deoxy-P-thioguanylyl-(3’→5’)-2’-deoxy-5-methyl-P-thiocytidylyl-(3’→5’)-P-thiothymidylyl-(3’→5’)-P-thiothymidylyl-(3’→5’)-2’-deoxy-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-P-thioguanylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-P-thioadenylyl- (3’→5’)-2’-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’→5’)-2’-O-(2-methoxyethyl)-5-methylcytidine nonadecasodiumsalt
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC230H305N67Na19O122P19S19
Molar mass7594.76 g·mol−1
3D model (JSmol)
  • COCCO[C@@H]1[C@H](OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H](C[C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=S)(OC[C@H]2O[C@H]([C@@H]([C@@H]2O)OCCOC)n2cc(C)c(nc2=O)N)O)OCCOC)n2cc(C)c(nc2=O)N)O)OCCOC)n2cnc3c2ncnc3N)O)OCCOC)n2cc(C)c(nc2=O)N)O)OCCOC)n2cnc3c2nc(N)[nH]c3=O)O)n2cc(C)c(nc2=O)N)O)n2cc(C)c(=O)[nH]c2=O)O)n2cc(C)c(=O)[nH]c2=O)O)n2cc(C)c(nc2=O)N)O)n2cnc3c2nc(N)[nH]c3=O)O)n2cc(C)c(=O)[nH]c2=O)O)n2cc(C)c(nc2=O)N)O)n2cc(C)c(=O)[nH]c2=O)O)n2cnc3c2nc(N)[nH]c3=O)O)n2cnc3c2ncnc3N)O)[C@H](O[C@H]1n1cc(C)c(nc1=O)N)COP(=S)(O[C@@H]1[C@@H](COP(=S)(O[C@@H]2[C@@H](COP(=S)(O[C@@H]3[C@@H](COP(=S)(O[C@@H]4[C@@H](CO)O[C@H]([C@@H]4OCCOC)n4cnc5c4nc(N)[nH]c5=O)O)O[C@H]([C@@H]3OCCOC)n3cc(C)c(nc3=O)N)O)O[C@H]([C@@H]2OCCOC)n2cc(C)c(nc2=O)N)O)O[C@H]([C@@H]1OCCOC)n1cc(C)c(=O)[nH]c1=O)O
  • InChI=1S/C230H324N67O122P19S19/c1-97-55-278(217(309)256-177(97)231)141-45-111(122(381-141)70-362-422(325,441)404-116-50-146(283-66-108(12)196(302)275-228(283)320)387-128(116)76-368-427(330,446)410-120-54-150(294-93-253-154-191(294)266-214(243)270-200(154)306)390-130(120)78-370-428(331,447)408-118-52-148(292-91-250-151-186(240)246-89-248-188(151)292)388-131(118)79-371-430(333,449)412-159-134(394-204(169(159)354-37-27-344-17)286-59-101(5)181(235)260-221(286)313)83-375-435(338,454)417-164-138(398-209(174(164)359-42-32-349-22)291-68-110(14)198(304)277-230(291)322)87-377-434(337,453)415-162-136(396-207(172(162)357-40-30-347-20)289-62-104(8)184(238)263-224(289)316)85-376-433(336,452)414-161-133(393-206(171(161)356-39-29-346-19)288-61-103(7)183(237)262-223(288)315)82-374-432(335,451)411-158-121(69-298)391-211(168(158)353-36-26-343-16)296-95-254-155-192(296)267-215(244)271-201(155)307)401-420(323,439)365-74-127-117(51-147(386-127)284-67-109(13)197(303)276-229(284)321)406-425(328,444)369-77-129-119(53-149(389-129)293-92-252-153-190(293)265-213(242)269-199(153)305)409-426(329,445)367-71-123-112(46-142(382-123)279-56-98(2)178(232)257-218(279)310)402-421(324,440)364-73-125-115(49-145(384-125)282-65-107(11)195(301)274-227(282)319)405-424(327,443)366-75-126-114(48-144(385-126)281-64-106(10)194(300)273-226(281)318)403-423(326,442)363-72-124-113(47-143(383-124)280-57-99(3)179(233)258-219(280)311)407-429(332,448)373-81-139-166(176(361-44-34-351-24)212(400-139)297-96-255-156-193(297)268-216(245)272-202(156)308)419-438(341,457)379-86-137-163(173(358-41-31-348-21)208(397-137)290-63-105(9)185(239)264-225(290)317)416-436(339,455)380-88-140-165(175(360-43-33-350-23)210(399-140)295-94-251-152-187(241)247-90-249-189(152)295)418-437(340,456)378-84-135-160(170(355-38-28-345-18)205(395-135)287-60-102(6)182(236)261-222(287)314)413-431(334,450)372-80-132-157(299)167(352-35-25-342-15)203(392-132)285-58-100(4)180(234)259-220(285)312/h55-68,89-96,111-150,157-176,203-212,298-299H,25-54,69-88H2,1-24H3,(H,323,439)(H,324,440)(H,325,441)(H,326,442)(H,327,443)(H,328,444)(H,329,445)(H,330,446)(H,331,447)(H,332,448)(H,333,449)(H,334,450)(H,335,451)(H,336,452)(H,337,453)(H,338,454)(H,339,455)(H,340,456)(H,341,457)(H2,231,256,309)(H2,232,257,310)(H2,233,258,311)(H2,234,259,312)(H2,235,260,313)(H2,236,261,314)(H2,237,262,315)(H2,238,263,316)(H2,239,264,317)(H2,240,246,248)(H2,241,247,249)(H,273,300,318)(H,274,301,319)(H,275,302,320)(H,276,303,321)(H,277,304,322)(H3,242,265,269,305)(H3,243,266,270,306)(H3,244,267,271,307)(H3,245,268,272,308)/t111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121+,122+,123+,124+,125+,126+,127+,128+,129+,130+,131+,132+,133+,134+,135+,136+,137+,138+,139+,140+,141+,142+,143+,144+,145+,146+,147+,148+,149+,150+,157+,158+,159+,160+,161+,162+,163+,164+,165+,166+,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,203+,204+,205+,206+,207+,208+,209+,210+,211+,212+,420?,421?,422?,423?,424?,425?,426?,427?,428?,429?,430?,431?,432?,433?,434?,435?,436?,437?,438?/m0/s1
  • Key:XLTMQWVJFPYGMC-QVKFEXRMSA-N

