Exenatide

Exenatide
Single conformer of the solution NMR structure of exenatide. PDB: 7MLL​
Clinical data
Pronunciation/ɛɡzˈɛnətaɪd/ ⓘ
Trade namesByetta, Bydureon, Bydureon BCise, others
AHFS/Drugs.comMonograph
MedlinePlusa605034
License data
Pregnancy
category
  • AU: C
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityN/A
Metabolismproteolysis
Elimination half-life2.4 h
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.212.123 Edit this at Wikidata
Chemical and physical data
FormulaC184H282N50O60S
Molar mass4186.63 g·mol−1
3D model (JSmol)
  • [H]/N=C(\N)/NCCC[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc2c[nH]c3c2cccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)NCC(=O)NCC(=O)N4CCC[C@H]4C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N5CCC[C@H]5C(=O)N6CCC[C@H]6C(=O)N7CCC[C@H]7C(=O)N[C@@H](CO)C(=O)N)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc8ccccc8)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)CNC(=O)[C@H](Cc9cnc[nH]9)N
  • InChI=1S/C184H282N50O60S/c1-16-94(10)147(178(289)213-114(52-58-144(257)258)163(274)218-121(73-101-77-195-105-39-24-23-38-103(101)105)168(279)215-116(68-90(2)3)165(276)205-107(41-26-28-61-186)158(269)219-122(75-134(189)243)154(265)198-79-135(244)196-83-139(248)231-63-30-43-129(231)175(286)225-127(87-238)174(285)223-125(85-236)155(266)200-80-136(245)202-96(12)181(292)233-65-32-45-131(233)183(294)234-66-33-46-132(234)182(293)232-64-31-44-130(232)176(287)222-124(84-235)150(190)261)229-170(281)119(71-99-34-19-17-20-35-99)217-166(277)117(69-91(4)5)214-159(270)108(42-29-62-194-184(191)192)212-177(288)146(93(8)9)228-151(262)95(11)203-156(267)111(49-55-141(251)252)208-161(272)112(50-56-142(253)254)209-162(273)113(51-57-143(255)256)210-164(275)115(59-67-295-15)211-160(271)110(47-53-133(188)242)207-157(268)106(40-25-27-60-185)206-172(283)126(86-237)224-167(278)118(70-92(6)7)216-169(280)123(76-145(259)260)220-173(284)128(88-239)226-180(291)149(98(14)241)230-171(282)120(72-100-36-21-18-22-37-100)221-179(290)148(97(13)240)227-138(247)82-199-153(264)109(48-54-140(249)250)204-137(246)81-197-152(263)104(187)74-102-78-193-89-201-102/h17-24,34-39,77-78,89-98,104,106-132,146-149,195,235-241H,16,25-33,40-76,79-88,185-187H2,1-15H3,(H2,188,242)(H2,189,243)(H2,190,261)(H,193,201)(H,196,244)(H,197,263)(H,198,265)(H,199,264)(H,200,266)(H,202,245)(H,203,267)(H,204,246)(H,205,276)(H,206,283)(H,207,268)(H,208,272)(H,209,273)(H,210,275)(H,211,271)(H,212,288)(H,213,289)(H,214,270)(H,215,279)(H,216,280)(H,217,277)(H,218,274)(H,219,269)(H,220,284)(H,221,290)(H,222,287)(H,223,285)(H,224,278)(H,225,286)(H,226,291)(H,227,247)(H,228,262)(H,229,281)(H,230,282)(H,249,250)(H,251,252)(H,253,254)(H,255,256)(H,257,258)(H,259,260)(H4,191,192,194)/t94-,95-,96-,97+,98+,104-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,146-,147-,148-,149-/m0/s1 ☒N
  • Key:HTQBXNHDCUEHJF-XWLPCZSASA-N ☒N
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Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes.[7] It is used together with diet, exercise, and potentially other antidiabetic medication.[7] It is a treatment option after metformin and sulfonylureas.[8] It is given by injection under the skin.[7]

Common side effects include low blood sugar, nausea, dizziness, abdominal pain, and pain at the site of injection.[7] Other serious side effects may include medullary thyroid cancer, angioedema, pancreatitis, and kidney injury.[7] Use in pregnancy and breastfeeding is of unclear safety.[9] Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist) also known as incretin mimetics.[7] It works by increasing insulin release from the pancreas and decreases excessive glucagon release.[7]

