Zolmitriptan: Difference between revisions
Jump to navigation
Jump to search
imported>AlyInWikiWonderland Ref, values. |
imported>AlyInWikiWonderland →Chemistry: Fix. |
||
| Line 1: | Line 1: | ||
{{Short description|Medication used in treatment of migraines}} | {{Short description|Medication used in treatment of migraines}} | ||
{{cs1 config|name-list-style=vanc}} | {{cs1 config|name-list-style=vanc|display-authors=6}} | ||
{{Drugbox | {{Drugbox | ||
| Watchedfields = verified | | Watchedfields = verified | ||
| Line 38: | Line 38: | ||
| ATC_suffix = CC03 | | ATC_suffix = CC03 | ||
| ATC_supplemental = | | ATC_supplemental = | ||
| ATCvet = QN02CC03 | |||
| PubChem = 60857 | | PubChem = 60857 | ||
| IUPHAR_ligand = 60 | | IUPHAR_ligand = 60 | ||
| Line 98: | Line 99: | ||
==Interactions== | ==Interactions== | ||
Following administration of the [[binding selectivity|non-selective]] [[cytochrome P450]] [[enzyme inhibitor|inhibitor]] [[cimetidine]], the [[elimination half-life]] and [[area-under-the-curve (pharmacokinetics)|total exposure]] of zolmitriptan and its [[active metabolite]] were approximately doubled.<ref name="statspe" /> The major [[metabolite]] of zolmitriptan, ''N''-desmethylzolmitriptan, which is active and has several-fold greater [[affinity (pharmacology)|affinity]] for the [[serotonin]] [[5-HT1B receptor|5-HT<sub>1B</sub>]] and [[5-HT1D receptor|5-HT<sub>1D</sub> receptor]]s than zolmitriptan, is [[drug metabolism|metabolized]] into an inactive form by [[monoamine oxidase A]] (MAO-A).<ref name="Yu2008" /> The [[reversible inhibitor of MAO-A]] (RIMA) [[moclobemide]] combined with zolmitriptan has been found to increase ''N''-desmethylzolmitriptan exposure and peak levels by 1.5- to 3-fold.<ref name="Yu2008" /> | Following administration of the [[binding selectivity|non-selective]] [[cytochrome P450]] [[enzyme inhibitor|inhibitor]] [[cimetidine]], the [[elimination half-life]] and [[area-under-the-curve (pharmacokinetics)|total exposure]] of zolmitriptan and its [[active metabolite]] were approximately doubled.<ref name="statspe" /> The major [[metabolite]] of zolmitriptan, ''N''-desmethylzolmitriptan (183C91), which is active and has several-fold greater [[affinity (pharmacology)|affinity]] for the [[serotonin]] [[5-HT1B receptor|5-HT<sub>1B</sub>]] and [[5-HT1D receptor|5-HT<sub>1D</sub> receptor]]s than zolmitriptan, is [[drug metabolism|metabolized]] into an inactive form by [[monoamine oxidase A]] (MAO-A).<ref name="Yu2008" /> The [[reversible inhibitor of MAO-A]] (RIMA) [[moclobemide]] combined with zolmitriptan has been found to increase ''N''-desmethylzolmitriptan exposure and peak levels by 1.5- to 3-fold.<ref name="Yu2008" /> | ||
==Pharmacology== | ==Pharmacology== | ||
| Line 109: | Line 110: | ||
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 16.2–316 (K<sub>i</sub>)<br />3,020–>10,000 ({{Abbrlink|EC<sub>50</sub>|half-maximal effective concentration}}) | | [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 16.2–316 (K<sub>i</sub>)<br />3,020–>10,000 ({{Abbrlink|EC<sub>50</sub>|half-maximal effective concentration}}) | ||
|- | |- | ||
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 0.468–20.4 (K<sub>i</sub>)<br />3. | | [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 0.468–20.4 (K<sub>i</sub>)<br />3.80–60.2 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />99.3% ({{Abbrlink|E<sub>max</sub>|maximal efficacy}}) | ||
|- | |- | ||
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 0.107–4 (K<sub>i</sub>)<br />0.309–1.26 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) | | [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 0.107–4 (K<sub>i</sub>)<br />0.309–1.26 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) | ||
| Line 161: | Line 162: | ||
| {{Abbrlink|DAT|Dopamine transporter}} || {{Abbr|ND|No data}} | | {{Abbrlink|DAT|Dopamine transporter}} || {{Abbr|ND|No data}} | ||
|- class="sortbottom" | |- class="sortbottom" | ||
| colspan="2" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. '''Refs:''' <ref name="BindingDB">{{cite web | | | colspan="2" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. '''Refs:''' <ref name="BindingDB">{{cite web | vauthors = Liu T | title=BindingDB BDBM50033383 (S)-4-((3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)methyl)oxazolidin-2-one::(S)-4-[3-(2-Dimethylamino-ethyl)-1H-indol-5-ylmethyl]-oxazolidin-2-one::311C90::CHEMBL1185::ZOLMITRIPTAN::ZOMIG::ZOMIG-ZMT | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50033383 | access-date=19 June 2025}}</ref><ref name="DeVriesVillalónSaxena1999">{{cite journal | vauthors = De Vries P, Villalón CM, Saxena PR | title=Pharmacology of triptans | journal=Emerging Drugs | volume=4 | issue=1 | date=1999 | issn=1361-9195 | doi=10.1517/14728214.4.1.107 | pages=107–125 }}</ref><ref name="Tfelt-HansenDeVriesSaxena2000">{{cite journal | vauthors = Tfelt-Hansen P, De Vries P, Saxena PR | title = Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy | journal = Drugs | volume = 60 | issue = 6 | pages = 1259–1287 | date = December 2000 | pmid = 11152011 | doi = 10.2165/00003495-200060060-00003 }}</ref><ref name="SaxenaTfelt-Hansen2001">{{cite journal | vauthors = Saxena PR, Tfelt-Hansen P | title=Success and failure of triptans | journal=The Journal of Headache and Pain | volume=2 | issue=1 | date=2001 | issn=1129-2369 | pmc=3611827 | doi=10.1007/s101940170040 | doi-access=free | pages=3–11 }}</ref><ref name="Brink1999">{{cite web | vauthors = van den Brink M | title=Coronary Side Effects of Antimigraine Drugs From Patient to Receptor | website= RePub, Erasmus University Repository | date=22 December 1999 | url=https://repub.eur.nl/pub/16171/ | access-date=19 June 2025 | quote = Table 1.2 Receptor binding properties (pKi values) of sumatriptan and second-generation triptans at 5-HT receptors. [...]