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词条 Rivaroxaban
释义

  1. Medical uses

  2. Contraindications

  3. Adverse effects

  4. Mechanism of action

  5. Chemistry

  6. History

  7. Society and culture

     Economics  Approval 

  8. Research

  9. See also

  10. References

  11. External links

{{short description|anticoagulant drug}}{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 459434616
| IUPAC_name = (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
| image = Rivaroxaban2DCSD.svg
| width = 250px
| image2 = Rivaroxaban xtal 2005.png
| width2 = 250px
| tradename = Xarelto, others
| Drugs.com = {{drugs.com|monograph|rivaroxaban}}
| licence_EU = yes
| licence_US = Rivaroxaban
| pregnancy_AU = C
| pregnancy_US = C
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = By mouth
| bioavailability = 80–100%; Cmax = 2–4 hours (10 mg oral)[1]
| metabolism = CYP3A4, CYP2J2 and CYP-independent mechanisms[1]
| elimination_half-life = 5–9 hours in healthy subjects aged 20 to 45[1][2]
| excretion = {{sfrac|2|3}} metabolized in liver and {{sfrac|1|3}} eliminated unchanged[1]
| IUPHAR_ligand = 6388
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 366789-02-8
| ATC_prefix = B01
| ATC_suffix = AF01
| PubChem = 6433119
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06228
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 8051086
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 9NDF7JZ4M3
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 198362
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D07086
| synonyms = BAY 59-7939
| C=19 | H=18 | Cl=1 | N=3 | O=5 | S=1
| molecular_weight = 435.882 g/mol
| smiles = c1cc(ccc1N2CCOCC2=O)N3C[C@@H](OC3=O)CNC(=O)c4ccc(s4)Cl
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H18ClN3O5S/c20-16-6-5-15(29-16)18(25)21-9-14-10-23(19(26)28-14)13-3-1-12(2-4-13)22-7-8-27-11-17(22)24/h1-6,14H,7-11H2,(H,21,25)/t14-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KGFYHTZWPPHNLQ-AWEZNQCLSA-N
}}Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and prevent blood clots.[6] Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery.[6] It is taken by mouth.[6]

Common side effects include bleeding.[6] Other serious side effects may include spinal hematoma and anaphylaxis.[6] It is unclear if use in pregnancy and breastfeeding is safe.[3] Compared to warfarin it has fewer interactions with other medications.[4] It works by blocking the activity of the clotting protein factor Xa.[5]

Rivaroxaban was patented in 2007, approved for medical use in the United States in 2011, and will lose patent protection in 2020.[6] It is available as a generic medication.[15] A month supply in the United Kingdom costs the NHS about 50 £ as of 2019.[7] In the United States the wholesale cost of this amount is about 430 USD.[8] In 2016 it was the 105th most prescribed medication in the United States with more than 7 million prescriptions.[9]

Medical uses

In those with non-valvular atrial fibrillation it appears to be as effective as warfarin in preventing ischemic strokes and embolic events.[10] Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin though rivaroxaban is associated with higher rates of bleeding in the gastrointestinal tract.[11]

In July 2012, the UK's National Institute for Health and Clinical Excellence recommended rivaroxaban to prevent and treat venous thromboembolism.[12]

Contraindications

Because of the difficulty associated with managing bleeding, rivaroxaban should be discontinued at least 24 hours before surgery, then restarted as soon as adequate homeostasis is established.[13]

Adverse effects

The most serious adverse effect is bleeding, including severe internal bleeding.[14][15][16] Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin but is associated with higher rates of bleeding in the gastrointestinal tract.[11] While a reversal agent for rivaroxaban is now available (Andexanet alfa/AndexXa), its safety and efficacy are not as well-established as the reversal agents for the older anticoagulant warfarin (vitamin K and prothrombin complex concentrate), meaning that serious bleeding may be more difficult to manage.{{mcn|date=August 2018}}

In October 2014, Portola Pharmaceuticals completed Phase I and II clinical trials for andexanet alfa as an antidote for Factor Xa inhibitors with few adverse effects, and started Phase III trials.[17][18] Andexanet alfa was expected to be approved in 2016.[19] Andexanet alfa was approved by the U.S. Food and Drug Administration in May, 2018, under the trade name AndexXa.[20][21]

{{As of| 2015}}, post-marketing assessments showed liver toxicity, and further studies are needed to quantify the risk.[22][23] The medication is contraindicated in people with significant liver disease and end-stage kidney disease, in whom the medication was not trialed.