Exenatide was approved for medical use in the United States in 2005.[7] In 2019, it was the 312th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10]

Medical use

Exenatide is used to treat type 2 diabetes as an add-on to metformin, a biguanide, or a combination of metformin and a sulfonylurea, or thiazolidinediones such as pioglitazone.[2][3]

A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2 mg compared to insulin glargine, exenatide 10 μg twice daily, sitagliptin and pioglitazone.[11] Exenatide, lead to greater weight loss than glucagon-like peptide analogues.[11] Due to shorter duration of studies, this review did not allow for long-term positive or negative effects to be assessed.[11]

Side effects

The main side effects of exenatide use are gastrointestinal in nature, including acid or sour stomach, belching, diarrhea, heartburn, indigestion, nausea, and vomiting.[11] These tend to subside with time;[11] exenatide is therefore not meant for people with severe gastrointestinal disease. Other side effects include dizziness, headache, and feeling jittery.[12] Drug interactions listed on the package insert include delayed or reduced concentrations of lovastatin, paracetamol (acetaminophen), and digoxin, although this has not been proven to alter the effectiveness of these other medications.

In response to postmarketing reports of acute pancreatitis in patients using exenatide, the US Food and Drug Administration (FDA) added a boxed warning to the labeling of Byetta in 2007.[13][14] In August 2008, four additional deaths from pancreatitis in users of exenatide were reported to the FDA; while no definite relationship had been established, the FDA was reportedly considering additional changes to the drug's labeling.[15] Examination of the medical records of the millions of patients part of the United Healthcare Insurance plans did not show any greater rate of pancreatitis among Byetta users than among diabetic patients on other medications. However, diabetics do have a slightly greater incidence of pancreatitis than do non-diabetics.[16][17]

It also may increase risk of mild sulfonylurea-induced hypoglycemia.[18]

Additionally, the FDA has raised concerns over the lack of data to determine if the long-acting once-weekly version of exenatide (but not the twice-daily form of exenatide) may increase thyroid cancer risk. This concern comes out of observing a very small but nevertheless increased risk of thyroid cancer in rodents that was observed for another drug (liraglutide) that is in the same class as exenatide. The data available for exenatide showed less of a risk towards thyroid cancer than liraglutide, but to better quantify the risk the FDA has required Amylin to conduct additional rodent studies to better identify the thyroid issue. The approved form of the once weekly exenatide [Bydureon] has a black box warning discussing the thyroid issue. Eli Lilly has reported they have not seen a link in humans, but that it cannot be ruled out. Eli Lilly has stated the drug causes an increase in thyroid problems in rats given high doses.[19]

In March 2013, the FDA issued a Drug Safety Communication announcing investigations into incretin mimetics due to findings by academic researchers.[20] A few weeks later, the European Medicines Agency launched a similar investigation into GLP-1 agonists and DPP-4 inhibitors.[21]

Mechanism of action

Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1); exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life in vivo.[22]

Exenatide is believed to facilitate glucose control in at least five ways:

  1. Exenatide augments pancreas response[23] (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; other drugs (like injectable insulin) are effective at lowering blood sugar, but can "overshoot" their target and cause blood sugar to become too low, resulting in the dangerous condition of hypoglycemia.
  2. Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
  3. Exenatide helps slow down gastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
  4. Exenatide has a subtle yet prolonged effect to reduce appetite, promote satiety via hypothalamic receptors (different receptors than for amylin). Most people using exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain.
  5. Exenatide reduces liver fat content. Fat accumulation in the liver or nonalcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice,[24] rat[25] and more recently in man.[26]

Chemistry

Exenatide is a 39-amino-acid peptide; it is a synthetic version of exendin-4, a peptide found in the venom of the Gila monster.[27]

History

During the early 1980s, Jean-Pierre Raufman worked as a postdoctoral researcher at the National Institutes of Health for John Pisano, an "eccentric biochemist" who specialized in collecting venoms from various animals and looking for novel substances that could affect human physiology.[28] In the course of this work, Raufman focused on investigating the Gila monster because he was curious about how it only eats once or twice per year.[29] He discovered molecules in the monster's saliva "that caused inflammation of the pancreas in test animals".[29] He later recalled: "We got a tremendous response from Gila monster venom".[30]