}}</ref><ref name="Broek2002">{{cite web | vauthors = van den Broek RW | title=Vascular Effects of Antimigraine Drugs: pharmacology of human in vitro models in migraine | website= RePub, Erasmus University Repository | date=13 March 2002 | url=https://repub.eur.nl/pub/16167/ | access-date=19 June 2025 | quote=Table 1.2 Receptor binding properties (pKi values) of the triptans at human 5-HT receptors. [...]}}</ref><ref name="MartinRobertsonMacLennan1997">{{cite journal | vauthors = Martin GR, Robertson AD, MacLennan SJ, Prentice DJ, Barrett VJ, Buckingham J, Honey AC, Giles H, Moncada S | title = Receptor specificity and trigemino-vascular inhibitory actions of a novel 5-HT1B/1D receptor partial agonist, 311C90 (zolmitriptan) | journal = British Journal of Pharmacology | volume = 121 | issue = 2 | pages = 157–164 | date = May 1997 | pmid = 9154322 | pmc = 1564661 | doi = 10.1038/sj.bjp.0701041 }}</ref><br /><ref name="GlenMartinHill1995">{{cite journal | vauthors = Glen RC, Martin GR, Hill AP, Hyde RM, Woollard PM, Salmon JA, Buckingham J, Robertson AD | title = Computer-aided design and synthesis of 5-substituted tryptamines and their pharmacology at the 5-HT1D receptor: discovery of compounds with potential anti-migraine properties | journal = Journal of Medicinal Chemistry | volume = 38 | issue = 18 | pages = 3566–3580 | date = September 1995 | pmid = 7658443 | doi = 10.1021/jm00018a016 }}</ref><ref name="PerezFourrierSigogneau1995">{{cite journal | vauthors = Perez M, Fourrier C, Sigogneau I, Pauwels PJ, Palmier C, John GW, Valentin JP, Halazy S | title = Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors | journal = Journal of Medicinal Chemistry | volume = 38 | issue = 18 | pages = 3602–3607 | date = September 1995 | pmid = 7658447 | doi = 10.1021/jm00018a020 }}</ref><ref name="PerezPauwelsFourrier1998">{{cite journal | vauthors = Perez M, Pauwels PJ, Fourrier C, Chopin P, Valentin JP, John GW, Marien M, Halazy S | title = Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist | journal = Bioorganic & Medicinal Chemistry Letters | volume = 8 | issue = 6 | pages = 675–680 | date = March 1998 | pmid = 9871581 | doi = 10.1016/s0960-894x(98)00090-0 }}</ref><ref name="Rubio-BeltránLabastida-RamírezHaanes2019">{{cite journal | vauthors = Rubio-Beltrán E, Labastida-Ramírez A, Haanes KA, van den Bogaerdt A, Bogers AJ, Zanelli E, Meeus L, Danser AH, Gralinski MR, Senese PB, Johnson KW, Kovalchin J, Villalón CM, MaassenVanDenBrink A | title = Characterization of binding, functional activity, and contractile responses of the selective 5-HT<sub>1F</sub> receptor agonist lasmiditan | journal = British Journal of Pharmacology | volume = 176 | issue = 24 | pages = 4681–4695 | date = December 2019 | pmid = 31418454 | pmc = 6965684 | doi = 10.1111/bph.14832 | quote = TABLE 1 Summary of pIC50 (negative logarithm of the molar concentration of these compounds at which 50% of the radioligand is displaced) and pKi (negative logarithm of the molar concentration of the Ki ) values of individual antimigraine drugs at 5‐HT receptors [...] TABLE 2 Summary of pEC50 values of cAMP (5‐HT1A/B/E/F and 5‐HT7), GTPγS (5‐HT1A/B/D/E/F), and IP (5‐HT2) assays of individual antimigraine drugs at 5‐HT receptors [...] }}</ref><ref name="PerezHalazyPauwels1999">{{cite journal | author=Perez, M. | author2=Halazy, S. | author3=Pauwels, P.J. | author4=Colpaert, F.C. | author5=John, G.W. | title=F-11356 | journal=Drugs of the Future | volume=24 | issue=6 | date=1999 | doi=10.1358/dof.1999.024.06.537284 | page=0605 | url=http://access.portico.org/stable?au=pjbf78x6c9d | access-date=23 June 2025}}</ref><ref name="ReuterNeeb2012">{{cite journal | vauthors = Reuter U, Neeb L | title=Lasmiditan hydrochloride | journal=Drugs of the Future | volume=37 | issue=10 | date=2012 | issn=0377-8282 | doi=10.1358/dof.2012.037.010.1873629 | page=709 | url=http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1873629&p_IsPs=N | access-date=19 June 2025}}</ref><ref name="MitsikostasWard2024">{{cite journal | vauthors = Mitsikostas DD, Ward TN | title = Evidence-based symptomatic treatment of migraine | journal = Handbook of Clinical Neurology | volume = 199 | issue = | pages = 203–218 | date = 2024 | pmid = 38307647 | doi = 10.1016/B978-0-12-823357-3.00004-5 }}</ref><ref name="Comer2002">{{cite journal | vauthors = Comer MB | title = Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan | journal = Headache | volume = 42 | issue = Suppl 2 | pages = S47-S53 | date = April 2002 | pmid = 12028320 | doi = 10.1046/j.1526-4610.42.s2.2.x }}</ref> | ||
|} | |} | ||