Mipomersen (INN; trade name Kynamro) is a drug used to treat homozygous familial hypercholesterolemia and is administered by subcutaneous injection. There is a serious risk of liver damage from this drug and it can only be prescribed in the context of a risk management plan.

Indications

Kynamro is used to treat homozygous familial hypercholesterolemia and is administered by injection.[1][2]

It cannot be freely prescribed; instead every person put on mipomersen is enrolled in a Risk Evaluation and Mitigation Strategies (REMS) program approved by the FDA.[1]

Pregnancy and lactation

Mipomersen is pregnancy category B; women who are pregnant or intending to become pregnant should only use this drug if needed. It is unknown if it is secreted in human breast milk, but it was found to be secreted in the breast milk of rats.[1]

Contraindications

The drug is contraindicated in people with moderate to severe liver impairment, active liver diseases, and unexplained high levels of transaminase liver enzymes.[1][3]

Adverse effects

The drug has a black box warning about the risk of liver damage; specifically it can cause elevations in the levels of transaminases and causes fatty liver disease.[1]

In clinical trials, 18% of subjects taking mipomersen stopped using the drug due to adverse effects; the most common adverse effects leading to discontinuation were injection site reactions, increases of transaminases, flu-like symptoms (fever, chills, abdominal pain, nausea, vomiting), and abnormal liver tests.[1]

Other adverse effects include: heart problems including angina and palpitations, edema, pain in legs or arms, headache, insomnia, and hypertension.[1]

Interactions

Other drugs known for causing liver problems might add to mipomersen's risk of liver damage. No pharmacokinetic interactions have been described.[3]

Pharmacology

Mechanism of action

Mipomersen binds to the messenger RNA coding for apolipoprotein B-100 (ApoB-100), a protein that is the main component of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). As a consequence, the RNA is degraded by the enzyme ribonuclease H, and ApoB-100 is not translated.[3]

Pharmacokinetics

After subcutaneous injection, mipomersen reaches highest blood levels after 3 to 4 hours. It accumulates in the liver,[citation needed] which is convenient since apolipoprotein B predominantly acts there. Protein binding is over 90%. The molecule is slowly broken up by endonucleases and subsequently by exonucleases. After 24 hours, less than 4% of the degradation products are found in the urine, and overall half-life is 1 to 2 months.[3]

Chemistry

Chemical structure[4]: 69 
Complete skeletal formula[1]: 10 

The compound is a 'second-generation' antisense oligonucleotide; the nucleotides are linked with phosphorothioate linkages rather than the phosphodiester linkages of RNA and DNA, and the sugar parts are deoxyribose in the middle part of the molecule and 2’-O-methoxyethyl-modified ribose at the two ends. These modifications make the drug resistant to degradation by nucleases, allowing it to be administered weekly.

