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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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
Data of lethal dose 50 (LD50) of indeloxazine are available on dog, rat and mouse.[31]
* Note that many TCAs, TeCAs, antipsychotics, ergolines, and some piperazines like buspirone and trazodone all antagonize α1-adrenergic receptors as well, which contributes to their side effects such as orthostatic hypotension.
* Note that many atypical antipsychotics and azapirones like buspirone (via metabolite 1-PP) antagonize α2-adrenergic receptors as well.
* Note that MAO-B inhibitors also influence norepinephrine/epinephrine levels since they inhibit the breakdown of their precursor dopamine.
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