Rivaroxaban has a boxed warning to make clear that people using the medication should not discontinue it before talking with their health care professional, because it can increase the risk of stroke.[24]

In 2015, rivaroxaban accounted for the highest number of reported cases of serious injury among regularly monitored medications to the FDA's Adverse Events Reporting System (AERS).[25]

Mechanism of action

Rivaroxaban inhibits both free Factor Xa and Factor Xa bound in the prothrombinase complex.[26] It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated.[1] It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring [1] as well as dietary restrictions are not needed.[19]

Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux also inhibit the activity of factor Xa but indirectly by binding to circulating antithrombin (AT III) and must be injected. Whereas, the orally active warfarin, phenprocoumon, and acenocoumarol are vitamin K antagonists (VKA) decrease a number of coagulation factors, including Factor X.[27]

Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg).[28]

Chemistry

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low.[29]

History

It was initially developed by Bayer. In the United States, it is marketed by Janssen Pharmaceutica (a part of Johnson & Johnson). It is the first available active direct factor Xa inhibitor which is taken by mouth.

Society and culture

Economics

Using rivaroxaban rather than warfarin costs 70 times more, according to Express Scripts Holding Co, the largest U.S. pharmacy benefits manager.[19] As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated.[30]

Approval

In September 2008, Health Canada granted marketing authorization for rivaroxaban to prevent venous thromboembolism (VTE) in people who have undergone elective total hip replacement or total knee replacement surgery.[31]

In the same month, the European Commission also granted marketing authorization of rivaroxaban to prevent venous thromboembolism in adults undergoing elective hip and knee replacement.[32]

On July 1, 2011, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.[33]

On November 4, 2011, the U.S. FDA approved rivaroxaban for stroke prevention in people with non-valvular atrial fibrillation.[34]

Research

Researchers at the Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban.[35] Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial.[36] The clinical trial, published 2011 in the New England Journal of Medicine[37] and headed by Robert Califf, then Commissioner of the FDA[38])[37] found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in patients with atrial fibrillation.[37] The validity of the study was called into question in 2014 when pharmaceutical sponsors Bayer and Johnson & Johnson revealed that the INRatio blood monitoring devices used were not functioning properly,[35][36] A subsequent analysis by the Duke team published in February 2016 found that this had no significant effect on efficacy and safety in the trial.[39]

See also

  • Apixaban
  • Betrixaban
  • Darexaban (YM150)
  • Edoxaban (DU-176b)

