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Thomson Walt

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Thomson Walt (คุย | ส่วนร่วม)
การแก้ไข 10,278 ครั้ง
Thomson Walt (คุย | ส่วนร่วม)
การแก้ไข 10,278 ครั้ง
บรรทัด 139:
 
The adverse effects of long-term linezolid therapy were first identified during postmarketing surveillance. Bone marrow suppression was not identified during Phase III trials, in which treatment did not exceed 21 days. Although some participants of early trials did experience thrombocytopenia, it was found to be reversible and did not occur significantly more frequently than in controls (participants not taking linezolid).<ref name=Moellering/> There have also been postmarketing reports of [[seizure]]s, and, {{as of|2009|lc=on}}, a single case each of [[Bell's palsy]] (paralysis of the [[facial nerve]]) and [[nephrotoxicity|kidney toxicity]].<ref name=Metaxas/>
==อันตรกิริยา==
Linezolid is a weak [[monoamine oxidase inhibitor]] (MAOI), and should not be used concomitantly with other MAOIs, large amounts of [[tyramine]]-rich foods (such as pork, aged cheeses, alcoholic beverages, or smoked and pickled foods), or [[serotonergic]] drugs. There have been [[postmarketing surveillance|postmarketing reports]] of [[serotonin syndrome]] when linezolid was given with or soon after the discontinuation of serotonergic drugs, particularly [[selective serotonin reuptake inhibitor]]s such as [[paroxetine]] and [[sertraline]].<ref name=French/><ref>{{cite journal |vauthors=Lawrence KR, Adra M, Gillman PK |title=Serotonin toxicity associated with the use of linezolid: a review of postmarketing data |journal=Clinical Infectious Diseases |volume=42 |issue=11 |pages=1578–83 |date=June 2006 |pmid=16652315 |doi=10.1086/503839 |issn=1058-4838}}</ref><ref name=Huang>{{cite journal |vauthors=Huang V, Gortney JS |title=Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists |journal=Pharmacotherapy |volume=26 |issue=12 |pages=1784–93 |date=December 2006 |pmid=17125439 |doi=10.1592/phco.26.12.1784 |issn=0277-0008}}</ref><ref>{{cite web |url=http://www.medscape.com/viewarticle/580101 |title=FDA Safety Changes: Mirena, Zyvox, Orencia |author=Waknine, Yael |date=September 5, 2008 |publisher=[[Medscape]] |accessdate=2008-09-06 |deadurl=no |archiveurl=https://web.archive.org/web/20081202190427/http://www.medscape.com/viewarticle/580101 |archivedate=December 2, 2008 |df= }} Freely available with registration.</ref> It may also enhance the blood pressure-increasing effects of [[sympathomimetic drug]]s such as [[pseudoephedrine]] or [[phenylpropanolamine]].<ref name=Moellering/><ref name=Stalker>{{cite journal |vauthors=Stalker DJ, Jungbluth GL |title=Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial |journal=Clinical Pharmacokinetics |volume=42 |issue=13 |pages=1129–40 |year=2003 |pmid=14531724 |doi=10.2165/00003088-200342130-00004 |issn=0312-5963}}</ref> It should also not be given in combination with [[pethidine]] ([[meperidine]]) under any circumstance due to the risk of [[serotonin syndrome]].
 
Linezolid does not [[enzyme inhibitor|inhibit]] or [[regulation of gene expression|induce]] the [[cytochrome P450]] (CYP) system, which is responsible for the metabolism of many commonly used drugs, and therefore does not have any CYP-related interactions.<ref name=PI2010/>
==เภสัชวิทยา==
 
===เภสัชจลนศาสตร์===
[[File:Linezolid metabolism.svg|thumb|Major metabolites of linezolid|alt=Upper left: structural formula of the unaltered linezolid molecule, with the morpholino group highlighted in red. Lower left: main carboxylic acid metabolite, accounting for 10% of an excreted dose; the morpholine ring has been cleaved at the nitrogen atom. Lower right: structural formulae of two distinct molecules, a carboxylic acid and a lactone, with an equilibrium arrow between them; this metabolite accounts for 45% of a dose. Upper right: structure of a minor carboxylic acid metabolite, which accounts for aroune 3.3% of a dose.]]
 