Zolmitriptan is a [[binding selectivity|selective]] [[serotonin]] [[5-HT1B receptor|5-HT<sub>1B</sub>]] and [[5-HT1D receptor|5-HT<sub>1D</sub> receptor]] [[agonist]] with weak [[affinity (pharmacology)|affinity]] for the serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]].<ref name="Tfelt-HansenDeVriesSaxena2000" /> It also has affinity for other [[serotonin receptor]]s, including the serotonin [[5-HT1E receptor|5-HT<sub>1E</sub>]], [[5-HT1F receptor|5-HT<sub>1F</sub>]], [[5-HT2B receptor|5-HT<sub>2B</sub>]], [[5-HT5A receptor|5-HT<sub>5A</sub>]], and [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]s.<ref name="Tfelt-HansenDeVriesSaxena2000" /> Conversely, its affinities for the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT3 receptor|5-HT<sub>3</sub>]], [[5-HT4 receptor|5-HT<sub>4</sub>]], and [[5-HT6 receptor|5-HT<sub>6</sub> receptor]]s are negligible or undetectable.<ref name="Tfelt-HansenDeVriesSaxena2000" /> | Zolmitriptan is a [[binding selectivity|selective]] [[serotonin]] [[5-HT1B receptor|5-HT<sub>1B</sub>]] and [[5-HT1D receptor|5-HT<sub>1D</sub> receptor]] [[agonist]] with weak [[affinity (pharmacology)|affinity]] for the serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]].<ref name="Tfelt-HansenDeVriesSaxena2000" /> It also has affinity for other [[serotonin receptor]]s, including the serotonin [[5-HT1E receptor|5-HT<sub>1E</sub>]], [[5-HT1F receptor|5-HT<sub>1F</sub>]], [[5-HT2B receptor|5-HT<sub>2B</sub>]], [[5-HT5A receptor|5-HT<sub>5A</sub>]], and [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]s.<ref name="Tfelt-HansenDeVriesSaxena2000" /> Conversely, its affinities for the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT3 receptor|5-HT<sub>3</sub>]], [[5-HT4 receptor|5-HT<sub>4</sub>]], and [[5-HT6 receptor|5-HT<sub>6</sub> receptor]]s are negligible or undetectable.<ref name="Tfelt-HansenDeVriesSaxena2000" /><ref name="Rubio-BeltránLabastida-RamírezHaanes2019" /> It is likewise inactive as a serotonin 5-HT<sub>2A</sub> receptor agonist.<ref name="Rubio-BeltránLabastida-RamírezHaanes2019" /> | ||
Zolmitriptan's major [[metabolite]], ''N''- | Zolmitriptan's major [[metabolite]], ''N''-desmethylzolmitriptan (183C91), is also active and has about 2- to 6-fold the affinity of zolmitriptan for the serotonin 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors.<ref name="Yu2008">{{cite journal | vauthors = Yu AM | title = Indolealkylamines: biotransformations and potential drug-drug interactions | journal = AAPS J | volume = 10 | issue = 2 | pages = 242–253 | date = June 2008 | pmid = 18454322 | pmc = 2751378 | doi = 10.1208/s12248-008-9028-5 | url = | quote = [...] the N-demethylated metabolites from zolmitriptan and eletriptan are both active at the 5-HT1B/1D sites. In particular, the N-desmethyl-zolmitriptan acts on 5-HT1B/1D receptors with an affinity about two- to six-fold of that of zolmitriptan and its steady state concentration is also higher than the parent drug. Therefore, N-desmethyl-zolmitriptan may have important contribution to the overall zolmitriptan drug effects. This active metabolite undergoes selective MAO-A-mediated deamination metabolism, resulting in an inactive indole acetic acid derivative (21) (Fig. 3). Because zolmitriptan is extensively N-demethylated and N-desmethyl-zolmitriptan is primarily excreted via deamination, potent MAO-A inhibitors are anticipated to alter the pharmacokinetics of N-desmethyl-zolmitriptan in humans. Indeed, concurrent use of selective MAO-A inhibitor, moclobemide, has been shown to cause 1.5- to 3-fold increase in the systemic exposure (AUC) and peak drug concentration (Cmax) of N-desmethyl-zolmitriptan (25).}}</ref> | ||
Its action on serotonin 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors causes [[vasoconstriction]] in [[intracranial]] [[blood vessel]]s; as well it can inhibit the release of [[pro-inflammatory]] [[neuropeptide]]s from [[trigeminal]] [[perivascular]] [[nerve ending]]s. It crosses the [[blood–brain barrier]] as evidenced by the presence of [[radiolabel]]ed zolmitriptan within the cells of the trigeminal nucleus caudalis and nucleus tractus solitarii.<ref name=statspe/> | Its action on serotonin 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors causes [[vasoconstriction]] in [[intracranial]] [[blood vessel]]s; as well it can inhibit the release of [[pro-inflammatory]] [[neuropeptide]]s from [[trigeminal]] [[perivascular]] [[nerve ending]]s. It crosses the [[blood–brain barrier]] as evidenced by the presence of [[radiolabel]]ed zolmitriptan within the cells of the trigeminal nucleus caudalis and nucleus tractus solitarii.<ref name=statspe/> | ||
| Line 172: | Line 173: | ||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
====Absorption==== | ====Absorption==== | ||
Zolmitriptan has a rapid [[onset of action]] and has been detected in the brain as early as within 5{{nbsp}}minutes of [[intranasal administration]]. On average, zolmitriptan has an [[oral administration|oral]] [[bioavailability]] of 40%, a mean [[volume of distribution]] of 8.3{{Nbsp}}L/kg after oral administration, and 2.4{{nbsp}}L/kg after intravenous administration.<ref name=statspe/> According to a study of healthy volunteers, food intake seems to have no significant effect on the effectiveness of zolmitriptan in both men and women.<ref>{{cite journal | vauthors = Seaber EJ, Peck RW, Smith DA, Allanson J, Hefting NR, van Lier JJ, Sollie FA, Wemer J, Jonkman JH | Zolmitriptan has a rapid [[onset of action]] and has been detected in the brain as early as within 5{{nbsp}}minutes of [[intranasal administration]]. On average, zolmitriptan has an [[oral administration|oral]] [[bioavailability]] of 40%, a mean [[volume of distribution]] of 8.3{{Nbsp}}L/kg after oral administration, and 2.4{{nbsp}}L/kg after intravenous administration.<ref name=statspe/> According to a study of healthy volunteers, food intake seems to have no significant effect on the effectiveness of zolmitriptan in both men and women.<ref>{{cite journal | vauthors = Seaber EJ, Peck RW, Smith DA, Allanson J, Hefting NR, van Lier JJ, Sollie FA, Wemer J, Jonkman JH | title = The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 5 | pages = 433–439 | date = November 1998 | pmid = 9833595 | pmc = 1873688 | doi = 10.1046/j.1365-2125.1998.00809.x | type = abstract }}</ref> | ||