When Raufman gave a lecture about his findings,[30] his research piqued the curiosity of John Eng, an endocrinologist at the Veterans Administration Medical Center in New York City.[28][29] Eng had trained under Rosalyn Sussman Yalow, who shared the 1977 Nobel Prize in Physiology or Medicine for development of the radioimmunoassay technique.[28][29]

In 1992, Eng used that technique to isolate a novel substance from Gila monster venom which he called exendin-4.[28][29][30] He tested exendin-4 on diabetic mice and discovered that it was not only effective for reducing blood glucose but was effective for several hours.[28][30] This was an enormously significant clinical finding, because it was GLP-1's extremely short half-life which had defeated earlier attempts to turn that substance into a drug.[28][30] Attempts to bypass that issue by infusing patients in clinical tests with very high doses of GLP-1—in order to overcome its rapid metabolism in the bloodstream—had produced extremely severe nausea, followed by immediate vomiting.[28][30]

Eng's employer, the U.S. Department of Veterans Affairs, turned out to have no interest in obtaining a drug patent on exendin-4, so Eng filed the patent application himself in 1993.[28] He then spent three years on fruitless efforts to persuade the pharmaceutical industry to develop exendin-4 into a drug.[28][30] Jens Juul Holst, a GLP-1 expert, later recalled seeing the skepticism which Eng encountered when he tried to present his work on a poster at industry conferences: "He was extremely frustrated ... Nobody was interested in his work. None of the important people. It was too strange for people to accept".[30]

At a 1996 American Diabetes Association conference in San Francisco, Eng finally caught the attention of scientist Andrew Young of Amylin Pharmaceuticals, who immediately recognized exendin-4's potential and arranged for his company to license Eng's patent.[28][29][30][31] Young was excited to see Eng's poster at the conference summarizing his findings, but then noticed an Eli Lilly and Company executive reading the same poster, and he became worried that Lilly might beat Amylin to a license.[30][31] When Eng arrived at Amylin's San Diego headquarters, he was astonished to discover how much information Amylin's scientists had already figured out about exendin-4 in the brief period of time after Young saw his poster, which convinced him that Amylin was the right company to partner with.[31] Amylin went on to create exenatide, a synthetic version of exendin-4, and later formed an alliance with Lilly in 2002 to bring the drug to market.[28][29][32]

Exenatide was approved by the FDA in April 2005, for people whose diabetes is not well controlled on other oral medications.[33][34][35] This was a landmark event which proved that targeting the GLP-1 receptor was a viable strategy and inspired other pharmaceutical companies to focus their research and development on that receptor.[28][30]

In 2011, Lilly and Amylin dissolved their partnership, with Amylin keeping the rights to exenatide.[36] Meanwhile, Lilly had been awakened to the possibilities of this class of drugs and continued to develop newer drugs of the same class. By October 2024, the blockbuster drug tirzepatide had transformed Lilly into the most valuable drug company in the world.[37]

Society and culture

53 consolidated lawsuits against manufacturers of "GLP-1/DPP-4 products" were dismissed in 2015.[38]

Research

In 2016, work published showing that it can reverse impaired calcium signalling in steatotic liver cells, which, in turn, might be associated with proper glucose control.[25]

It is being evaluated for use in the treatment of Parkinson's disease.[39] A phase 3 clinical trial, started in January 2020 has an Estimated Study Completion Date of 30 June 2024 (NCT04232969).[40]