One of the advantages of linezolid is its high [[bioavailability]] (close to 100%) when given by mouth: the entire dose reaches the bloodstream, as if it had been given [[intravenous therapy|intravenously]]. This means that people receiving intravenous linezolid may be switched to oral linezolid as soon as their condition allows it, whereas comparable antibiotics (such as vancomycin and quinupristin/dalfopristin) can only be given intravenously.<ref name="American Family Physician">{{cite journal |vauthors=Ament PW, Jamshed N, Horne JP |title=Linezolid: its role in the treatment of gram-positive, drug-resistant bacterial infections |journal=[[American Family Physician]] |volume=65 |issue=4 |pages=663–70 |date=February 2002 |pmid=11871684 |url=http://www.aafp.org/afp/20020215/663.html |issn=0002-838X |deadurl=no |archiveurl=https://web.archive.org/web/20080724045942/http://www.aafp.org/afp/20020215/663.html |archivedate=2008-07-24 |df= }}</ref>
Taking linezolid with food somewhat slows its absorption, but the [[area under the curve (pharmacokinetics)|area under the curve]] is not affected.<ref name=Herrmann/>
 
Linezolid has low [[plasma protein binding]] (approximately 31%, but highly variable) and an [[volume of distribution|apparent volume of distribution]] at [[steady state]] of around 40–50&nbsp;liters.<ref name=Lexi-Comp>{{cite web |url=http://www.merck.com/mmpe/lexicomp/linezolid.html |title=Linezolid |date=August 2008 |author=Lexi-Comp |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]] |deadurl=no |archiveurl=https://web.archive.org/web/20090426220140/http://www.merck.com/mmpe/lexicomp/linezolid.html |archivedate=2009-04-26 |df= }} Retrieved on May 14, 2009.</ref> Peak serum concentrations (C<sub>max</sub>) are reached one to two hours after administration of the drug.<!--and are around 13&nbsp;mg/L after a single dose and 16–19&nbsp;mg/L after repeated administration;<ref name=Lexi-Comp/><ref name=Herrmann/> trough concentrations (C<sub>min</sub>) are 4–8&nbsp;mg/L.<ref name=Herrmann/> *see [[Wikipedia:Featured article candidates/Linezolid/archive1]] for an explanation of why this is commented out*--> Linezolid is readily distributed to all tissues in the body apart from [[bone]] matrix and [[white adipose tissue]].<ref name=Barbachyn/> Notably, the concentration of linezolid in the epithelial lining fluid of the [[lower respiratory tract]] is at least equal to, and often higher than, that achieved in serum (some authors have reported [[bronchus|bronchial]] fluid concentrations up to four times higher than serum concentrations), which may account for its [[efficacy]] in treating pneumonia. [[Cerebrospinal fluid]] (CSF) concentrations vary; peak CSF concentrations are lower than serum ones, due to slow diffusion across the [[blood–brain barrier]], and trough concentrations in the CSF are higher for the same reason.<ref name=Herrmann/> The average half-life is three hours in children, four hours in teenagers, and five hours in adults.<ref name=PI2010/>
 
Linezolid is [[drug metabolism|metabolized]] in the [[liver]], by [[redox|oxidation]] of the [[morpholine]] ring, without involvement of the [[cytochrome P450]] system. This metabolic pathway leads to two major inactive [[metabolite]]s (which each account for around 45% and 10% of an excreted dose at steady state), one minor metabolite, and several trace metabolites, none of which accounts for more than 1% of an excreted dose.<ref name=Slatter>{{cite journal |vauthors=Slatter JG, Stalker DJ, Feenstra KL, etal |title=Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C]linezolid to healthy human subjects |journal=Drug Metabolism and Disposition |volume=29 |issue=8 |pages=1136–45 |date=August 1, 2001 |pmid=11454733 |url=http://dmd.aspetjournals.org/content/29/8/1136.full.pdf |issn=0090-9556}}</ref> [[Clearance (medicine)|Clearance]] of linezolid varies with age and gender; it is fastest in children (which accounts for the shorter half-life), and appears to be 20% lower in women than in men.<ref name=PI2010/><ref name=Slatter/><ref name=Sisson>{{cite journal |vauthors=Sisson TL, Jungbluth GL, Hopkins NK |title=Age and sex effects on the pharmacokinetics of linezolid |journal=European Journal of Clinical Pharmacology |volume=57 |issue=11 |pages=793–7 |date=January 2002 |pmid=11868801 |doi=10.1007/s00228-001-0380-y |issn=0031-6970}}</ref> There is a strong correlation between linezolid clearance and creatinine clearance (CLCR).<ref name=Bialvaei>{{cite journal |vauthors=Bialvaei AZ, Rahbar M, Yousefi M, etal |title=Linezolid: a promising option in the treatment of Gram-positives |journal=Journal of Antimicrobial Chemotherapy|volume=72 |issue=2 |pages=354–364 |date=February 2017 |pmid=27999068 |url=https://academic.oup.com/jac/article/72/2/354/2629138/Linezolid-a-promising-option-in-the-treatment-of |doi=10.1093/jac/dkw450}}</ref>
 
