Pathways

Luliconazole is a topical antifungal agent used to treat fungal infections. Luliconazole is a topical antifungal agent that acts by unknown mechanisms but is postulated to involve altering the synthesis of fungi cell membranes. It was approved by the FDA (USA) in November 2013 and is marketed under the brand name Luzu. Luliconazole is also approved in Japan. Luliconazole kills the organisms Trichophyton rubrum and Epidermophyton floccosum, most likely by altering their fungal cell membranes. The exact mechanism of action for luliconazole's anti-fungal activity is still not known, but luliconazole is thought to inhibit the enzyme lanosterol 14-alpha demethylase. Lanosterol 14-alpha demethylase is the enzyme that catalyzes the synthesis of 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol from lanosterol. With this enzyme inhibited ergosterol synthesis cannot occur which causes a significant low concentration of ergosterol in the fungal cell. Ergosterol is essential in maintaining membrane integrity in fungi. Without ergosterol, the fungus cell cannot synthesize membranes thereby increasing fluidity and preventing growth of new cells. This leads to cell lysis which causes it to collapse and die.

Luliconazole is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Luliconazole passes through the liver and is then excreted from the body mainly through the kidney.

Lumateperone, also known as ITI-007, is approved for the treatment of schizophrenia in adults. It is also approved for the treatment of depressive episodes associated with bipolar disorder (i.e. bipolar depression) in adults, as monotherapy and/or adjunctive therapy with lithium or valproate. Unlike other antipsychotics, lumateperone has partial agonist activity at presynaptic dopamine (D2) receptors, resulting in reduced presynaptic release of dopamine, and antagonistic activity at postsynaptic dopamine (D2) receptors. Lumateperone's pre-synaptic partial agonist activity prevents positive feedback at D2 receptors while simultaneously blocking dopaminergic neurotransmission at the post-synaptic D2 receptor. This dual action at D2 receptors prevents an increase in dopamine in the synaptic cleft while simultaneously blocking post-synaptic D2 receptors. It is thought that this is responsible for the fact that lumateperone requires D2 receptor occupancy as low as 40%, an uncommon characteristic in antipsychotics. Both reduced receptor occupancy and its dual action at D2 receptors are thought to contribute to lumateperone's low incidence of extrapyramidal side effects, such as tardive dyskinesia and parkinsonian-like effects. These characteristics allow lumateperone to efficiently reduce dopamine signaling. Lumateperone also targets dopamine (D1) receptors, and a useful secondary result of D1 activation is increased glutamatergic N-methyl-D-aspartate (NMDA) GluN2B receptor phosphorylation. This is significant since NMDA mediated glutamate signaling appears to be impaired in patients who have schizophrenia. Lumateperone is capable of modulating serotonin by inhibiting serotonin transporters (SERT), and by behaving as a 5-HT2A receptor antagonist. Lumateperone has been found to augment the activities of NMDA and AMPA receptors in the prefrontal cortex. Although the exact mechanism is unknown, it has been found that this is partly through a D1-receptor-mediated mechanism that results in the phosphorylation of GluN2B subunits of NMDA receptors in the mesolimbic pathways of the brain. This correlates with lumateperone's regioselectivity for mesolimbic circuits and lower affinity for nigrostriatal dopamine pathways. It is thought that this activity may be an important contributor to its effects as an antipsychotic and antidepressant, as NMDA-receptor activity is known to be deficient in schizophrenic patients. It is an inhibitor of the serotonin reuptake transporter, which is the mechanism of action of SSRI antidepressants, resulting in potential antidepressant activity and efficacy against the negative symptoms of schizophrenia (i.e., depression).This may be an essential factor in lumateperone's efficacy in both bipolar depression as well as the negative symptoms associated with schizophrenia. lumateperone exhibits 60x greater affinity for 5-HT2A receptors than D2 receptors. This is thought to be significant in lumateperone's gradient of clinical effects, which provides lumateperone with a potentially more extensive range of clinical use. At low dosages, lumateperone's effects are mainly sedative and anti-aggressive. The ability of lumateperone to exhibit these effects at low dosages may result from a lack of D2 receptor binding and preferential, potent 5HT2A antagonism at low dosages. In contrast, increasing dosages show increasing D2 receptor binding and occupancy in addition to 5HT2A receptor binding, resulting in antipsychotic efficacy.

Lumateperone, also known as ITI-007, is approved for the treatment of schizophrenia in adults. It is also approved for the treatment of depressive episodes associated with bipolar disorder (i.e. bipolar depression) in adults, as monotherapy and/or adjunctive therapy with lithium or valproate. Unlike other antipsychotics, lumateperone has partial agonist activity at presynaptic dopamine (D2) receptors, resulting in reduced presynaptic release of dopamine, and antagonistic activity at postsynaptic dopamine (D2) receptors. Lumateperone's pre-synaptic partial agonist activity prevents positive feedback at D2 receptors while simultaneously blocking dopaminergic neurotransmission at the post-synaptic D2 receptor. This dual action at D2 receptors prevents an increase in dopamine in the synaptic cleft while simultaneously blocking post-synaptic D2 receptors. It is thought that this is responsible for the fact that lumateperone requires D2 receptor occupancy as low as 40%, an uncommon characteristic in antipsychotics. Both reduced receptor occupancy and its dual action at D2 receptors are thought to contribute to lumateperone's low incidence of extrapyramidal side effects, such as tardive dyskinesia and parkinsonian-like effects. These characteristics allow lumateperone to efficiently reduce dopamine signaling. Lumateperone also targets dopamine (D1) receptors, and a useful secondary result of D1 activation is increased glutamatergic N-methyl-D-aspartate (NMDA) GluN2B receptor phosphorylation. This is significant since NMDA mediated glutamate signaling appears to be impaired in patients who have schizophrenia. Lumateperone is capable of modulating serotonin by inhibiting serotonin transporters (SERT), and by behaving as a 5-HT2A receptor antagonist. Lumateperone has been found to augment the activities of NMDA and AMPA receptors in the prefrontal cortex. Although the exact mechanism is unknown, it has been found that this is partly through a D1-receptor-mediated mechanism that results in the phosphorylation of GluN2B subunits of NMDA receptors in the mesolimbic pathways of the brain. This correlates with lumateperone's regioselectivity for mesolimbic circuits and lower affinity for nigrostriatal dopamine pathways. It is thought that this activity may be an important contributor to its effects as an antipsychotic and antidepressant, as NMDA-receptor activity is known to be deficient in schizophrenic patients. It is an inhibitor of the serotonin reuptake transporter, which is the mechanism of action of SSRI antidepressants, resulting in potential antidepressant activity and efficacy against the negative symptoms of schizophrenia (i.e., depression).This may be an essential factor in lumateperone's efficacy in both bipolar depression as well as the negative symptoms associated with schizophrenia. lumateperone exhibits 60x greater affinity for 5-HT2A receptors than D2 receptors. This is thought to be significant in lumateperone's gradient of clinical effects, which provides lumateperone with a potentially more extensive range of clinical use. At low dosages, lumateperone's effects are mainly sedative and anti-aggressive. The ability of lumateperone to exhibit these effects at low dosages may result from a lack of D2 receptor binding and preferential, potent 5HT2A antagonism at low dosages. In contrast, increasing dosages show increasing D2 receptor binding and occupancy in addition to 5HT2A receptor binding, resulting in antipsychotic efficacy.