====Distribution==== | ====Distribution==== | ||
Zolmitriptan is a more [[lipophilic]] [[chemical compound|compound]] with greater [[central nervous system|central]] [[drug permeability|permeability]] than certain other [[triptan]]s like [[sumatriptan]].<ref name="Martin1997">{{cite journal | vauthors = Martin GR | title = Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine | journal = Cephalalgia | volume = 17 | Zolmitriptan is a more [[lipophilic]] [[chemical compound|compound]] with greater [[central nervous system|central]] [[drug permeability|permeability]] than certain other [[triptan]]s like [[sumatriptan]].<ref name="Martin1997">{{cite journal | vauthors = Martin GR | title = Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine | journal = Cephalalgia | volume = 17 | issue = Suppl 18 | pages = 4–14 | date = October 1997 | pmid = 9399012 | doi = 10.1177/0333102497017S1802 | url = }}</ref><ref name="LionettoCasollaMastropietri2012">{{cite journal | vauthors = Lionetto L, Casolla B, Mastropietri F, D'Alonzo L, Negro A, Simmaco M, Martelletti P | title = Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines | journal = Expert Opin Drug Metab Toxicol | volume = 8 | issue = 8 | pages = 1043–1050 | date = August 2012 | pmid = 22762358 | doi = 10.1517/17425255.2012.701618 | url = }}</ref> It has been found to cross the [[blood–brain barrier]] and enter the [[central nervous system]] both in animals and humans.<ref name="DeenChristensenHougaard2017">{{cite journal | vauthors = Deen M, Christensen CE, Hougaard A, Hansen HD, Knudsen GM, Ashina M | title = Serotonergic mechanisms in the migraine brain - a systematic review | journal = Cephalalgia | volume = 37 | issue = 3 | pages = 251–264 | date = March 2017 | pmid = 27013238 | doi = 10.1177/0333102416640501 | url = | quote = The central mechanisms of triptans are a subject of intense debate and have been investigated in several studies. Brain PET studies reported that zolmitriptan crosses the BBB and binds to central 5-HT1B receptors with relatively low occupancy (77,78). It is still unknown whether sumatriptan has a central effect.}}</ref> In a clinical [[pharmacokinetic]] study, brain concentrations were about 20% of plasma concentrations.<ref name="WallKågedalBergström2005" /> However, in another clinical study, the drug achieved relatively low [[receptor occupancy|occupancy]] of central [[serotonin]] [[5-HT1B receptor|5-HT<sub>1B</sub> receptor]]s (4–5%) as measured by [[positron emission tomography]] (PET) [[medical imaging|imaging]].<ref name="DeenChristensenHougaard2017" /><ref name="VarnäsJučaiteMcCarthy2013">{{cite journal | vauthors = Varnäs K, Jučaite A, McCarthy DJ, Stenkrona P, Nord M, Halldin C, Farde L, Kanes S | title = A PET study with [11C]AZ10419369 to determine brain 5-HT1B receptor occupancy of zolmitriptan in healthy male volunteers | journal = Cephalalgia | volume = 33 | issue = 10 | pages = 853–860 | date = July 2013 | pmid = 23430984 | doi = 10.1177/0333102413476372 | url = }}</ref><ref name="WallKågedalBergström2005">{{cite journal | vauthors = Wall A, Kågedal M, Bergström M, Jacobsson E, Nilsson D, Antoni G, Frändberg P, Gustavsson SA, Långström B, Yates R | title = Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study | journal = Drugs in R&D | volume = 6 | issue = 3 | pages = 139–147 | date = 2005 | pmid = 15869317 | doi = 10.2165/00126839-200506030-00002 | url = }}</ref> | ||
====Metabolism==== | ====Metabolism==== | ||
| Line 186: | Line 187: | ||
Zolmitriptan is a [[triptan]] and a [[substituted tryptamine]].<ref name="Zolmig-Label" /><ref name="PubChem" /> It is specifically the [[chemical derivative|derivative]] of [[dimethyltryptamine|''N'',''N''-dimethyltryptamine]] (DMT) in which the [[hydrogen]] [[atom]] at position 5 of the [[indole]] [[ring (chemistry)|ring]] has been [[chemical substituent|substituted]] with a [(4''S'')-2-oxo-1,3-oxazolidin-4-yl]methyl [[functional group|group]].<ref name="PubChem" /> | Zolmitriptan is a [[triptan]] and a [[substituted tryptamine]].<ref name="Zolmig-Label" /><ref name="PubChem" /> It is specifically the [[chemical derivative|derivative]] of [[dimethyltryptamine|''N'',''N''-dimethyltryptamine]] (DMT) in which the [[hydrogen]] [[atom]] at position 5 of the [[indole]] [[ring (chemistry)|ring]] has been [[chemical substituent|substituted]] with a [(4''S'')-2-oxo-1,3-oxazolidin-4-yl]methyl [[functional group|group]].<ref name="PubChem" /> | ||
The experimental [[partition coefficient|log P]] of zolmitriptan is 1.6 to 1.8.<ref name="PubChem" /> For comparison, the experimental log P of [[sumatriptan]] is 0.93.<ref name="PubChem-Sumatriptan">{{cite web | title=Sumatriptan | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/5358 | access-date=27 October 2024}}</ref> | The experimental [[partition coefficient|log P]] of zolmitriptan is 1.6 to 1.8.<ref name="PubChem" /><ref name="TekesSzegiHashemi2013">{{cite journal | vauthors = Tekes K, Szegi P, Hashemi F, Laufer R, Kalász H, Siddiq A, Ertsey C | title = Medicinal chemistry of antimigraine drugs | journal = Curr Med Chem | volume = 20 | issue = 26 | pages = 3300–3316 | date = 2013 | pmid = 23746273 | doi = 10.2174/0929867311320260012 | url = }}</ref> For comparison, the experimental log P of [[sumatriptan]] is 0.8 to 0.93.<ref name="PubChem-Sumatriptan">{{cite web | title=Sumatriptan | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/5358 | access-date=27 October 2024}}</ref><ref name="TekesSzegiHashemi2013" /> Zolmitriptan is much more [[lipophilic]] than sumatriptan.<ref name="Tfelt-HansenDeVriesSaxena2000" /><ref name="TekesSzegiHashemi2013" /> | ||