===กลไกการออกฤทธิ์===
{{further|Protein biosynthesis|Translation (genetics)#Basic mechanisms}}
[[File:Ribosome mRNA translation en.svg|thumb|Simplified schematic of mRNA translation. Linezolid occupies the A site (at center) and prevents tRNA from binding.|alt=Diagram: A colored ribbon, representing messenger RNA (mRNA), passes through a cartoon diagram of an assembled ribosome. Cartoon representations of transfer RNA (tRNA) enter and exit the ribosome and occupy its A and P sites. A string of colored spheres, representing a newly formed protein, comes out of the top of the ribosome.]]
The oxazolidinones are [[protein synthesis inhibitor]]s: they stop the growth and reproduction of bacteria by disrupting [[prokaryotic translation|translation]] of [[messenger RNA]] (mRNA) into [[protein]]s in the [[ribosome]]. Although its mechanism of action is not fully understood,<ref name=Skripkin>{{cite journal |vauthors=Skripkin E, McConnell TS, DeVito J, etal |title=Rχ-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance |journal=[[Antimicrobial Agents and Chemotherapy]] |volume=52 |issue=10 |pages=3550–7 |date=October 2008 |pmid=18663023 |pmc=2565890 |doi=10.1128/AAC.01193-07 |issn=0066-4804 |url=http://aac.asm.org/cgi/reprint/52/10/3550.pdf }}</ref> linezolid appears to work on the first step of protein synthesis, ''[[MRNA-ribosome|initiation]]'', unlike most other protein synthesis inhibitors, which inhibit ''[[Prokaryotic translation#Elongation|elongation]]''.<ref name=Swaney1998/><ref name="American Family Physician"/>
 
It does so by preventing the formation of the initiation complex, composed of the [[30S]] and [[50S]] subunits of the ribosome, [[transfer RNA|tRNA]], and mRNA. Linezolid binds to the [[23S ribosomal RNA|23S]] portion of the 50S subunit (the center of [[peptidyl transferase]] activity),<ref name=Colca>{{cite journal |vauthors=Colca JR, McDonald WG, Waldon DJ, etal |title=Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics |journal=[[Journal of Biological Chemistry]] |volume=278 |issue=24 |pages=21972–9 |date=June 2003 |pmid=12690106 |doi=10.1074/jbc.M302109200 |url=http://www.jbc.org/content/278/24/21972.full.pdf |issn=0021-9258 |deadurl=no |archiveurl=https://web.archive.org/web/20170910172617/http://www.jbc.org/content/278/24/21972.full.pdf |archivedate=2017-09-10 |df= }}</ref> close to the [[binding site]]s of [[chloramphenicol]], [[lincomycin]], and other antibiotics. Due to this unique mechanism of action, [[cross-resistance]] between linezolid and other protein synthesis inhibitors is highly infrequent or nonexistent.<ref name=Herrmann/><ref name=Moellering/>
 