The complete sequence is portrayed below:[5][1]: 10 

5’—G*—mC*—mC*—mU*—mC*—dA—dG—dT—dmC—dT—dG—dmC—dT—dT—dmC—G*—mC*—A*—mC*—mC*—3’
* = 2’-O-(2-methoxyethyl)
m = 5-methyl
d = 2’-deoxy

History

The drug was discovered and developed to Phase 2 by Ionis Pharmaceuticals and subsequently licensed to Genzyme Corporation in 2008 by an auction bid. Ionis earned an upfront payment of $325 million, with payments of a further $825 million if milestones are met.[6]

Mipomersen was rejected by the European Medicines Agency in 2012[7] and again in 2013 due to concerns about the liver and cardiovascular adverse effects.[8]

In January 2013, The United States Food and Drug Administration approved mipomersen for the treatment of homozygous familial hypercholesterolemia.[9][10]

References

  1. ^ a b c d e f g h i "Kynamro (mipomersen sodium) Injection, Solution for Subcutaneous Injection. Full Prescribing Information" (PDF). Kastle Therapeutics, Chicago, IL.
  2. ^ Feingold KR, Grunfeld C (August 10, 2016). "Cholesterol Lowering Drugs". In Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al. (eds.). Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. PMID 27809434.
  3. ^ a b c d Drugs.com: Mipomersen Professional Drug Facts.
  4. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 61" (PDF). World Health Organization. 2009.
  5. ^ Geary RS, Baker BF, Crooke ST (February 2015). "Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro(®)): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B". Clinical Pharmacokinetics. 54 (2): 133–146. doi:10.1007/s40262-014-0224-4. PMC 4305106. PMID 25559341.
  6. ^ "Genzyme and Isis Complete Licensing of Mipomersen". FreshNews.com. 24 June 2008. Archived from the original on 29 September 2011.
  7. ^ "EMA committee shoots down Sanofi's cholesterol drug mipomersen". FierceBiotech. December 14, 2012.
  8. ^ "Refusal of the marketing authorisation for Kynamro (mipomersen)" (PDF). European Medicines Agency (EMA). March 21, 2013.
  9. ^ Pollack A (29 January 2013). "F.D.A. Approves Genetic Drug to Treat Rare Disease". The New York Times. Retrieved 31 January 2013.
  10. ^ "FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder". U.S. Food and Drug Administration. 29 January 2013. Retrieved 31 January 2013.

Read other articles:

Afrodit

AfroditPatung Afrodit di Museum Arkeologi Nasional, AthenaDewi cinta, kecantikan, dan seksualitasSimbolLumba-lumba, mawar, kerang, tanaman myrtle, burung dara, burung gereja, cermin, korset dan angsaPasanganHefaistos, Ares, Poseidon, Hermes, Dionisos, Adonis, dan AnkhisesOrang tuaUranus (versi lain menyatakan bahwa orang tuanya adalah Zeus dan Dione)SaudaraNimfa pohon, Erinyes, dan para Gigant (dengan Uranus sebagai ayah)AnakEros,[1] Fobos, Deimos, Harmonia, Pothos, Hedilogos, Anteros...

 

David Bonetti

David BonettiLahirc. 1947MeninggalApril 4, 2018 (umur 71)Brookline, Massachusetts, U.S.AlmamaterUniversitas BrandeisPekerjaanKritikus seni David Bonetti (c. 1947 – 4 April 2018) adalah kritikus seni asal Amerika Serikat. Kehidupan awal David Bonetti lahir kira-kira pada tahun 1947 dan tumbuh dewasa di Boston, Massachusetts.[1] Ayahnya adalah seorang Italia dan ibunya adalah seorang Irlandia.[2] Ia lulus dari Universitas Brandeis pada tahun 1969.[2] ...

 

Boone County, Kentucky

County in Kentucky, United States County in KentuckyBoone CountyCountyThe old Boone County courthouse in Burlington FlagSealLogoLocation within the U.S. state of KentuckyKentucky's location within the U.S.Coordinates: 38°58′N 84°44′W / 38.97°N 84.73°W / 38.97; -84.73Country United StatesState KentuckyFounded1798Named forDaniel BooneSeatBurlingtonLargest cityFlorenceArea • Total256 sq mi (660 km2) • Land246 s...