[[Structural analog|Analogue]]s of zolmitriptan include other triptans like sumatriptan, [[naratriptan]], [[rizatriptan]], [[eletriptan]], [[almotriptan]], and [[frovatriptan]].<ref name="Tfelt-HansenDeVriesSaxena2000" /> | [[Structural analog|Analogue]]s of zolmitriptan include other triptans like sumatriptan, [[naratriptan]], [[rizatriptan]], [[eletriptan]], [[almotriptan]], and [[frovatriptan]].<ref name="Tfelt-HansenDeVriesSaxena2000" /><ref name="TekesSzegiHashemi2013" /> | ||
==History== | |||
Zolmitriptan was [[patent]]ed in 1990<ref name="Fis2006" /> and was first described in the [[scientific literature]] by 1994.<ref name="GoadsbyEdvinsson1994">{{cite journal | vauthors = Goadsby PJ, Edvinsson L | title = Joint 1994 Wolff Award Presentation. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90 | journal = Headache | volume = 34 | issue = 7 | pages = 394–399 | date = 1994 | pmid = 7928323 | doi = 10.1111/j.1526-4610.1994.hed3407394.x }}</ref><ref name="Martin1994">{{cite journal | vauthors = Martin GR | date = 1994 | title = Pre-clinical profile of the novel 5-HT 1D receptor agonist 311C90. | journal = New Advances in Headache Research | volume = 4 | pages = 3–4 }}</ref><ref name="PeckDixonSeaber1994">{{cite journal | vauthors = Peck R, Dixon R, Seaber E, On N, Mercer J, Posner J, Roland PE | title = Clinical pharmacology of 311C90.| journal = New Advances in Headache Research | date = 1994 | volume = 4 | pages = 9–10 }}</ref> It was first introduced for medical use in the [[United States]] in 1997.<ref name="Fis2006" /><ref name="Zolmig-Label" /><ref name="AdisInsight">{{cite web | title=AstraZeneca/Burroughs Wellcome | website=AdisInsight | date=5 November 2023 | url=https://adisinsight.springer.com/drugs/800002911 | access-date=20 June 2025}}</ref> | |||
==Society and culture== | ==Society and culture== | ||
| Line 209: | Line 213: | ||
{{See also|Serenic#Examples|Empathogen#Mechanism of action|List of investigational aggression drugs}} | {{See also|Serenic#Examples|Empathogen#Mechanism of action|List of investigational aggression drugs}} | ||
Zolmitriptan, in a [[modified-release dosage|modified-release]] [[drug formulation|formulation]] with code name ''ML-004'' (or ''ML004''), is under development by MapLight Therapeutics for the treatment of [[pervasive developmental disorder]]s (e.g., [[autism]]), [[psychomotor agitation|agitation]], and [[aggression]].<ref name="AdisInsight-ML-004">{{cite web | title=ML 004 | website=AdisInsight | date=8 June 2023 | url=https://adisinsight.springer.com/drugs/800061291 | access-date=27 October 2024}}</ref><ref name="Synapse2024">{{cite web | title=Delving into the Latest Updates on ML-004 with Synapse | website=Synapse | date=28 September 2024 | url=https://synapse.patsnap.com/drug/64e037a51d55415f8f4919a04aef3082 | access-date=27 October 2024}}</ref><ref name="TheTransmitter2023">{{cite web | | Zolmitriptan, in a [[modified-release dosage|modified-release]] [[drug formulation|formulation]] with code name ''ML-004'' (or ''ML004''), is under development by MapLight Therapeutics for the treatment of [[pervasive developmental disorder]]s (e.g., [[autism]]), [[psychomotor agitation|agitation]], and [[aggression]].<ref name="AdisInsight-ML-004">{{cite web | title=ML 004 | website=AdisInsight | date=8 June 2023 | url=https://adisinsight.springer.com/drugs/800061291 | access-date=27 October 2024}}</ref><ref name="Synapse2024">{{cite web | title=Delving into the Latest Updates on ML-004 with Synapse | website=Synapse | date=28 September 2024 | url=https://synapse.patsnap.com/drug/64e037a51d55415f8f4919a04aef3082 | access-date=27 October 2024}}</ref><ref name="TheTransmitter2023">{{cite web | vauthors = Hess P | title=Going on Trial: Serotonin drug; psilocybin phase 2; placebo response data | website=The Transmitter: Neuroscience News and Perspectives | date=28 April 2023 | url=https://www.thetransmitter.org/spectrum/going-on-trial-serotonin-drug-psilocybin-phase-2-placebo-response-data/ | access-date=27 October 2024}}</ref><ref name="WangClarkHanratty2024">{{cite journal | vauthors = Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, Bristow LJ | title = TAAR1 and 5-HT1B receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid | journal = Pharmacol Biochem Behav | volume = 245 | issue = | pages = 173862 | date = August 2024 | pmid = 39197535 | doi = 10.1016/j.pbb.2024.173862 | url = | quote = Interest in 5-HT1B as a target for ASD is further evidenced by the ongoing Phase 2 clinical trial of ML-004, a modified release form of the 5-HT1B/1D agonist zolmitriptan, which is being evaluated for the treatment of social communication deficits in adolescent and adult subjects with ASD (NCT05081245).}}</ref><ref name="Cortica">{{cite web | title=Maplight Autism Study | website=Cortica | url=https://www.corticacare.com/research/maplight | access-date=27 October 2024 | quote=Purpose: The purpose of this study is to find out whether ML-004, an extended-release version of zolmitriptan, can support with sociability and emotional regulation in adults with ASD.