In 2008, the [[crystal structure]] of linezolid bound to the 50S subunit of a ribosome from the [[archaea]]n ''Haloarcula marismortui'' was elucidated by a team of scientists from [[Yale University]] and deposited in the [[Protein Data Bank]].<ref>{{cite journal |vauthors=Ippolito JA, Kanyo ZF, Wang D, etal |title=Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50S ribosomal subunit |journal=[[Journal of Medicinal Chemistry]] |volume=51 |issue=12 |pages=3353–6 |date=June 2008 |pmid=18494460 |doi=10.1021/jm800379d |issn=0022-2623}}</ref> Another team in 2008 determined the structure of linezolid bound to a 50S subunit of ''[[Deinococcus radiodurans]]''. The authors proposed a refined model for the mechanism of action of oxazolidinones, finding that linezolid occupies the [[MRNA-ribosome|A site]] of the 50S ribosomal subunit, inducing a [[conformational change]] that prevents tRNA from entering the site and ultimately forcing tRNA to separate from the ribosome.<ref>{{cite journal |vauthors=Wilson DN, Schluenzen F, Harms JM, Starosta AL, Connell SR, Fucini P |title=The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning |journal=[[Proceedings of the National Academy of Sciences]] |volume=105 |issue=36 |pages=13339–44 |date=September 2008 |pmid=18757750 |pmc=2533191 |doi=10.1073/pnas.0804276105 |issn=0027-8424 |url=http://www.pnas.org/content/105/36/13339.full.pdf |deadurl=no |archiveurl=https://web.archive.org/web/20170910172617/http://www.pnas.org/content/105/36/13339.full.pdf |archivedate=2017-09-10 |df= }}</ref>
==คุณสมบัติทางเคมี==
At [[pH#Living systems|physiological pH]], linezolid exists in an uncharged state. It is moderately water-soluble (approximately 3&nbsp;mg/mL), with a [[partition coefficient|log''P'']] of 0.55.<ref name=Herrmann/>
 
[[File:Linezolid showing oxazolidinone pharmacophore.svg|thumb|left|Numbered structure of linezolid, showing the [[pharmacophore]] required for good activity (in blue) and desirable structural features (in orange).|alt=Skeletal formula of N-<nowiki/>{[(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide, highlighting the morpholino and fluoro groups in orange, with the rest in blue. The carbon atoms of the parent chain are numbered.]]
The oxazolidinone [[pharmacophore]]—the chemical "template" essential for antimicrobial [[biological activity|activity]]—consists of a [[2-Oxazolidone|1,3-oxazolidin-2-one]] [[functional group|moiety]] with an [[aryl]] group at position 3 and an ''S''-[[methyl group]], with another [[substituent]] attached to it, at position 5 (the ''R''-[[enantiomer]]s of all oxazolidinones are devoid of antibiotic properties).<ref name=Brickner/> In addition to this essential core, linezolid also contains several structural characteristics that improve its effectiveness and safety. An [[acetamide]] substituent on the 5-methyl group is the best choice in terms of antibacterial efficacy, and is used in all of the more active oxazolidinones developed thus far; in fact, straying too far from an acetamide group at this position makes the drug lose its antimicrobial power, although weak to moderate activity is maintained when some [[bioisostere|isosteric]] groups are used. A [[fluorine]] atom at the 3′ position practically doubles ''in vitro'' and ''in vivo'' activity, and the [[electron donor|electron-donating]] [[nitrogen]] atom in the [[morpholine]] ring helps maintain high antibiotic potency and an acceptable safety profile.<ref name=Barbachyn/><ref name=Brickner/>
 
The [[anticoagulant]] [[rivaroxaban]] (Xarelto) bears a striking structural similarity to linezolid; both drugs share the oxazolidinone pharmacophore, differing in only three areas (an extra [[ketone]] and chloro[[thiophene]], and missing the fluorine atom). However this similarity appears to carry no clinical significance.<ref>{{cite web |url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000944/WC500120736.pdf |title=CHP Assessment Report for Xarelto (EMA/CHMP/301607/2011) |author=European Medicines Agency |year=2011 |accessdate=2012-03-15 |deadurl=no |archiveurl=https://web.archive.org/web/20120130062132/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000944/WC500120736.pdf |archivedate=2012-01-30 |df= }}</ref>
 