References

1. ^1 2 3 4 5 {{cite web |url=http://www.xarelto.com/scripts/pages/en/information-on-xarelto/summary_of_product_characteristics/index.php |title=Xarelto: Summary of Product Characteristics |publisher=Bayer Schering Pharma AG |year=2008 |accessdate=2009-02-11}}
2. ^{{cite journal |last1=Abdulsattar |first1=Y |last2=Bhambri |first2=R |last3=Nogid |first3=A |title=Rivaroxaban (xarelto) for the prevention of thromboembolic disease: an inside look at the oral direct factor xa inhibitor.|journal=P & T : A Peer-Reviewed Journal for Formulary Management|date=May 2009|volume=34|issue=5|pages=238–44|pmid=19561868|pmc=2697099}}
3. ^{{cite web |title=Rivaroxaban Use During Pregnancy |url=https://www.drugs.com/pregnancy/rivaroxaban.html |website=Drugs.com |accessdate=3 March 2019 |language=en}}
4. ^{{cite book |last1=Kiser |first1=Kathryn |title=Oral Anticoagulation Therapy: Cases and Clinical Correlation |date=2017 |publisher=Springer |isbn=9783319546438 |page=11 |url=https://books.google.de/books?id=byYmDwAAQBAJ&pg=PA11 |language=en}}
5. ^1 2 3 4 5 {{cite web |title=Rivaroxaban Monograph for Professionals |url=https://www.drugs.com/monograph/rivaroxaban.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |accessdate=3 March 2019 |language=en}}
6. ^{{cite web|title=Generic Xarelto Availability|url=https://www.drugs.com/availability/generic-xarelto.html|website=Drugs.com|accessdate=9 May 2017}}
7. ^1 {{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=127-128|edition=76}}
8. ^{{cite web |title=NADAC as of 2019-02-27 |url=https://data.medicaid.gov/Drug-Pricing-and-Payment/NADAC-as-of-2019-02-27/s7c9-pfa6 |website=Centers for Medicare and Medicaid Services |accessdate=3 March 2019 |language=en}}
9. ^{{cite web |title=The Top 300 of 2019 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |website=clincalc.com |accessdate=22 December 2018}}
10. ^{{cite journal|last1=Gómez-Outes |first1=A |last2= Terleira-Fernández |first2=AI|last3=Calvo-Rojas |first3=G|last4=Suárez-Gea |first4=ML |last5=Vargas-Castrillón |first5=E |title= Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups. |journal= Thrombosis |date= 2013 |volume= 2013 |pages= 1–18 |pmid= 24455237 |doi= 10.1155/2013/640723 |pmc= 3885278}}
11. ^1 {{cite journal |vauthors= Brown DG, Wilkerson EC, Love WE |title= A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons |journal= Journal of the American Academy of Dermatology |volume=72 |issue=3 |pages= 524–34 |date=March 2015 |pmid= 25486915 |doi= 10.1016/j.jaad.2014.10.027}}
12. ^NICE guidance TA261 NICE guidance TA261. National Institute for Health and Clinical Excellence, July 2012
13. ^{{cite journal |last1=Sunkara |first1=T |last2=Ofori |first2=E |last3=Zarubin |first3=V |last4=Caughey |first4=ME |last5=Gaduputi |first5=V |last6=Reddy |first6=M |title=Perioperative Management of Direct Oral Anticoagulants (DOACs): A Systemic Review. |journal=Health Services Insights |date=2016 |volume=9 |issue=Suppl 1 |pages=25–36 |doi=10.4137/HSI.S40701 |pmid=28008269 |pmc=5156547}}
14. ^{{cite web |title= Medication Guide – Xarelto |url= http://www.fda.gov/downloads/Drugs/DrugSafety/UCM280333.pdf |publisher= U.S. Food and Drug Administration |accessdate= 1 September 2014}}
15. ^{{cite web |title= Xarelto Side Effects |url= http://www.webmd.com/drugs/2/drug-156265/xarelto-oral/details/list-sideeffects |publisher= WebMD |accessdate=1 September 2014}}
16. ^{{cite web |title=Xarelto Side Effects Center |url= http://www.rxlist.com/xarelto-side-effects-drug-center.htm |publisher= RxList |accessdate= 1 September 2014}}
17. ^{{cite web |last1= Schroeder |first1=C. |title= Possible Antidote Could Help Blood Thinner Patients In Bleeding Emergencies |url= https://www.drugnews.net/news/antidote-xarelto-blood-thinner-patients-emergency/ |website= DrugNews |accessdate= 20 August 2015}}