}}</ref><ref name="PharmTech2024">{{cite web | url=https://www.pharmaceutical-technology.com/data-insights/zolmitriptan-maplight-therapeutics-autism-spectrum-disorder-asd-likelihood-of-approval/ | archive-url=https://web.archive.org/web/20240522133617/https://www.pharmaceutical-technology.com/data-insights/zolmitriptan-maplight-therapeutics-autism-spectrum-disorder-asd-likelihood-of-approval/ | archive-date=22 May 2024 | title=Zolmitriptan by MapLight therapeutics for Autism Spectrum Disorder (ASD): Likelihood of Approval }}</ref> The drug has been found to reduce aggression in rodents<ref name="Rasia-FilhoGiovenardide Almeida2008">{{cite journal | vauthors = Rasia-Filho AA, Giovenardi M, de Almeida RM | title = Drugs and aggression | journal = Recent Pat CNS Drug Discov | volume = 3 | issue = 1 | pages = 40–49 | date = January 2008 | pmid = 18221240 | doi = 10.2174/157488908783421456 | url = | quote = In addition, the 5-HT1B receptors are of potential importance as target for treatment of different disorders such as depression, schizophrenia, Parkinson’s disease, and impulsive disorders [133]. Drugs acting as agonists at 5- HT1B receptors, when administered systemically, potently and efficaciously inhibit several types of aggressive behavior in mice [17,135; and for review see 63]. Systemically administered 5-HT1B receptor agonists such as CP-94,253, ampirtoline and zolmitriptan exert anti-aggressive effects in mice with moderate or high levels of aggression, without impairing non-aggressive activities [17, 23, 129,135]. Further support for the significant role of this receptor subtype derives from the finding of increased aggression in mutant 129Sv mice lacking the 5-HT1B receptor gene [136, and see 137].}}</ref><ref name="deBoerKoolhaas2005">{{cite journal | vauthors = de Boer SF, Koolhaas JM | title = 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis | journal = Eur J Pharmacol | volume = 526 | issue = 1-3 | pages = 125–139 | date = December 2005 | pmid = 16310183 | doi = 10.1016/j.ejphar.2005.09.065 | url = | quote = Using such an ethopharmacological approach in either rats or mice, it has recently been claimed that only certain specific 5-HT1A receptor agonists (i.e., alnespirone and S-15535; de Boer et al., 1999, 2000), a mixed 5-HT1A/1B receptor agonist (i.e., eltoprazine; Olivier et al., 1995) and several specific 5-HT1B receptor agonists (i.e., CGS12066b, CP-94,253, anpirtoline, zolmitriptan, sumatriptan; Bell and Hobson, 1994; Fish et al., 1999; De Almeida et al., 2001; Miczek et al., 2004) exert behavioral specific anti-aggressive effects. In particular, it was claimed that agonists acting on the 5-HT1B receptors have more selective anti-aggressive effects in mice than those acting on 5-HT1A receptors (Miczek et al., 2004; Olivier, 2004).}}</ref><ref name="deAlmeidaNikulinaFaccidomo2001">{{cite journal | vauthors = de Almeida RM, Nikulina EM, Faccidomo S, Fish EW, Miczek KA | title = Zolmitriptan--a 5-HT1B/D agonist, alcohol, and aggression in mice | journal = Psychopharmacology (Berl) | volume = 157 | issue = 2 | pages = 131–141 | date = September 2001 | pmid = 11594437 | doi = 10.1007/s002130100778 | url = }}</ref> and has also been reported to decrease aggression in humans.<ref name="TricklebankRobbinsSimmons2021">{{cite journal | vauthors = Tricklebank MD, Robbins TW, Simmons C, Wong EH | title = Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology | journal = Psychopharmacology (Berl) | volume = 238 | issue = 6 | pages = 1417–1436 | date = June 2021 | pmid = 33694032 | pmc = 7945970 | doi = 10.1007/s00213-021-05787-x | url = | quote = A high proportion of violent acts are committed under the influence of alcohol. Aggressive behaviour can also be primed in the mouse by exposure to alcohol (De Almeida et al. 2001). In findings that are consistent with our knowledge of the relationship between serotonin and aggression (Pihl and Lemarquand 1998), this impact of alcohol can be ameliorated by treatment with the 5-HT1B/1D receptor agonist zolmitriptan, an approved anti-migraine drug. However, these findings have seemingly been overlooked despite the consistency of rodent and human data (Gowin et al. 2010).}}</ref><ref name="GowinSwannMoeller2010">{{cite journal | vauthors = Gowin JL, Swann AC, Moeller FG, Lane SD | title = Zolmitriptan and human aggression: interaction with alcohol | journal = Psychopharmacology (Berl) | volume = 210 | issue = 4 | pages = 521–531 | date = July 2010 | pmid = 20407761 | pmc = 9150756 | doi = 10.1007/s00213-010-1851-6 | url = }}</ref> As of June 2023, zolmitriptan is in [[Phases of clinical research#Phase II|phase 2]] [[clinical trial]]s for pervasive developmental disorders, [[Phases of clinical research#Phase I|phase 1]] clinical trials for agitation, and is in the [[preclinical research|preclinical stage of development]] for aggression.<ref name="AdisInsight-ML-004" /><ref name="Synapse2024" /><ref name="TheTransmitter2023" /> | ||
==References== | ==References== | ||
Latest revision as of 21:52, 27 June 2025
Template:Short description Template:Cs1 config Template:Drugbox Zolmitriptan, sold under the brand name Zomig among others, is a serotonergic medication which is used in the acute treatment of migraine attacks with or without aura and cluster headaches.[1] It is taken by mouth as a swallowed or disintegrating tablet or as a nasal spray.[1]
