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Indeloxazine

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Indeloxazine

Indeloxazine
Systematic (IUPAC) name
2-(3H-Inden-4-yloxymethyl)morpholine
Clinical data
Legal status
  • Prescription only
Routes Oral
Pharmacokinetic data
Half-life 2.2 hours
Identifiers
CAS number  YesY
ATC code None
PubChem
ChemSpider  YesY
UNII  YesY
KEGG  YesY
Chemical data
Formula C14H17NO2 
Mol. mass 231.290 g/mol
 YesY   

Indeloxazine (Elen, Noin) is a drug that has been used in Japan for the treatment of cerebrovascular disease since 1988.[1][2] Sometimes it is referred to as a cerebral activator.

It acts as a serotonin releasing agent,[3] norepinephrine reuptake inhibitor,[3] and NMDA receptor antagonist,[4] and enhances acetylcholine release through indirect activation of the 5-HT4 receptor.[5][6][7] It has nootropic,[6][7][8][9] anticonvulsant,[10] and antidepressant effects.[3][11][12]

Medical uses

Indeloxazine was originally marketed in Japan in the 1980s by Yamanouchi Pharmaceutical Co., Ltd. This drug was once used in Japan and South Korea for the treatment of psychiatric symptoms associated with cerebrovascular disease, namely depression resulting from stroke, emotional disturbance, and reduced volition.[3]

History

After this drug together with idebenone, propentofylline, and bifemelane had made US$6.25 billion, the ministry of Health and Welfare of Japan (MHW) proscribed these four drugs that were classified as cerebral-metabolism enhancers on May 25, 1998, [13] because research revealed that these drugs showed no improved effects in comparison with placebos.[13] The approval of indeloxazine was the result of MHW’s new drug approval system in which physicians subjectively judged the Zenpan Kaizen Do (the global improvement rating, GIR), the name of the primary endpoint of Japanese controlled clinical trials (CCTs).[13] Such a drug approval system was believed lack of reproducibility.[13][14]

Research

Anti-ischemic effects

The effects of indeloxazine on cerebral energy metabolism were studied in mice and rats. Data showed that administration of indeloxazine resulted in increases in brain ATP and glucose levels without the affecting lactate level in mice and an elevation in local cerebral glucose utilization in 10 brain regions of the frontal cortex in rats.[15] Such increases in the cerebral glucose and ATP concentrations before ischemia delayed the onset of massive ionic fluxes during ischemia, therefore increasing the survival of the ischemia-induced death of hippocampal CA1 pyramidal cells after transient cerebral ischemia.[16] Besides, animal models demonstrated that indeloxazine could improve anoxia-induced impairment of passive and active avoidance learning abilities in a way similar to calcium hopantenate, which should not be attributed to cerebral vasodilative or central depressant activities, because indeloxazine at doses inducing anti-anoxic actions showed no effect on cerebral blood flow in cats and pentobarbital sleeping time in mice.[17]Interestingly, data from mice suggested that indeloxazine and its (+)-isomer were approximately 3-10 times more potent than the (-)-isomer with regard to their anti-ischemic activities.[15]

Effects on central monoaminergic systems

Indeloxazine exerted positive effects on central monoaminergic systems evidenced by the ameliorated reserpine-induced hypothermia in mice, ponto-genicullo-occipital (PGO) waves in reserpinized cats and caudate spindle activity in cats after administering indeloxazine.[18] In another study, oral administration of indeloxazine (10 or 30 mg/kg) to rats subjected to left middle cerebral artery occlusion significantly decreased 5-hydroxy-indoleacetic acid and increased the serotonin in the bilateral frontal cortex and hippocampus and contralateral corpus striatum.[19] At the dose of 30 mg/kg of indeloxazine, norepinephrine in the contralateral frontal cortex was increased and 3-methoxy-4-hydroxy-phenylethylglycol in the contralateral hippocampus was decreased, suggesting the promoting action on central monoaminergic systems.[19] In microdialysis studies, intraperitoneal injection of indeloxazine (3-10 mg/kg) increased the extracellular levels of both serotonin and norepinephrine in rat frontal cortex of freely moving rats in a dose dependent manner, suggesting the inhibitory effects of indeloxazine on serotonin and norepinephrine uptake.[3] 

Optical isomers of indeloxazine showed different potency in modulating cerebral functions. Indeloxazine and its (-)-isomer in inhibiting norepinephrine uptake was approximately 25-30 times more potent than that of the (+)-isomer, while the (+)-isomer showed about 3 times less potent activity than indeloxazine and the (-)-isomer in desynchronizing the spontaneous electroencephalogram (EEG) in both mature and aged rats and in accelerating recovery of consciousness induced by concussive head trauma in mice.[20]

Effects on sleep

The effects of 40 mg of indeloxazine on sleep were investigated in 6 healthy male students. Results showed that indeloxazine prolonged both sleep latency and rapid eye movement (REM) latency, and increased stage 1 sleep, but decreased stages 3, 4 and REM sleep.[21]