18. ^{{cite journal |title= Recent advances in the development of specific antidotes for target-specific oral anticoagulants |vauthors= Mo Y, Yam FK |journal= Pharmacotherapy |date= Feb 2015 |volume=35 |issue=2 |pages=198–207 |doi= 10.1002/phar.1532 |pmid= 25644580}}
19. ^1 2 {{Cite news |url= https://www.reuters.com/article/us-pharmaceuticals-bloodthinners-idUSKBN0U617320151223 |title= New blood thinner 'antidote' to help doctors move past warfarin |last=Bill Berkrot |date=December 23, 2015 |newspaper=Reuters}}
20. ^{{cite web |title= Accelerated Approval for AndexXa |url=https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606693.pdf |website= FDA |accessdate= 1 August 2018}}
21. ^{{Cite news|url=https://globenewswire.com/news-release/2018/05/04/1496534/0/en/U-S-FDA-Approves-Portola-Pharmaceuticals-Andexxa-First-and-Only-Antidote-for-the-Reversal-of-Factor-Xa-Inhibitors.html|title=U.S. FDA Approves Portola Pharmaceuticals’ Andexxa®, First and Only Antidote for the Reversal of Factor Xa Inhibitors|last=Inc.|first=Portola Pharmaceuticals,|work=GlobeNewswire News Room|access-date=1 August 2018|language=en-US}}
22. ^{{Cite journal|title = Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system|journal = British Journal of Clinical Pharmacology|date = 2015-08-01|issn = 1365-2125|pmc = 4541976|pmid = 25689417|pages = 285–293|volume = 80|issue = 2|doi = 10.1111/bcp.12611|first = Emanuel|last = Raschi|first2 = Elisabetta|last2 = Poluzzi|first3 = Ariola|last3 = Koci|first4 = Francesco|last4 = Salvo|first5 = Antoine|last5 = Pariente|first6 = Maurizio|last6 = Biselli|first7 = Ugo|last7 = Moretti|first8 = Nicholas|last8 = Moore|first9 = Fabrizio|last9 = De Ponti}}
23. ^{{Cite journal|title = Rivaroxaban postmarketing risk of liver injury|journal = Journal of Hepatology|date = 2014-08-01|issn = 1600-0641|pmid = 24681117|pages = 293–300|volume = 61|issue = 2|doi = 10.1016/j.jhep.2014.03.026|first = Stefan|last = Russmann|first2 = David F.|last2 = Niedrig|first3 = Mathias|last3 = Budmiger|first4 = Caroline|last4 = Schmidt|first5 = Bruno|last5 = Stieger|first6 = Sandra|last6 = Hürlimann|first7 = Gerd A.|last7 = Kullak-Ublick|url = http://www.zora.uzh.ch/id/eprint/94814/1/2014_J_Hepatol_rivaroxaban_russmann.pdf}}
24. ^{{cite web|title = Xarelto (rivaroxaban) label|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022406s015lbl.pdf|publisher=U.S. Food and Drug Association}}
25. ^{{cite web|last1=Schroeder|first1=C|title=ISMP Ranks Xarelto Most Dangerous Drug in the United States|url=https://www.drugnews.net/news/ismp-ranks-xarelto-most-dangerous-drug-in-US|website=DrugNews|publisher=DrugNews|accessdate=10 August 2016}}
26. ^{{cite journal |vauthors=Roehrig S, Straub A, Pohlmann J, etal |title=Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor |journal=Journal of Medicinal Chemistry |volume=48 |issue=19 |pages=5900–08 |date=September 2005 |pmid=16161994 |doi=10.1021/jm050101d}}
27. ^{{cite journal |author=Turpie AG |title=New oral anticoagulants in atrial fibrillation |journal=European Heart Journal |volume=29 |issue=2 |pages=155–65 | date=January 2008 |pmid=18096568 |doi=10.1093/eurheartj/ehm575}}
28. ^{{cite journal |vauthors=Eriksson BI, Borris LC, Dahl OE, etal |title=A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement |journal=Circulation |volume=114 |issue=22 |pages=2374–81 | date=November 2006 |pmid=17116766 |doi=10.1161/CIRCULATIONAHA.106.642074}}
29. ^{{cite web |url=http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-en6.pdf |title=CHP Assessment Report for Xarelto (EMEA/543519/2008) |author=European Medicines Agency |year=2008 |accessdate=2009-06-11 }}{{dead link|date=April 2018 |bot=InternetArchiveBot |fix-attempted=yes }}
30. ^{{Cite web |url=http://www.press.bayer.com/baynews/baynews.nsf/id/6B53106BB5B7A379C125803C0060247B/$File/2016-0232E.pdf?open&mod=29.09.2016_07:31:43 |title=Bayer comments on article in The British Medical Journal (BMJ) regarding Xarelto |date=29 September 2016 |publisher=Bayer AG Communications, Government Relations & Corporate Brand}}