Tenis language

Moribund Austronesian language of northeast Papua New Guinea TenisTenchNative toPapua New GuineaRegionTench Island (New Ireland Province)Native speakers30 (2000)[1]Language familyAustronesian Malayo-PolynesianOceanicSt. MatthiasTenisLanguage codesISO 639-3tnsGlottologteni1244ELPTenisTench is classified as Critically Endangered by the UNESCO Atlas of the World's Languages in Danger Tenis, or Tench, is the nearly extinct language of Tench Island in the St Matthias Islands of t...

 

Talupulamma Lova

Hindu temple in India Talupulamma TempleReligionAffiliationHinduismDistrictKakinada districtDeityTalupulamma ThalliFestivalsAnnual JataraAshada Masa UtsavamsLocationLocationLova, KakinadaStateAndhra PradeshCountryIndiaLocation in Andhra PradeshGeographic coordinates17°22′26″N 82°29′44″E / 17.3739°N 82.4955°E / 17.3739; 82.4955ArchitectureTypeDravidian architecture Talupulamma Temple is a pilgrimage site located in Lova of Kakinada district in Andhra Pradesh...

 

Macon County Courthouse and Annex

United States historic placeMacon County Courthouse and AnnexU.S. National Register of Historic Places Show map of MissouriShow map of the United StatesLocationCourthouse Sq., Macon, MissouriCoordinates39°44′32″N 92°28′22″W / 39.74222°N 92.47278°W / 39.74222; -92.47278Area1.5 acres (0.61 ha)Built1865 (1865)ArchitectAldrich, Levi; Konefas, John H.Architectural styleRomanesque, ItalianateNRHP reference No.78001668[1]Added to N...

Asyeik

Asyeik, Asyek, atau Tarei Asyeik adalah suatu upacara adat untuk memanggil roh lelehur pada etnis Kerinci, Jambi. Upacara ini telah ada sejak zaman prasejarah dan masyarakat Kerinci saat itu masih menganut kepercayaan animisme dan dinamisme. Upacara ini dipimpin oleh seorang pawang atau dukun, sehingga upacara ini dianggap magis dan sakral.[1] Sejak Islam menyebar di Kerinci, upacara ini mengalami akulturasi seperti pada mantra-mantra dan tujuan doa yang disampaikan. Walau begitu, upa...

 

The Bros

The BrosPoster rilis teatrikalNama lainHangul부라더 Alih Aksara yang DisempurnakanBuladeo SutradaraChang You-jeongProduserYi Jae-minDitulis olehChang You-jeongHeo Seong-hyePemeranMa Dong-seokLee Dong-hwiLee HaneePenata musikKim Jun-seongPenyuntingKim Sun-minPerusahaanproduksiHong FilmSoo FilmDistributorMegabox Plus MTanggal rilis 02 November 2017 (2017-11-02) (Korea Selatan) Durasi102 menitNegaraKorea SelatanBahasaKoreaPendapatankotorUS$10,8 juta[1] The Bros ad...

 

2017 Malaysian Grand Prix

2017 Formula 1 race 2017 Malaysian Grand Prix Race 15 of 20 in the 2017 Formula One World Championship← Previous raceNext race → Layout of the Sepang International CircuitRace detailsDate 1 October 2017 (2017-10-01)Official name 2017 Formula 1 Petronas Malaysia Grand Prix[1][2]Location Sepang International Circuit, Sepang, Selangor, MalaysiaCourse Permanent racing facilityCourse length 5.543 km (3.444 miles)Distance 56 laps, 310.408 km (1...

Missguided

UK-based clothing retailer MGL Realisations (2022) LimitedTrade nameMissguidedCompany typePrivateIndustryRetailFounded2009; 15 years ago (2009)FounderNitin PassiHeadquartersTrafford Park, UKKey peopleGreg PaterasProductsClothingParentSheinWebsitemissguided.co.uk MGL Realisations (2022) Limited (trading as Missguided) was a UK-based fast-fashion retailer selling clothes aimed at women aged 16-35 years old.[1] Missguided's headquarters were in Stretford, Greater Manche...

 

Gerald Giam

Dalam artikel ini, nama keluarganya adalah Giam (严). Gerald Giam Gerald Giam Yean Song (Hanzi sederhana: 严燕松; Hanzi tradisional: 嚴燕松; Pinyin: Yán Yànsōng; lahir 22 November 1977) adalah seorang politikus Singapura dan anggota oposisi Partai Pekerja Singapura. Ia menjadi anggota parlemen sejak 10 Juli 2020. Pranala luar Gerald Giam Diarsipkan 2023-07-18 di Wayback Machine. on Parliament of Singapore Gerald Giam - General Election 2020 Candidate[pranala nonaktif...

