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User:Alimak12/sandbox

Alimak12/sandbox
Clinical data
Trade namesHumoryl
Pregnancy
category
  • C
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: uncontrolled
Pharmacokinetic data
Bioavailability50-62%
Protein binding50% (albumin)
Elimination half-life1-3 hours
Identifiers
  • 5-(hydroxymethyl)-3-m-tolyloxazolidin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC11H13NO3
Molar mass207.229 g/mol g·mol−1
3D model (JSmol)
Melting point136.25 °C (277.25 °F)
Boiling point375.25 °C (707.45 °F)
  • O=C2OC(CO)CN2c1cccc(c1)C
  • InChI=1S/C11H13NO3/c1-8-3-2-4-9(5-8)12-6-10(7-13)15-11(12)14/h2-5,10,13H,6-7H2,1H3 checkY
  • Key:MXUNKHLAEDCYJL-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Toloxatone is a drug that selectively and reversibly inhibits monoamine oxidase A (MAO-A) activity on the outer membranes of neuronal mitochondria.[1] It slows the catabolism of monoamines, such as dopamine, norepinephrine, and serotonin, and potentiates their activity in the synaptic cleft. Imbalances in these monoaminergic systems, as well as a significant increase in MAO-A concentrations and activity, have been heavily implicated in major depressive disorders.[2] This drug acts to restore chemical balance in the brain, and therefore is primarily marketed as an antidepressant. It has also been effective in the treatment of mood disorders, manic-depressive disorder, various depressive states, and psychosis.[3]

History edit

The first MAO inhibitors to be marketed as antidepressants for humans were both nonselective and irreversible. Though they were moderately successful in combatting depression, adverse side effects included hepatotoxicity, orthostatic hypotension, and tyramine-induced hypertensive crisis (also known as the “cheese effect”).[3] It was determined that many of these side effects were due to interactions with hydrazine moieties, which participated in covalent bonding with the active site of MAO, rendering the interaction irreversible.[3]

In 1985, toloxatone was launched as the first reversible inhibitor of MAO-A (RIMA). Its reversibility significantly lowered the number of aversive side effects.[3] Soon after, pharmaceutical companies employed the “piggy-back” approach to targeted drug design, and small modifications were made to the structure of toloxatone. Other RIMAs, such as pirlindole and moclobemide, soon entered the market with even fewer side effects.[4] With the successful development of serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), both of which have fewer adverse side effects, RIMA development has slowed significantly.[4]

Pharmacodynamics edit

Toloxatone is a reversible inhibitor of MAO-A (RIMA). By inhibiting MAO-A, monoaminergic neurotransmitters are degraded less quickly and their effects in the synapse are potentiated. The drug's affinity for MAO-A is over 100 times greater than MAO-B, rendering it very selective.[5]

Due to their irreversibility, nonselective MAO inhibitors, tolaxatone’s predecessors, could quickly build up to toxic levels in the human body. MAO inhibitors form a reversible complex with FAD, a MAO cofactor, where they are oxidized.[6] After gaining reactivity via oxidation, the inhibitors covalently bind to the enzyme.[6]

In contrast, MAO-A inhibitors’ mechanism of action is still largely unknown.[1] X-ray diffraction crystallography suggests that it is a planar molecule with pi-pi interactions and significant electron delocalization, both of which contribute to the molecule’s stability.[6][7] Reversible binding interactions are more likely to occur when a molecule exhibits these properties[7]. Additionally, electronic absorption spectroscopy studies have suggested that toloxatone forms a reversible complex with riboflavin.[6]

Pharmacokinetics edit

Toloxatone is administered orally via a 200 mg tablet three times a day.[8] It has a high hepatic excretion ratio and plasma concentrations are dramatically reduced during the first pass effect, resulting in low bioavailability (50-62%).[9] 87% and 91% of the dose is completely metabolized 8 and 12 hours after administration, respectively.[10] Eventually, the drug undergoes complete hepatic elimination, and less than 1% is excreted unmetabolized.[11] Many of these metabolites are a glucuronide of toloxatone and 3-(3-carboxyphenyl)-5-hydroxymethyl-2-oxazolidinone. Toloxatone’s half-life is very short at 1-3 hours.[11] Maximum plasma concentrations, approximately 1.5 to 3 mg/L, are reached 30-60 minutes after administration.[12] Toloxatone binds extensively with the carrier protein albumin during plasma circulation.[8] The drug is uncharged, and likely passes the blood-brain barrier through passive diffusion.[12] Studies in mice have suggested that a toxic dose is 1500 mg/kg of body weight.[13] Liver-impaired patients often require a dose adjustment because of the hepatic system’s large role in metabolizing this drug.[11]

Side effects edit

Many of the reported side effects involve gastrointestinal discomfort, dyspepsia, and constipation.[3] These symptoms may be related to the method of administration, since the drug is introduced into the blood stream through absorption in the intestines. Other side effects include headaches, dizziness, delusions, euphoria, aggression, and generalized anxiety.[3] Unlike many other antidepressants, toloxatone does not interfere with memory or sleep patterns.[14]

Availability edit

Toloxatone was an original structure and the first RIMA to be proven effective in treating depression in humans. As such, it was quickly modified in an effort to improve pharmacokinetic properties.[4] Though toloxatone is extremely selective for MAO-A, other RIMAs have similar selectivity indices, higher potencies, and higher efficacies.[5] Within ten years of toloxatone's introduction to the market, a slew of similar but novel drugs, including befloxatone, brofaromine, BW 1370U87, and RS 8359, had all been synthesized and shown to be more potent MAO-A inhibitors.[15] Additionally, SSRIs have emerged as a class of antidepressant drugs with greater tolerability in humans and wider clinical applications than MAO-A inhibitors.[16] For these reasons, toloxatone has never been manufactured or distributed outside of France, where it was originally synthesized and remains available today.[17]