Effects on hearing disorders

It has been reported that indeloxazine is used alone for the treatment or prevention of a hearing disorder, such as hearing loss or tinnitus. The theoretical explanation is that indeloxazine can increase brain serotonin, norepinephrine and acetylcholine, thus improving central auditory processing, speech recognition and hearing perception, and that its NMDA inhibiting activity offers protection for the inner ear hair cells. [22]

Effects on neurogenic pain

The (+)-isomer of Indeloxazine (AS1069562) was shown to have analgesic effects in a rat model of chronic constriction injury (CCI)–induced neuropathic pain and the spinal monoamine turnover. AS1069562 could significantly alleviate mechanical allodynia, thermal hyperalgesia, improve spontaneous pain–associated behavior in CCI rats.[23] A study using mouse models of prostaglandin-induced spinal hypersensitivity proved that AS1069562 showed inhibitory effects on both C-fiber- and non-C-fiber-dependent prostaglandin-induced allodynia.[24] In another study AS1069562 that was given by single daily administration for 4 weeks to a rat model of streptozotocin (STZ)-induced diabetic neuropathy significantly improved mechanical allodynia, and the analgesic effect of AS1069562 continued after a consecutive 1-week treatment discontinuation with undetectable plasma concentration of AS1069562.[25]

Adverse effects

Symptoms of parkinsonism

Elderly patents (60-82 years old) who were treated with 60 mg or 120 mg of indeloxazine daily developed typical symptoms of parkinsonism; when indeloxazine was withdrawn, the symptoms disappeared.[26][27] The symptoms of parkinsonism recurred in one patient when indeloxazine was reinstated. The reason for this might be that the brain dopamine content decreases in elderly persons and that indeloxazine disrupted the balance in brain norepinephrine, dopamine, and acetylcholine levels.[26][27]

Teratogenic potential

Multiple sources have pointed out that indeloxazine maybe a potential teratogen, so pregnant or nursing women should not handle and consume it.[28][29][30]

Toxicity data

Data of lethal dose 50 (LD50) of indeloxazine are available on dog, rat and mouse.[31]