 

Azurit

Azurit Azurit-Kristallaggregat aus New Nevada Lode, La Sal, Utah, USA (Größe: 4,0 cm × 3,0 cm × 2,0 cm) Allgemeines und Klassifikation IMA-Symbol Azu[1] Andere Namen Bergblau Chessylith Kupferblau Kupferlasur AZURITE (INCI)[2] Chemische Formel Cu3(CO3)2(OH)2 Mineralklasse(und ggf. Abteilung) Carbonate und Nitrate System-Nummer nach Strunz (8. Aufl.) Lapis-Systematik(nach Strunz und Weiß) Strunz (9. Aufl.)Dana Vb/B.01 V/C.01-010 5.BA.05 16a.02.01.01 Ä...

Hull New Theatre

Theatre in Kingston upon Hull, England Hull New TheatreAddressKingston SquareHull, East Riding of YorkshireEnglandCoordinates53°44′49″N 0°20′10″W / 53.747000°N 0.336000°W / 53.747000; -0.336000OwnerHull City CouncilCapacity1,330Opened1939 The Hull New Theatre is a theatre in Kingston upon Hull, East Riding of Yorkshire, England. It opened in 1939 as a successor to the Hull Repertory Theatre Company.[1] The Hull New Theatre features musicals, opera, ...

 

School

Institution for the education of students by teachers For other uses, see School (disambiguation). Schooling redirects here. For the surname, see Schooling (surname). First primary school in Nigeria, built in 1845[1] A high school building in Argos, Greece A school is both the educational institution and building designed to provide learning spaces and learning environments for the teaching of students under the direction of teachers. Most countries have systems of formal education, w...

 

لوعة الحب (فيلم)

  لمعانٍ أخرى، طالع لوعة الحب (توضيح). لوعة الحبمعلومات عامةالصنف الفني دراماتاريخ الصدور 1960 اللغة الأصلية العربيةمأخوذ عن الوحش الآدمي [الإنجليزية]البلد الجمهورية العربية المتحدةموقع التصوير إستوديو مصرالطاقمالمخرج صلاح أبو سيفطلبة رضوانالقصة جليل البنداريالحوا�...

Expansion of Jerusalem in the 19th century

19th-century event in the Levant Jerusalem in 1873, shown in three dimensions. The expansion of Jerusalem outside of the Old City walls, which included shifting the city center to the new neighborhoods, started in the mid-19th century and by the early 20th century had entirely transformed the city. Prior to the 19th century, the main built up areas outside the walls were the complex around King David's Tomb on the southern Mount Zion, and the village of Silwan. In the mid-19th century, with a...

 

Chương Mỹ

Chương Mỹ Huyện Huyện Chương Mỹ Chùa Quảng NghiêmHành chínhQuốc gia Việt NamVùngĐồng bằng sông HồngThành phốHà NộiHuyện lỵthị trấn Chúc SơnTrụ sở UBNDSố 102 khu Bắc Sơn, thị trấn Chúc SơnPhân chia hành chính2 thị trấn, 30 xãThành lập1888[1]Tổ chức lãnh đạoChủ tịch UBNDĐinh Mạnh HùngChủ tịch HĐNDTrịnh Tiến TườngBí thư Huyện ủyNguyễn Văn ThắngĐịa lýTọa độ: 20°55′2...

 

デビルマンレディー

この項目では、永井豪作・原作の漫画およびアニメについて説明しています。作中の主人公については「不動ジュン」をご覧ください。 この記事で示されている出典について、該当する記述が具体的にその文献の何ページあるいはどの章節にあるのか、特定が求められています。 ご存知の方は加筆をお願いします。（2017年4月） デビルマンレディー ジャンル サスペン...

10e méridien ouest

Cercle Arctique T. Cancer Équateur T. Capricorne Cercle AntarctiqueTracé du méridien de 10° ouest En géographie, le 10e méridien ouest est le méridien joignant les points de la surface de la Terre dont la longitude est égale à 10° ouest. Géographie Dimensions Comme tous les autres méridiens, la longueur du 10e méridien correspond à une demi-circonférence terrestre, soit 20 003,932 km. Au niveau de l'équateur, il est distant du méridien de Greenwich de 1&#...

 

Эраст Фандорин

Эраст Фандорин Олег Меньшиков в роли Фандорина в фильме «Статский советник» Создание Создатель Борис Акунин Воплощение Исполнения роли Илья Носков («Азазель», фильм), Егор Бероев («Турецкий гамбит», фильм) Олег Меньшиков («Статский советник», фильм) Пётр Красилов («Эраст...