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ a b "Byetta 10 micrograms solution for injection, prefilled pen - Summary of Product Characteristics". Electronic Medicines Compendium. 30 March 2017. Retrieved 21 April 2018.
  3. ^ a b "Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen - Summary of Product Characteristics". Electronic Medicines Compendium. 10 November 2017. Archived from the original on 20 August 2020. Retrieved 21 April 2018.
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  8. ^ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 684–685. ISBN 978-0-85711-338-2.
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  10. ^ "Exenatide - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  11. ^ a b c d e Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A (October 2011). "Glucagon-like peptide analogues for type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews. 2011 (10): CD006423. doi:10.1002/14651858.cd006423.pub2. PMC 6486297. PMID 21975753.
  12. ^ Drugs.com Accessed September 6, 2008.
  13. ^ 2007 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements, from the U.S. Food and Drug Administration. Accessed 28 August 2008.
  14. ^ "Byetta (exenatide) FDA warning". Food and Drug Administration. Retrieved 18 October 2007.
  15. ^ Diabetes Drug Tied to New Deaths. The New York Times. 26 August 2008; accessed 28 August 2008.
  16. ^ Lai SW, Muo CH, Liao KF, Sung FC, Chen PC (September 2011). "Risk of acute pancreatitis in type 2 diabetes and risk reduction on anti-diabetic drugs: a population-based cohort study in Taiwan". The American Journal of Gastroenterology. 106 (9): 1697–1704. doi:10.1038/ajg.2011.155. PMID 21577242. S2CID 25665019.
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  18. ^ Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD (November 2004). "Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes". Diabetes Care. 27 (11): 2628–2635. doi:10.2337/diacare.27.11.2628. PMID 15504997.
  19. ^ Silverman E (12 April 2010). "Lilly's Once-Weekly Byetta May Have Cancer Risk". Pharmalot. Archived from the original on 6 June 2010.
  20. ^ "FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes". FDA. U.S. Food and Drug Administration. 3 March 2013. Retrieved 14 March 2013.
  21. ^ "European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes". EMA. European Medicines Agency Sciences Medicines Health. 26 March 2013. Archived from the original on 28 August 2021. Retrieved 26 March 2013.
  22. ^ Koole C, Reynolds CA, Mobarec JC, Hick C, Sexton PM, Sakmar TP (April 2017). "Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R)". The Journal of Biological Chemistry. 292 (17): 7131–7144. doi:10.1074/jbc.M117.779496. PMC 5409479. PMID 28283573.
  23. ^ Bunck MC, Diamant M, Cornér A, Eliasson B, Malloy JL, Shaginian RM, et al. (May 2009). "One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial". Diabetes Care. 32 (5): 762–768. doi:10.2337/dc08-1797. PMC 2671094. PMID 19196887.
  24. ^ Ding X, Saxena NK, Lin S, Gupta NA, Gupta N, Anania FA (January 2006). "Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice". Hepatology. 43 (1): 173–181. doi:10.1002/hep.21006. PMC 2925424. PMID 16374859.
  25. ^ a b Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, et al. (September 2016). "The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1863 (9): 2135–2146. doi:10.1016/j.bbamcr.2016.05.006. PMID 27178543.
  26. ^ Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ (October 2006). "Incretin mimetics as a novel therapeutic option for hepatic steatosis". Liver International. 26 (8): 1015–1017. doi:10.1111/j.1478-3231.2006.01315.x. PMID 16953843. S2CID 32332119.
  27. ^ Raufman JP (January 1996). "Bioactive peptides from lizard venoms". Regulatory Peptides. 61 (1): 1–18. doi:10.1016/0167-0115(96)00135-8. PMID 8701022. S2CID 5293453.
  28. ^ a b c d e f g h i j k l Molteni M, Chen E (30 September 2023). "GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next?". STAT News. Retrieved 16 October 2024.
  29. ^ a b c d e f g Schwarcz J (26 May 2023). "The Right Chemistry: How the Gila monster assisted weight-loss research". The Montreal Gazette. Retrieved 16 October 2024.
  30. ^ a b c d e f g h i j k Winkler R, Cohen B (23 June 2023). "Monster Diet Drugs Like Ozempic Started With Actual Monsters". The Wall Street Journal. Retrieved 16 October 2024.
  31. ^ a b c Dunaief D (31 August 2023). "Setauket scientist Andrew Young's work paves way for drugs like Ozempic". TBR News Media. Retrieved 16 October 2024.
  32. ^ Pollack A (21 September 2002). "Eli Lilly in Deal For the Rights To a New Drug For Diabetes". The New York Times. p. C1.
  33. ^ Pollack A (30 April 2005). "Lizard-Derived Diabetes Drug Is Approved by the F.D.A.". The New York Times. Retrieved 2 November 2024.
  34. ^ "CDER Drug and Biologic Approvals for Calendar Year 2005". U.S. Food and Drug Administration (FDA). 4 September 2006. Archived from the original on 4 September 2006. Retrieved 8 March 2024.
  35. ^ "Drug Approval Package: Byetta (Exenatide) NDA #021773". U.S. Food and Drug Administration (FDA). Retrieved 8 March 2024.
  36. ^ Staton T (8 November 2011). "Amylin gets Byetta custody in split with Lilly". Fierce Pharma. Retrieved 2 November 2024.
  37. ^ Barnes O (2 October 2024). "Can Eli Lilly become the first $1tn drugmaker?". Financial Times.
  38. ^ Moylan T (11 November 2015). "Preemption Summary Judgment Granted In Incretin-Mimetic Multidistrict Litigation". Lexisnexis.
  39. ^ Kim DS, Choi HI, Wang Y, Luo Y, Hoffer BJ, Greig NH (September 2017). "A New Treatment Strategy for Parkinson's Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway". Cell Transplantation. 26 (9): 1560–1571. doi:10.1177/0963689717721234. PMC 5680957. PMID 29113464.
  40. ^ Bailey S (30 November 2021). "The Bydureon (exenatide) phase 3 trial". Cure Parkinson's. Retrieved 11 September 2022.