===การสังเคราะห์===
Linezolid is a completely [[organic synthesis|synthetic]] drug: it does not occur in nature (unlike erythromycin and many other antibiotics) and was not developed by building upon a naturally occurring skeleton (unlike most [[beta-lactam antibiotic|beta-lactam]]s, which are [[semisynthesis|semisynthetic]]). Many approaches are available for oxazolidinone synthesis, and several routes for the synthesis of linezolid have been reported in the chemistry literature.<ref name=Brickner/><ref name=Xu>{{cite journal|vauthors=Xu GY, Zhou Y, Xu MC |title=A convenient synthesis of antibacterial linezolid from (''S'')-glyceraldehyde acetonide |journal=Chinese Chemical Letters |volume=17 |issue=3 |pages=302–4 |year=2006 |url=http://www.imm.ac.cn/journal/ccl/1703/170306-302-b050449-p3.pdf |deadurl=yes |archiveurl=https://web.archive.org/web/20110707013015/http://www.imm.ac.cn/journal/ccl/1703/170306-302-b050449-p3.pdf |archivedate=2011-07-07 |df= }}</ref> Despite good [[yield (chemistry)|yields]], the original method (developed by Upjohn for [[pilot plant]]-scale production of linezolid and eperezolid) is lengthy, requires the use of expensive chemicals—such as [[palladium on carbon]] and the highly sensitive reagents [[methanesulfonyl chloride]] and [[n-Butyllithium|''n''-butyllithium]]—and needs low-temperature conditions.<ref name=Brickner/><ref name=Xu/><ref name=Kaiser>{{cite journal |vauthors=Kaiser CR, Cunico W, Pinheiro AC, de Oliveira AG, Peralta MA, de Souza MV |title=Oxazolidinonas: uma nova classe de compostos no combate à tuberculose |trans-title=Oxazolidinones: a new class of compounds against tuberculosis |language=Portuguese |journal=Revista Brasileira de Farmácia |volume=88 |issue=2 |pages=83–8 |year=2007 |url=http://www.rbfarma.org.br/images/edicoes-em-pdf/2007/RBF_V88_N2_2007/PAG83a88_OXAZOLIDINONAS.pdf |format=pdf |deadurl=yes |archiveurl=https://www.webcitation.org/67ft9fcH1?url=http://www.rbfarma.org.br/images/edicoes-em-pdf/2007/RBF_V88_N2_2007/PAG83a88_OXAZOLIDINONAS.pdf |archivedate=2012-05-15 |df= }}</ref> Much of the high cost of linezolid has been attributed to the expense of its synthesis.<ref name=Kaiser/> A somewhat more concise and cost-effective route better suited to large-scale production was patented by Upjohn in 1998.<ref name=Barbachyn/><ref>{{US patent reference | number = 5837870 | y = 1997 | m = 03 | d = 28 | inventor = Pearlman BA, Perrault WR, Barbachyn MR, ''et al.'' | title = Process to prepare oxazolidinones}} Retrieved on 2009-06-13.</ref>
 
Later syntheses have included an "[[atom economy|atom-economical]]" method starting from [[D-Mannitol|<small>D</small>-mannitol]], developed by Indian pharmaceutical company [[Dr. Reddy's Laboratories|Dr. Reddy's]] and reported in 1999,<ref>{{cite journal |vauthors=Lohray BB, Baskaran S, Rao BS, Reddy BY, Rao IN |title=A short synthesis of oxazolidinone derivatives linezolid and eperezolid: A new class of antibacterials |journal=[[Tetrahedron Letters]] |volume=40 |issue=26 |pages=4855–6 |date=June 1999 |doi=10.1016/S0040-4039(99)00893-X}}</ref> and a route starting from (''S'')-glyceraldehyde acetonide (prepared from [[vitamin C]]), developed by a team of researchers from [[Hunan Normal University]] in [[Changsha]], [[Hunan]], China.<ref name=Xu/> On June 25, 2008, during the 12th Annual Green Chemistry and Engineering Conference in New York, Pfizer reported the development of their "second-generation" synthesis of linezolid: a [[convergent synthesis|convergent]], [[green chemistry|green]] synthesis starting from (''S'')-[[epichlorohydrin]], with higher yield and a 56% reduction in total waste.<ref>Perrault WR, Keeler JB, Snyder WC, ''et al.'' (June 25, 2008). [http://acs.confex.com/acs/green08/techprogram/P52019.HTM "Convergent green synthesis of linezolid (Zyvox)"] {{webarchive|url=https://web.archive.org/web/20110728022612/http://acs.confex.com/acs/green08/techprogram/P52019.HTM |date=2011-07-28 }}, in ''12th Annual Green Chemistry and Engineering Conference'', June 24–26, 2008, New York, NY. Retrieved on 2009-06-08.</ref>
 
==อ้างอิง==
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