Side effects include tightness in the neck or throat, jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, chest pressure, and dry mouth.[1] The drug acts as a selective serotonin 5-HT1B and 5-HT1D receptor agonist.[1] Structurally, it is a triptan and a tryptamine derivative.[1][2]
It was patented in 1990 and was approved for medical use in 1997.[3][1]
Medical uses
Migraine
Zolmitriptan is used for the acute treatment of migraines with or without aura in adults.[1] It is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine.[1]
Off-label uses
- Acute treatment of cluster headaches—Level A recommendation from the American Academy of Neurology[4]
- Acute treatment of menstrual migraine[4]
Available forms
Zolmitriptan is available as a swallowed tablet, an orally disintegrating tablet, and as a nasal spray, in doses of 2.5 and 5Template:Nbspmg. People who get migraines from aspartame should not use the disintegrating tablet (Zomig ZMT) as it contains aspartame.[5]
A 2014 Cochrane review has shown that zolmitriptan 5Template:Nbspmg nasal spray was significantly more effective than the 5Template:Nbspmg oral tablet.[6]
Contraindications
Zolmitriptan is contraindicated in patients with cerebrovascular or cardiovascular disease because serotonin 5-HT1B receptors are present in coronary arteries. Such conditions include, but are not limited to, coronary artery disease, stroke, and peripheral vascular disease.[4] It is also contraindicated in hemiplegic migraine.[4]
Side effects
Side effects include neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensations, nausea, heaviness sensation, and dry mouth.[1]
As for cardiovascular side effects, zolmitriptan can increase systolic blood pressure in the elderly and increase diastolic blood pressure in both the elderly and young people. Additionally, there is the side effect of a dose-related increase in sedation. There is a risk for medication withdrawal headache or medication overuse headache.[4]
Zolmitriptan has a weak affinity for serotonin 5-HT1A receptors; these receptors have been implicated in the development of serotonin syndrome.[4]
Overdose
There is limited experience with overdose of zolmitriptan and there is no specific antidote for zolmitriptan overdose.[1] A dose of zolmitriptan of 50Template:Nbspmg, which is 10- to 40-fold the clinically used dose range of 1.25 to 5Template:Nbspmg, commonly resulted in sedation in patients in a clinical study.[1] Zolmitriptan has a relatively short elimination half-life of 3Template:Nbsphours, and so symptoms of overdose may be expected to resolve within around 15Template:Nbsphours post-intake.[1]
Interactions
Following administration of the non-selective cytochrome P450 inhibitor cimetidine, the elimination half-life and total exposure of zolmitriptan and its active metabolite were approximately doubled.[4] The major metabolite of zolmitriptan, N-desmethylzolmitriptan (183C91), which is active and has several-fold greater affinity for the serotonin 5-HT1B and 5-HT1D receptors than zolmitriptan, is metabolized into an inactive form by monoamine oxidase A (MAO-A).[7] The reversible inhibitor of MAO-A (RIMA) moclobemide combined with zolmitriptan has been found to increase N-desmethylzolmitriptan exposure and peak levels by 1.5- to 3-fold.[7]
Pharmacology
Pharmacodynamics
| Target | Affinity (Ki, nM) |
|---|---|
| 5-HT1A | 16.2–316 (Ki) 3,020–>10,000 (Template:Abbrlink) |
| 5-HT1B | 0.468–20.4 (Ki) 3.80–60.2 (EC50) 99.3% (Template:Abbrlink) |
| 5-HT1D | 0.107–4 (Ki) 0.309–1.26 (EC50) |
| 5-HT1E | 10–18.6 (Ki) 6.61–62 (EC50) |
| 5-HT1F | 28.2–617 (Ki) 10–420 (EC50) |
| 5-HT2A | >10,000 (Ki) >10,000 (EC50) |
| 5-HT2B | 64.6–>10,000 (Ki) >10,000 (EC50) |
| 5-HT2C | 79,400 (Ki) (guinea pig) ND (EC50) |
| 5-HT3 | >3,160 (mouse) |
| 5-HT4 | >3,160 (guinea pig) |
| 5-HT5A | 398 (rat) |
| 5-HT6 | >3,160 |
| 5-HT7 | 87.1–95.5 (Ki) 525 (EC50) |
| α1A–α1D | ND |
| α2 | 79,000 |
| α2A–α2C | ND |
| β1–β3 | ND |
| D1, D2 | >100,000 |
| D3–D5 | ND |
| H1–H4 | ND |
| M1–M5 | ND |
| I1, I2 | ND |
| σ1, σ2 | ND |
| Template:Abbrlink | ND |
| Template:Abbrlink | ND |
| Template:Abbrlink | ND |
| Template:Abbrlink | ND |
| Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [8][9][10][11][12][13][14] [15][16][17][18][19][20][21][22] | |
Zolmitriptan is a selective serotonin 5-HT1B and 5-HT1D receptor agonist with weak affinity for the serotonin 5-HT1A receptor.[10] It also has affinity for other serotonin receptors, including the serotonin 5-HT1E, 5-HT1F, 5-HT2B, 5-HT5A, and 5-HT7 receptors.[10] Conversely, its affinities for the serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT6 receptors are negligible or undetectable.[10][18] It is likewise inactive as a serotonin 5-HT2A receptor agonist.[18]
Zolmitriptan's major metabolite, N-desmethylzolmitriptan (183C91), is also active and has about 2- to 6-fold the affinity of zolmitriptan for the serotonin 5-HT1B and 5-HT1D receptors.[7]
Its action on serotonin 5-HT1B and 5-HT1D receptors causes vasoconstriction in intracranial blood vessels; as well it can inhibit the release of pro-inflammatory neuropeptides from trigeminal perivascular nerve endings. It crosses the blood–brain barrier as evidenced by the presence of radiolabeled zolmitriptan within the cells of the trigeminal nucleus caudalis and nucleus tractus solitarii.[4]
Pharmacokinetics
Absorption