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Anton RakyBiographieNaissance 5 janvier 1868Seelenberg (d)Décès 22 août 1943 (à 75 ans)BerlinNationalité allemandeActivités Ingénieur, géologuemodifier - modifier le code - modifier Wikidata Anton Raky (né le 5 janvier 1868 à Seelenberg dans le Taunus, mort le 22 août 1943 à Berlin) est un pionnier du forage profond et de la prospection géologique (minière et pétrolière). Famille Anton Raky est le fils de Franz Raky et de Karoline Abt. Il épouse 1893 en Durrenbach Martha...

 

 

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Physiographic world map with mountain ranges and highland areas in brown, pink, and gray This is a list of mountain ranges on Earth and a few other astronomical bodies. First, the highest and longest mountain ranges on Earth are listed, followed by more comprehensive alphabetical lists organized by continent. Ranges in the oceans and on other celestial bodies are listed afterwards. Mountain ranges on Earth By height Name Continent(s) Country/ies Highest point Altitude(metres abovesea level) ...

 

 

Andrew Turner

Untuk orang lain dengan nama yang sama, lihat Andrew Turner. Andrew Turner Anggota Parlemen untuk Isle of WightMasa jabatan7 Juni 2001 – 3 Mei 2017PendahuluPeter BrandPenggantiBob Seely Informasi pribadiLahir24 Oktober 1953 (umur 70)Coventry, Warwickshire, InggrisKebangsaanBritania RayaPartai politikKonservatifAlma materKeble College, OxfordSunting kotak info • L • B Andrew John Turner (lahir 24 Oktober 1953)[1] adalah seorang politikus Britania Raya yang...

رابح بيطاط

رابح بيطاط رئيس الدولة الجزائرية الثالثفترة مؤقتة في المنصب27 ديسمبر 1978 – 9 فبراير 1979(شهرًا واحدًا و13 يومًا) هواري بومدين الشاذلي بن جديد نائب الرئيس في أول حكومة أحمد بن بلة في المنصب27 سبتمبر 1962 – نوفمبر 1963 الرئيس *فرحات عباس أحمد بن بلة وزير النقل في المنصب21 يوليو 1970 – 5 ما...

 

 

منتخب أرمينيا لكرة السلة

منتخب أرمينيا لكرة السلة أرمينيا التصنيف 80 ▼ 2 (16 سبتمبر 2019)[1] انضم للاتحاد الدولي 1991 منطفة فيبا الاتحاد الأوروبي لكرة السلة البلد أرمينيا تأسس عام 1991  الألعاب الأولمبية المشاركة لا يوجد الميداليات لا يوجد كأس العالم لكرة السلة المشاركة لا يوجد الميداليات لا يوجد بط...

 

 

Bruce Berenyi

American baseball player (born 1954) Baseball player Bruce BerenyiBerenyi in 1986PitcherBorn: (1954-08-21) August 21, 1954 (age 69)Bryan, Ohio, U.S.Batted: RightThrew: RightMLB debutJuly 5, 1980, for the Cincinnati RedsLast MLB appearanceJuly 9, 1986, for the New York MetsMLB statisticsWin–loss record44–55Earned run average4.03Strikeouts607 Teams Cincinnati Reds (1980–1984) New York Mets (1984–1986) Bruce Michael Berenyi (born August 21, 1954) is a f...