See also edit

References edit

  1. ^ a b Cesura, AM; Pletscher, A (1992). "The new generation of monoamine oxidase inhibitors". Progress in Drug Research. Fortschritte der Arzneimittelforschung. Progres des Recherches Pharmaceutiques. 38: 171–297. doi:10.1007/978-3-0348-7141-9_3. ISBN 978-3-0348-7143-3. PMID 1609114.
  2. ^ Meyer, JH; Ginovart, N; Boovariwala, A; Sagrati, S; Hussey, D; Garcia, A; Young, T; Praschak-Rieder, N; Wilson, AA; Houle, S (November 2006). "Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression". Archives of General Psychiatry. 63 (11): 1209–16. doi:10.1001/archpsyc.63.11.1209. PMID 17088501.
  3. ^ a b c d e f Arns, M.W. "Prediction of Treatment Efficacy and Side Effects: Major Depression: A literature summary" (PDF). Brainquiry. Retrieved 11/8/2014. {{cite web}}: Check date values in: |accessdate= (help)
  4. ^ a b c Berlin, I; Zimmer, R; Thiede, HM; Payan, C; Hergueta, T; Robin, L; Puech, AJ (December 1990). "Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase-A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects". British Journal of Clinical Pharmacology. 30 (6): 805–16. doi:10.1111/j.1365-2125.1990.tb05445.x. PMC 1368300. PMID 1705137.
  5. ^ a b Delini-Stula, A; Radeke, E; Waldmeier, PC (1988). "Basic and clinical aspects of the activity of the new monoamine oxidase inhibitors". Psychopharmacology Series. 5: 147–58. doi:10.1007/978-3-642-73280-5_14. ISBN 978-3-642-73282-9. PMID 3045798.
  6. ^ a b c d Wouters, J; Moureau, F; Evrard, G; Koenig, JJ; Jegham, S; George, P; Durant, F (August 1999). "A reversible monoamine oxidase A inhibitor, befloxatone: structural approach of its mechanism of action". Bioorganic & Medicinal Chemistry. 7 (8): 1683–93. doi:10.1016/s0968-0896(99)00102-9. PMID 10482460.
  7. ^ a b Moureau, F; Wouters, J; Depas, M; Vercauteren, D; Durant, F; Durcey, F; Jarreau, F. X. (1995). "A reversible monoamine oxidase inhibitor, Toloxatone: comparison of its physicochemical properties with those of other inhibitors including Brofaromine, Harmine, R40519 and Moclobemide". European Journal of Medicinal Chemistry. 30 (11): 823-837. doi:10.1016/0223-5234(96)88302-4.
  8. ^ a b Provost, JC; Funck-Brentano, C; Rovei, V; D'Estanque, J; Ego, D; Jaillon, P (October 1992). "Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects". Clinical Pharmacology and Therapeutics. 52 (4): 384–93. doi:10.1038/clpt.1992.159. PMID 1424410. S2CID 25516813.
  9. ^ Benedetti, MS; Rovei, V; Dencker, SJ; Nagy, A; Johansson, R (1982). "Pharmacokinetics of toloxatone in man following intravenous and oral administrations". Arzneimittel-Forschung. 32 (3): 276–80. PMID 7200786.
  10. ^ Malnoë, A; Benedetti, MS (May 1979). "Metabolic fate of 3-(3-methylphenyl)-5-hydroxymethyl-2-oxazolidinone (toloxatone), a new antidepressant agent, in man". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 9 (5): 281–8. doi:10.3109/00498257909038731. PMID 494659.
  11. ^ a b c Schoerlin, MP; Guentert, TW (August 1989). "[Pharmacokinetics and metabolism of reversible MAO-A inhibitors in the human]". Psychiatrische Praxis. 16 Suppl 1: 11–7. PMID 2685852.
  12. ^ a b Vistelle, R; Lamiable, D; Zinsou, M; Leon, A; Wiczewski, M (February 1992). "Toloxatone pharmacokinetics in the plasma and cerebrospinal fluid of the rabbit". The Journal of Pharmacy and Pharmacology. 44 (2): 124–6. doi:10.1111/j.2042-7158.1992.tb03576.x. PMID 1352813. S2CID 2426316.
  13. ^ Azoyan, P; Garnier, R; Baud, FJ; Efthymiou, ML (NaN). "[Acute toloxatone poisoning. Apropos of 122 cases]". Therapie. 45 (2): 139–44. PMID 2353326. {{cite journal}}: Check date values in: |date= (help)
  14. ^ Berlin, I; Zimmer, R; Thiede, HM; Payan, C; Hergueta, T; Robin, L; Puech, AJ (December 1990). "Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase-A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects". British Journal of Clinical Pharmacology. 30 (6): 805–16. doi:10.1111/j.1365-2125.1990.tb05445.x. PMC 1368300. PMID 1705137.
  15. ^ Curet, O; Damoiseau, G; Aubin, N; Sontag, N; Rovei, V; Jarreau, FX (April 1996). "Befloxatone, a new reversible and selective monoamine oxidase-A inhibitor. I. Biochemical profile". The Journal of Pharmacology and Experimental Therapeutics. 277 (1): 253–64. doi:10.1163/2211730x96x00144. PMID 8613928.
  16. ^ Harms, D; Schmidt, D (July 1987). "[Histology of solid tumors and its significance for therapy]". Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde. 135 (7): 431–6. PMID 3627130.
  17. ^ Briley, Mike; Nutt, David (2000). Anxiolytics. Springer.

Category:Monoamine oxidase inhibitors Category:Oxazolidinones

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