31. ^{{cite press release |title=Bayer's Xarelto Approved in Canada |publisher=Bayer |date=2008-09-16 |url=http://www.fiercebiotech.com/press-releases/bayers-xarelto-approved-canada |accessdate=2010-01-31}}
32. ^{{cite press release |title=Bayer’s Novel Anticoagulant Xarelto now also approved in the EU |publisher=Bayer |date=2008-02-10 |url=http://www.bionity.com/news/e/87733/ |accessdate=2010-01-31}}
33. ^{{cite press release |title=FDA Approves Xarelto® (rivaroxaban tablets) to Help Prevent Deep Vein Thrombosis in Patients Undergoing Knee or Hip Replacement Surgery |publisher=Janssen Pharmaceutica |date=2011-07-01 |url=http://m.prnewswire.com/news-releases/fda-approves-xarelto-rivaroxaban-tablets-to-help-prevent-deep-vein-thrombosis-in-patients-undergoing-knee-or-hip-replacement-surgery-124872829.html |accessdate=2011-07-01 |deadurl=yes |archiveurl=https://web.archive.org/web/20111105145422/http://m.prnewswire.com/news-releases/fda-approves-xarelto-rivaroxaban-tablets-to-help-prevent-deep-vein-thrombosis-in-patients-undergoing-knee-or-hip-replacement-surgery-124872829.html |archivedate=2011-11-05 |df= }}
34. ^{{cite news|title=FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278646.htm|accessdate=27 April 2016|work=US Food and Drug Association|date=4 November 2011}}
35. ^1 {{cite news|last1=Thomas|first1=Katie|title=Document Claims Drug Makers Deceived a Top Medical Journal|url=https://www.nytimes.com/2016/03/02/business/document-claims-drug-makers-deceived-a-top-medical-journal.html?_r=0|newspaper=The New York Times|accessdate=3 May 2016 |ref=nyt_drug_deceived |date=1 March 2016}}
36. ^1 {{cite web|last1=Patel|first1=Vir|title=Duke clinical trial under scrutiny in drug case|url=http://www.dukechronicle.com/article/2016/04/duke-clinical-trial-under-scrutiny-in-drug-case|website=The Chronicle|publisher=Duke Student Publishing Company|ref=rocket_af_duke}}
37. ^1 2 {{cite journal|title=Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation|issue=10|pages=883–891|url=http://www.nejm.org/doi/full/10.1056/NEJMoa1009638#t=article|journal=The New England Journal of Medicine|volume=365|ref=Rivaroxaban_vs_Warfarin|doi=10.1056/NEJMoa1009638|pmid=21830957|pmc=3860773|date=2011-09-08|last1=Patel|first1=Manesh R.|last2=Mahaffey|first2=Kenneth W.|last3=Garg|first3=Jyotsna|last4=Pan|first4=Guohua|last5=Singer|first5=Daniel E.|last6=Hacke|first6=Werner|last7=Breithardt|first7=Günter|last8=Halperin|first8=Jonathan L.|last9=Hankey|first9=Graeme J.|last10=Piccini|first10=Jonathan P.|last11=Becker|first11=Richard C.|last12=Nessel|first12=Christopher C.|last13=Paolini|first13=John F.|last14=Berkowitz|first14=Scott D.|last15=Fox|first15=Keith A.A|last16=Califf|first16=Robert M.}}
38. ^{{cite web|title=Meet Robert M. Califf, M.D., Commissioner of Food and Drugs|url=http://www.fda.gov/AboutFDA/CentersOffices/ucm452317.htm|website=U.S. Food and Drug Administration|publisher=U.S. Food and Drug Administration|accessdate=3 May 2016|ref=Meet_Califf}}
39. ^{{Cite journal|title=Point-of-Care Warfarin Monitoring in the ROCKET AF Trial|url=http://www.nejm.org/doi/full/10.1056/NEJMc1515842#t=article|journal=The New England Journal of Medicine|volume=374|issue=8|pages=785–788|date=February 3, 2016|ref=monitor_rocket_af|doi=10.1056/NEJMc1515842|pmid=26839968|last1=Patel|first1=Manesh R.|last2=Hellkamp|first2=Anne S.|last3=Fox|first3=Keith A. A.}}

External links

  • [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d0e105f6-28f3-45ee-83bd-7d458835242b Rivaroxaban at DailyMed]
  • Rivaroxaban bound to proteins in the PDB
{{Antithrombotics}}

9 : RTT|Anticoagulants|Morpholines|Thiophenes|Chloroarenes|Oxazolidinones|Lactams|Janssen Pharmaceutica|Bayer AG
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