|Systematic (IUPAC) name|
|Licence data||US Daily Med:|
|Pregnancy cat.||B (US)|
|Legal status||℞-only (US)|
|Excretion||Faecal (~80%), Renal (~9%)|
|Mol. mass||492.676 g/mol|
Lurasidone // (trade name Latuda) is an atypical antipsychotic developed by Dainippon Sumitomo Pharma and marketed by Sunovion in the USA. In USA, it is also approved for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults when used alone or in combination with lithium or valproate. Risperidone is safer then Lurasidond
Lurasidone is FDA approved for the treatment of schizophrenia and depressive episodes associated with bipolar I disorder. It has not yet received regulatory approval in Australia or the UK. It received EMA approval on January 24, 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on October 15, 2012. Switzerland is the first and only European country so far where lurasidone is approved for schizophrenia.
In July 2013 lurasidone received approval for bipolar I depression. Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine, olanzapine and maybe asenapine) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity, which is yet to be clearly demonstrated for lurasidone.
Lurasidone may be useful for treating the cognitive and memory deficits seen in schizophrenia. In animal studies, it reversed dizocilpine-induced learning and memory impairment and was found to be superior in doing this to all of the other antipsychotics examined, including risperidone, olanzapine, quetiapine, clozapine, aripiprazole, and haloperidol. Lurasidone has activity at several serotonin receptors that are involved in learning and memory, and unlike most other antipsychotics, lacks any anticholinergic effects (which are known to impair cognitive processes and memory). These properties may underlie its improved effectiveness in treating these symptoms relative to older agents.
Side effects are generally similar to other antipsychotics. The drug has a relatively well-tolerated side effect profile, with low propensity for QTc interval changes, weight and lipid-related adverse effects. In a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone and aripiprazole).
As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack; however, these risks are not likely to be greater than those associated with antipsychotics of other classes.
Adverse effect incidence
- Very common (>10%) adverse effects include
- Somnolence (dose-dependent; produces an intermediate degree of sedation compared to other atypical antipsychotics)
- Akathisia (dose-dependent)
- Fasting glucose increased
- Common (1-10%) adverse effects include
- Uncommon (0.1-1%) adverse effects include
- Rare (<0.1%) adverse effects include
- Unknown frequency adverse effects include
- Transient ischaemic attack
- Hyperprolactinaemia (seems to be a rather prominent adverse effect according to the aforementioned meta-analysis)
- α1-adrenergic receptor (Ki = 48 nM)
- α2A-adrenergic receptor (Ki = 1.6 nM)
- α2C-adrenergic receptor (Ki = 10.8 nM)
- D1 receptor (Ki = 262 nM)
- D2 receptor (Ki = 1.7 nM)
- 5-HT2A receptor (Ki = 2.0 nM)
- 5-HT2C receptor (Ki = 415 nM)
- 5-HT7 receptor (Ki = 0.5 nM)
- 5-HT1A receptor (Ki = 6.8 nM)
Note: All values are rounded to the nearest tenth.
Lurasidone is metabolized in the liver via the enzyme CYP3A4. This means that its plasma concentrations may be increased when combined with CYP3A4 inhibitors like ketoconazole or grapefruit juice, possibly leading to more side effects. Co-administration of CYP3A4 inducers like rifampicin or St. John's wort can reduce plasma levels and consequently decrease the effects of the drug.
The large scale synthesis of lurasidone began with the bis-mesylation of commercially available diol 1 to furnish disulfone 2. Dialkylation of piperazine 3 with disulfone 2 under basic conditions afforded spirocyclic tetralkyl ammonium species 4. By subjecting tetralkyl ammonium salt 4 to basic conditions in the presence of succinimide 5 an interesting regioselective ring-opening alkylation reaction occurs to form the 1,2-trans-substituted cyclohexane motif of lurasidone. Finally, exposure of lurasidone to hydrochloric acid provided the lurasidone hydrochloride salt.
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