Randall Simon

American baseball player This biography of a living person needs additional citations for verification. Please help by adding reliable sources. Contentious material about living persons that is unsourced or poorly sourced must be removed immediately from the article and its talk page, especially if potentially libelous.Find sources: Randall Simon – news · newspapers · books · scholar · JSTOR (June 2010) (Learn how and when to remove this message) Baseb...

 

 

Raíz de una función

Si busca la raíz enésima de un número, vea Función raíz. ƒ(x)=cosx en el intervalo [-2π,2π], las intersecciones con el eje x de las coordenadas cartesianas (las raíces) están indicadas en rojo: -3π/2, -π/2, π/2, 3π/2. En matemática, se conoce como raíz de un polinomio o cero de una función (definida sobre un cierto cuerpo algebraico) f(x) a todo elemento x perteneciente al dominio de dicha función tal que se cumpla: f ( x ) = 0 {\displaystyle f(x)=0\,} . Por ejemplo, dada la...

 

 

Suelli

Disambiguazione – Se stai cercando altri significati, vedi Suelli (disambigua). Suellicomune(IT) Suelli(SC) Suèddi Suelli – VedutaChiesa di San Pietro LocalizzazioneStato Italia Regione Sardegna ProvinciaSud Sardegna AmministrazioneSindacoMassimiliano Garau (lista civica) dal 30-5-2010 (3º mandato dal 26-10-2020) TerritorioCoordinate39°33′41.88″N 9°07′54.73″E39°33′41.88″N, 9°07′54.73″E Altitudine256 m s.l.m. Superficie19,2 km²...

St. Charles County, Missouri

County in Missouri, United States St. Charles County redirects here. For the similarly-named Louisiana parish, see St. Charles Parish, Louisiana. County in MissouriSt. Charles CountyCountySt. Charles County Courthouse in St. Charles FlagLocation within the U.S. state of MissouriMissouri's location within the U.S.Coordinates: 38°45′36″N 90°37′00″W / 38.76°N 90.6167°W / 38.76; -90.6167Country United StatesState MissouriFoundedOctober 1, 1812Named fo...

 

 

Jay Park

American rapper (born 1987) For the writer, see Park Jae-beom. For the former Day6 member, see Jae Park. In this Korean name, the family name is Park. Jay ParkPark in 2022Background informationBirth namePark Jae-beomBorn (1987-04-25) April 25, 1987 (age 37)[1]Edmonds, Washington, U.S.OriginSeattle, Washington, U.S.GenresK-pophip hopR&BOccupation(s)Rappersingersongwriterrecord producerdancerentrepreneurYears active2002–presentLabelsAOMGH1ghrRoc Nation[2][3]Mo...

 

 

Bullwhip effect

Form of distribution marketing This article includes a list of general references, but it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (July 2013) (Learn how and when to remove this message) Illustration of the bullwhip effect: the final customer places an order (whip), which increasingly distorts interpretations of demand as one proceeds upstream along the supply chain. The bullwhip effect is a supply chain phenom...

Renang pada Olimpiade Musim Panas 1992

Renang pada Olimpiade Musim Panas 1992LokasiPiscines Bernat PicornellBarcelonaTanggal26–31 Juli 1992Jumlah disiplin31Peserta641 dari 92 negara← 19881996 → Renang pada Olimpiade Musim Panas 1992 adalah pelaksanaan cabang olahraga renang pada penyelenggaraan Olimpiade Musim Panas 1992. Kompetisi pada cabang olahraga ini berlangsung di Piscines Bernat Picornell, Barcelona. Edisi ini menandingkan 31 nomor. 641 atlet dari 92 negara bertanding dalam edisi ini....

 

 

South Lebanon conflict (1985–2000)

War between Israel and Hezbollah Not to be confused with the 1978 South Lebanon conflict or the 1982 Lebanon War. South Lebanon conflictPart of the Israeli–Lebanese conflict, the Iran–Israel proxy conflict, and the Israeli–Palestinian conflictIsraeli APCs approaching an SLA outpost in southern Lebanon, 1987Date16 February 1985 – 25 May 2000LocationRepublic of LebanonResult Hezbollah victory[1] Israeli withdrawal from Lebanon[2] Collapse and surrender of the SLA and its...