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Viloxazine is known to increase [[blood plasma|plasma]] levels of [[phenytoin]] by an average of 37%.{{Ref|phenytoin}} It is also known to significantly increase plasma levels of [[theophylline]] and decrease its clearance from the body,{{Ref|theophylline_1}} sometimes resulting in accidental overdose of theophylline.{{Ref|theophylline_2}}
Viloxazine is known to increase [[blood plasma|plasma]] levels of [[phenytoin]] by an average of 37%.{{Ref|phenytoin}} It is also known to significantly increase plasma levels of [[theophylline]] and decrease its clearance from the body,{{Ref|theophylline_1}} sometimes resulting in accidental overdose of theophylline.{{Ref|theophylline_2}}
==Synthesis==
[[File:Viloxazine-synthesis.svg|thumb|center|700px|Viloxazine synthesis:<ref>K. B. Mallion et al., {{Cite patent|GB|1138405}}; eidem, {{US patent|3714161}} (1969, 1973 both to [[I.C.I.]]).</ref> Manufacturing process:<ref name=Lee>S. A. Lee, {{Cite patent|GB|1260886}}; idem, {{US patent|3712890}} (1972, 1973 both to [[I.C.I.]]).</ref>]]
Reaction of aryloxyepoxide ('''1''') with the [[mesylate]] from [[ethanolamine]] (2-aminoethylbisulfate, Ethanolamine-O-sulfate) leads to Viloxazine in a single step.<ref name=Lee/>

It is likely that reaction is initiated by opening of the oxirane by the amino group. Internal displacement of the leaving group by the resulting alkoxide forms the morpholine ring.


== See also ==
== See also ==

Revision as of 16:45, 8 July 2015

Viloxazine
Clinical data
Routes of
administration		Oral, intravenous (infusion)[1]
ATC code
Legal status
Legal status
  • Not a controlled substance
Pharmacokinetic data
Elimination half-life2-5 hours
ExcretionRenal[2]
Identifiers
  • (RS)-2-[(2-ethoxyphenoxy)methyl]morpholine[3]
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.051.148 Edit this at Wikidata
Chemical and physical data
FormulaC13H19NO3
Molar mass237.295 g/mol g·mol−1
3D model (JSmol)
  • O(c1ccccc1OCC)CC2OCCNC2
  • InChI=1S/C13H19NO3/c1-2-15-12-5-3-4-6-13(12)17-10-11-9-14-7-8-16-11/h3-6,11,14H,2,7-10H2,1H3 checkY
  • Key:YWPHCCPCQOJSGZ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Viloxazine (Vivalan, Emovit, Vivarint, Vicilan) is a bicyclic antidepressant[5] morpholine derivative that acts as a selective norepinephrine reuptake inhibitor (NRI).[6] It produces a marked stimulant effect that is similar to the amphetamines, except without any signs of dependence.[1] It is a racemic compound with two stereoisomers, the (S)-(–)-isomer being five times as pharmacologically active as the (R)-(+)-isomer.[7]

Uses

Approved

Viloxazine hydrochloride was approved in Italy, Belgium, England, Ireland, Germany, Portugal, Spain, the former Yugoslavia, France, Slovakia,[8] for the treatment of clinical depression.[9]

Unapproved/off-Label/investigational

Viloxazine has undergone two randomized controlled trials for nocturnal enuresis (bedwetting) in children, both of those times versus imipramine.[10],[11] By 1990, it was seen as a less cardiotoxic alternative to imipramine, and to be especially effective in heavy sleepers.[12]

In narcolepsy, viloxazine has been shown to suppress auxiliary symptoms such as cataplexy and also abnormal sleep-onset REM[13] without really improving daytime somnolence.[14]

In a cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy. {ref Vignatelli L, D'Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003724. doi:10.1002/14651858.CD003724.pub3}

Viloxazine has also been studied for the treatment of alcoholism, with some success.[15]

While viloxazine may be effective in clinical depression, it did relatively poorly in a double-blind randomized controlled trial versus amisulpride in the treatment of dysthymia, according to Leon and colleagues at the University of Valle in Colombia.[16]

Mechanism of action

In 1976, Lippman and Pugsley reported that viloxazine, like imipramine, inhibited norepinephrine reuptake in the hearts of rats and mice; unlike imipramine, (or desipramine or amitriptyline, for that matter) it did not block reuptake of norepinephrine in either the medullae or the hypothalami of rats. As for serotonin, while its reuptake inhibition was comparable to that of desipramine (i.e., very weak), viloxazine did potentiate serotonin-mediated brain functions in a manner similar to amitriptyline and imipramine, which are relatively potent inhibitors of serotonin reuptake.[17] Unlike any of the other drugs tested, it did not exhibit any anticholinergic effects.[18]

It is also known to up-regulate GABAB receptors in the frontal cortex.[19]

Side effects

Side effects include nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, (there were three cases worldwide, and most animal studies (and clinical trials that included epilepsy patients) indicated the presence of anticonvulsant properties, so is not completely contraindicated in epilepsy,[20]) and increased libido.[21]

Drug interactions

Viloxazine is known to increase plasma levels of phenytoin by an average of 37%.[22] It is also known to significantly increase plasma levels of theophylline and decrease its clearance from the body,[23] sometimes resulting in accidental overdose of theophylline.[24]

Synthesis

Viloxazine synthesis:[2] Manufacturing process:[3]

Reaction of aryloxyepoxide (1) with the mesylate from ethanolamine (2-aminoethylbisulfate, Ethanolamine-O-sulfate) leads to Viloxazine in a single step.[3]

It is likely that reaction is initiated by opening of the oxirane by the amino group. Internal displacement of the leaving group by the resulting alkoxide forms the morpholine ring.