See also

References

  1. ^ Index nominum, international drug ... - Google Books. 2000.  
  2. ^ r Ganellin, C; j Triggle, D; MacDonald, F. (1997). Dictionary of pharmacological agents - Google Books.  
  3. ^ a b c d e Yamaguchi T, Ohyama M, Suzuki M, et al. (September 1998). "Neurochemical and behavioral characterization of potential antidepressant properties of indeloxazine hydrochloride". Neuropharmacology 37 (9): 1169–76.  
  4. ^ Kaneko S, Sugimura M, Inoue T, Satoh M (June 1991). "Effects of several cerebroprotective drugs on NMDA channel function: evaluation using Xenopus oocytes and [3H]MK-801 binding". European Journal of Pharmacology 207 (2): 119–28.  
  5. ^ Yamaguchi T, Suzuki M, Yamamoto M (December 1997). "Facilitation of acetylcholine release in rat frontal cortex by indeloxazine hydrochloride: involvement of endogenous serotonin and 5-HT4 receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 356 (6): 712–20.  
  6. ^ a b Yamamoto M, Takahashi K, Ohyama M, et al. (May 1994). "Possible involvement of central cholinergic system in ameliorating effects of indeloxazine, a cerebral activator, on disturbance of learning behavior in rats". Progress in Neuro-psychopharmacology & Biological Psychiatry 18 (3): 603–13.  
  7. ^ a b Yamamoto M, Ooyama M, Ozawa Y, et al. (July 1993). "Effects of indeloxazine hydrochloride, a cerebral activator, on passive avoidance learning impaired by disruption of cholinergic transmission in rats". Neuropharmacology 32 (7): 695–701.  
  8. ^ Ogawa N, Haba K, Sora YH, Higashida A, Sato H, Ogawa S (1988). "Comparison of the effects of bifemelane hydrochloride and indeloxazine hydrochloride on scopolamine hydrobromide-induced impairment in radial maze performance". Clinical Therapeutics 10 (6): 704–11.  
  9. ^ Yamamoto M, Shimizu M (July 1987). "Cerebral activating properties of indeloxazine hydrochloride". Neuropharmacology 26 (7A): 761–70.  
  10. ^ Nakamura J, Anraku T, Shirouzu M, Iwashita Y, Nakazawa Y (June 1993). "Effects of indeloxazine HCl on kindled amygdaloid seizures in rats: comparison with the effects of phenytoin, diazepam, ethanol, and imipramine". Pharmacology, Biochemistry, and Behavior 45 (2): 445–50.  
  11. ^ Hayes AG, Chang T (January 1983). "Determination of indeloxazine, a new antidepressant agent, in human plasma by gas-liquid chromatography with electron-capture detection". Journal of Chromatography 272 (1): 176–80.  
  12. ^ Kojima T, Niigata K, Fujikura T, et al. (September 1985). "Syntheses of (+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride (YM-08054, indeloxazine hydrochloride) and its derivatives with potential cerebral-activating and antidepressive properties". Chemical & Pharmaceutical Bulletin 33 (9): 3766–74.  
  13. ^ a b c d Hayashi, K; Hashimoto, K; Yanagi, M; Umeda, T; Hama, R (8 August 1998). "Drug approval in Japan questioned.". Lancet 352 (9126): 491.  
  14. ^ Yanagi, M; Hashimoto, K; Umeda, T (1995). "Problems on the clinical evaluation methods with Zenpan Kaizen do (in Japanese)". Jap J Clin Pharmacol Therapeutics (26): 115 - 116. 
  15. ^ a b Shimizu-Sasamata, M; Terai, M; Harada, M; Yamamoto, M (1993). "Anti-hypoxic and anti-ischemic actions of indeloxazine hydrochloride and its optical isomers: possible involvement of cerebral energy metabolism.". Archives internationales de pharmacodynamie et de therapie 324: 33–46.  
  16. ^ Kano, T; Katayama, Y; Miyazaki, S; Kinoshita, K; Kawamata, T; Tsubokawa, T (March 1993). "Effects of indeloxazine on hippocampal CA1 pyramidal cell damage following transient cerebral ischemia in the gerbil.". Neuropharmacology 32 (3): 307–10.  
  17. ^ Yamamoto, M; Shimizu, M (April 1987). "Effects of indeloxazine hydrochloride (YM-08054) on anoxia.". Archives internationales de pharmacodynamie et de therapie 286 (2): 272–81.  
  18. ^ Yamamoto, M; Kawabata, S; Shimizu, M (December 1989). "Pharmacological effects of indeloxazine, a new cerebral activator, on brain functions distinct from other cerebral metabolic enhancers.". Neuropharmacology 28 (12): 1291–7.  
  19. ^ a b Shimizu-Sasamata, M; Yamamoto, M; Okada, M; Yamaguchi, T; Tamura, A (1991). "Effects of indeloxazine hydrochloride on behavioral and biochemical changes in the chronic phase of focal cerebral ischemia in rats.". Archives internationales de pharmacodynamie et de therapie 314: 74–89.  
  20. ^ Shimizu-Sasamata, M; Yamamoto, M; Harada, M (June 1993). "Cerebral activating properties of indeloxazine HCl and its optical isomers.". Pharmacology, biochemistry, and behavior 45 (2): 335–41.  
  21. ^ Kajimura, N; Mizuki, Y; Kai, S; Suetsugi, M; Sekimoto, M; Fujii, S; Yamada, M; Yamadera, H; Okuma, T (March 1991). "Effects of indeloxazine hydrochloride on sleep in normal humans.". Methods and findings in experimental and clinical pharmacology 13 (2): 139–45.  
  22. ^ Anderson, J.J; Kranzler, J; Rao, S (2007). "Prevention and treatment of hearing disorders". Google Patents. 
  23. ^ Murai, N.; Aoki, T.; Tamura, S.; Sekizawa, T.; Kakimoto, S.; Tsukamoto, M.; Oe, T.; Enomoto, R.; Hamakawa, N.; Matsuoka, N. (12 December 2013). "AS1069562, the (+)-Isomer of Indeloxazine, Exerts Analgesic Effects in a Rat Model of Neuropathic Pain with Unique Characteristics in Spinal Monoamine Turnover". Journal of Pharmacology and Experimental Therapeutics 348 (3): 372–382.  
  24. ^ Murai, Nobuhito; Tsukamoto, Mina; Tamura, Seiji; Aoki, Toshiaki; Matsuoka, Nobuya (June 2014). "Antinociceptive effects of AS1069562, the (+)-isomer of indeloxazine, on spinal hypersensitivity induced by intrathecal injection of prostaglandin in mice: Comparison with duloxetine and amitriptyline". European Journal of Pharmacology 733: 54–61.  
  25. ^ Murai, Nobuhito; Aoki, Toshiaki; Tamura, Seiji; Yamamoto, Hiroko; Hamakawa, Nozomu; Matsuoka, Nobuya (April 2014). "AS1069562, the (+)-isomer of indeloxazine, but not duloxetine has a curative-like analgesic effect in a rat model of streptozotocin-induced diabetic neuropathy". Neuropharmacology 79: 10–16.  
  26. ^ a b Ogawa, N (1989). "Parkinsonism induced by indeloxazine hydrochloride in the elderly.". Clinical therapeutics 11 (6): 802–6.  
  27. ^ a b Fujisawa, Y; Tsuji, T; Sasaki, K (1989). "Parkinsonism induced by indeloxazine hydrochloride.". Clinical therapeutics 11 (6): 807–11.  
  28. ^ "Teratogens". 
  29. ^ "Indeloxazine: Mechanism of Action, Benefits, Side Effects and Dosage". 
  30. ^ "Indeloxazine Information". 
  31. ^ "Indeloxazine hydrochloride". 



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