Zolmitriptan has a rapid onset of action and has been detected in the brain as early as within 5Template:Nbspminutes of intranasal administration. On average, zolmitriptan has an oral bioavailability of 40%, a mean volume of distribution of 8.3Template:NbspL/kg after oral administration, and 2.4Template:NbspL/kg after intravenous administration.[4] According to a study of healthy volunteers, food intake seems to have no significant effect on the effectiveness of zolmitriptan in both men and women.[23]
Distribution
Zolmitriptan is a more lipophilic compound with greater central permeability than certain other triptans like sumatriptan.[24][25] It has been found to cross the blood–brain barrier and enter the central nervous system both in animals and humans.[26] In a clinical pharmacokinetic study, brain concentrations were about 20% of plasma concentrations.[27] However, in another clinical study, the drug achieved relatively low occupancy of central serotonin 5-HT1B receptors (4–5%) as measured by positron emission tomography (PET) imaging.[26][28][27]
Metabolism
Zolmitriptan is metabolized into three major metabolites by the human hepatic cytochrome P450 enzymes—primarily CYP1A2. Two-thirds of the parent compound breaks down into the active metabolite N-desmethylzolmitriptan (183C91), while the remaining one-third separates into the other two inactive metabolites: zolmitriptan N-oxide and an indole acetic acid derivative.[7] N-Desmethylzolmitriptan circulates at higher levels than those of zolmitriptan.[7] This metabolite is deaminated by monoamine oxidase A (MAO-A).[7]
Elimination
Zolmitriptan has an elimination half-life of about 3Template:Nbsphours before it undergoes renal elimination; its clearance is greater than the glomerular filtration rate suggesting that there is some renal tubular secretion of the compound.[4]
Chemistry
Zolmitriptan is a triptan and a substituted tryptamine.[1][2] It is specifically the derivative of N,N-dimethyltryptamine (DMT) in which the hydrogen atom at position 5 of the indole ring has been substituted with a [(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl group.[2]
The experimental log P of zolmitriptan is 1.6 to 1.8.[2][29] For comparison, the experimental log P of sumatriptan is 0.8 to 0.93.[30][29] Zolmitriptan is much more lipophilic than sumatriptan.[10][29]
Analogues of zolmitriptan include other triptans like sumatriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan.[10][29]
History
Zolmitriptan was patented in 1990[3] and was first described in the scientific literature by 1994.[31][32][33] It was first introduced for medical use in the United States in 1997.[3][1][34]
Society and culture
Brand names
Zolmitriptan is marketed by AstraZeneca with the brand names Zomig, Zomigon (Argentina, Canada, and Greece), AscoTop (Germany) and Zomigoro (France).
Economics
In 2008, Zomig generated nearly $154 million in sales.[35]
AstraZeneca's U.S. patent on Zomig tablets expired on November 14, 2012, and its pediatric exclusivity extension expired on May 14, 2013.[36] The patent in certain European countries has already expired too, and generic drug maker Actavis released a generic version in those countries, starting in March 2012.[37]
Legal status
In Russia, versions of zolmitriptan which are not registered in the National registry of medications may be regarded as narcotic drugs (derivatives of dimethyltriptamine).[38]
Research
Obsessive–compulsive disorder
Zolmitriptan showed no effect on obsessive–compulsive disorder (OCD) symptoms nor on mood or anxiety in a clinical study.[39][40]
Social deficits and aggression
Script error: No such module "Labelled list hatnote".
Zolmitriptan, in a modified-release formulation with code name ML-004 (or ML004), is under development by MapLight Therapeutics for the treatment of pervasive developmental disorders (e.g., autism), agitation, and aggression.[41][42][43][44][45][46] The drug has been found to reduce aggression in rodents[47][48][49] and has also been reported to decrease aggression in humans.[50][51] As of June 2023, zolmitriptan is in phase 2 clinical trials for pervasive developmental disorders, phase 1 clinical trials for agitation, and is in the preclinical stage of development for aggression.[41][42][43]
References
Further reading
- Script error: No such module "Citation/CS1".
External links
- Script error: No such module "citation/CS1".
Script error: No such module "Navbox". Template:Serotonin receptor modulators Script error: No such module "Navbox". Template:AstraZeneca Template:Portal bar
- ↑ a b c d e f g h i j k l m n Script error: No such module "citation/CS1".
- ↑ a b c d Script error: No such module "citation/CS1".
- ↑ a b c Script error: No such module "citation/CS1".
- ↑ a b c d e f g h i j Script error: No such module "Citation/CS1".File:CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b c d e f Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b c d e f Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b c Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b Script error: No such module "Citation/CS1".
- ↑ a b Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b c d Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "citation/CS1". (332 KB)Script error: No such module "Check for unknown parameters".. Drug Topics (May 26, 2009). Retrieved on August 25, 2009.
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ a b Script error: No such module "citation/CS1".
- ↑ a b Script error: No such module "citation/CS1".
- ↑ a b Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