See also

References

  1. ^ Pinder, RM; Brogden, RN; Speight, TM; Avery, GS (June 1977). "Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness". Drugs. 13 (6): 401–21. doi:10.2165/00003495-197713060-00001. PMID 324751.
  2. ^ K. B. Mallion et al., GB 1138405 ; eidem, U.S. patent 3,714,161 (1969, 1973 both to I.C.I.).
  3. ^ a b S. A. Lee, GB 1260886 ; idem, U.S. patent 3,712,890 (1972, 1973 both to I.C.I.).
  1. ^ "SID 180462-- PubChem Substance Summary". Retrieved 5 November 2005.
  2. ^ "MEDLINE subject headings for Viloxazine". Retrieved 5 November 2005.
  3. ^ Case DE, Reeves PR (February 1975). "The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans". Xenobiotica. 5 (2): 113–29. doi:10.3109/00498257509056097. PMID 1154799.
  4. ^ Bouchard JM, Strub N, Nil R (October 1997). "Citalopram and viloxazine in the treatment of depression by means of slow drop infusion. A double-blind comparative trial". Journal of Affective Disorders. 46 (1): 51–8. doi:10.1016/S0165-0327(97)00078-5. PMID 9387086.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ 【合法】個人輸入代行薬【未認可】 (The relevant section is English[citation needed])
  6. ^ Müller-Oerlinghausen B, Rüther E (July 1979). "Clinical profile and serum concentration of viloxazine as compared to amitriptyline". Pharmakopsychiatrie, Neuro-Psychopharmakologie. 12 (4): 321–37. doi:10.1055/s-0028-1094627. PMID 386390.
  7. ^ Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagorevskiĭ VA (May 1984). "Behavioral and radioreceptor analysis of viloxazine stereoisomers". Biulleten' Eksperimental'noĭ Biologii i Meditsiny (in Russian). 97 (5): 576–8. PMID 6326891. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)CS1 maint: multiple names: authors list (link)
  8. ^ AstraZeneca Slovensko (2000). "VIVALAN tbl obd". Retrieved 2005-11-05. [dead link]
  9. ^ AstraZeneca International (2003). "Vivalan (viloxazine hydrochloride)". Retrieved 2005-11-06.
  10. ^ Attenburrow AA, Stanley TV, Holland RP (January 1984). "Nocturnal enuresis: a study". The Practitioner. 228 (1387): 99–102. PMID 6364124.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Yurdakök M, Kinik E, Güvenç H, Bedük Y (1987). "Viloxazine versus imipramine in the treatment of enuresis". The Turkish Journal of Pediatrics. 29 (4): 227–30. PMID 3332732.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Libert MH (1990). "The use of viloxazine in the treatment of primary enuresis". Acta Urologica Belgica (in French). 58 (1): 117–22. PMID 2371930. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)
  13. ^ Guilleminault C, Mancuso J, Salva MA; et al. (1986). "Viloxazine hydrochloride in narcolepsy: a preliminary report". Sleep. 9 (1 Pt 2): 275–9. PMID 3704453. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  14. ^ Mitler MM, Hajdukovic R, Erman M, Koziol JA (January 1990). "Narcolepsy". Journal of Clinical Neurophysiology. 7 (1): 93–118. doi:10.1097/00004691-199001000-00008. PMC 2254143. PMID 1968069.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Altamura AC, Mauri MC, Girardi T, Panetta B (1990). "Alcoholism and depression: a placebo controlled study with viloxazine". International Journal of Clinical Pharmacology Research. 10 (5): 293–8. PMID 2079386.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ León CA, Vigoya J, Conde S, Campo G, Castrillón E, León A (March 1994). "Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia". Acta Psiquiátrica Y Psicológica de América Latina (in Spanish). 40 (1): 41–9. PMID 8053353. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)CS1 maint: multiple names: authors list (link)
  17. ^ Lippman W, Pugsley TA (August 1976). "Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities". Canadian Journal of Physiology and Pharmacology. 54 (4): 494–509. doi:10.1139/y76-069. PMID 974878.
  18. ^ see Lippman and Pugsley, 1976.
  19. ^ Lloyd KG, Thuret F, Pilc A (October 1985). "Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock". The Journal of Pharmacology and Experimental Therapeutics. 235 (1): 191–9. PMID 2995646.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Edwards JG, Glen-Bott M (September 1984). "Does viloxazine have epileptogenic properties?". Journal of Neurology, Neurosurgery, and Psychiatry. 47 (9): 960–4. doi:10.1136/jnnp.47.9.960. PMC 1027998. PMID 6434699.
  21. ^ Chebili S, Abaoub A, Mezouane B, Le Goff JF (1998). "Antidepressants and sexual stimulation: the correlation". L'Encéphale (in French). 24 (3): 180–4. PMID 9696909. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)CS1 maint: multiple names: authors list (link)
  22. ^ Pisani F, Fazio A, Artesi C; et al. (February 1992). "Elevation of plasma phenytoin by viloxazine in epileptic patients: a clinically significant drug interaction". Journal of Neurology, Neurosurgery, and Psychiatry. 55 (2): 126–7. doi:10.1136/jnnp.55.2.126. PMC 488975. PMID 1538217. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  23. ^ Perault MC, Griesemann E, Bouquet S, Lavoisy J, Vandel B (September 1989). "A study of the interaction of viloxazine with theophylline". Therapeutic Drug Monitoring. 11 (5): 520–2. doi:10.1097/00007691-198909000-00005. PMID 2815226.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Laaban JP, Dupeyron JP, Lafay M, Sofeir M, Rochemaure J, Fabiani P (1986). "Theophylline intoxication following viloxazine induced decrease in clearance". European Journal of Clinical Pharmacology. 30 (3): 351–3. doi:10.1007/BF00541543. PMID 3732375.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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