The Experts below are selected from a list of 24 Experts worldwide ranked by ideXlab platform
Marcus Tullius Scotti - One of the best experts on this subject based on the ideXlab platform.
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benzo and thienobenzo diazepines multi target drugs for cns disorders
Mini-reviews in Medicinal Chemistry, 2015Co-Authors: F J B Mendonca, Luciana Scotti, Hamilton Mitsugu Ishiki, S P S Botelho, M S Da Silva, Marcus Tullius ScottiAbstract:Benzodiazepines (BZ or BZD) are a class of gabaminergic psychoactive chemicals used in hypnotics, sedation, in the treatment of anxiety, and in other CNS disorders. These drugs include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and others. There are two distinct types of pharmacological binding sites for benzodiazepines in the brain (BZ1 and BZ2), these sites are on GABA-A receptors, and are classified as short, intermediate, or long-acting. From the Thienobenzodiazepine class (TBZ), Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) (Zyprexa) was used as an example to demonstrate the antagonism of this class of compounds for multiples receptors including: dopamine D1-D5, α-adrenoreceptor, histamine H1, muscarinic M1-M5 and 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT6 receptors. Olanzapine is an atypical antipsychotic agent, structurally related to clozapine, and extensively used for the treatment of schizophrenia, bipolar disorder-associated mania, and the behavioral symptoms of Alzheimer's disease. The functional blockade of these multiple receptors contributes to the wide range of its pharmacologic and therapeutic activities, having relatively few side effects when compared to other antipsychotics agents. Thienobenzodiazepines (such as Olanzapine) are characterized as multi- receptor- targeted- acting- agents. This mini-review discusses these 2 drug classes that act on the central nervous system, the main active compounds used, and the various receptors with which they interact. In addition, we propose 12 olanzapine analogues, and generated Random Forest models, from a data set obtained from the ChEMBL database, to classify the structures as active or inactive against 5 dopamine receptors (D1, D2, D3, D4, D5 and D6), and dopamine transporter.
Yoshinori Makino - One of the best experts on this subject based on the ideXlab platform.
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feasibility of olanzapine multi acting receptor targeted antipsychotic agent for the prevention of emesis caused by continuous cisplatin or ifosfamide based chemotherapy
Investigational New Drugs, 2018Co-Authors: Seiko Bun, Kan Yonemori, Toru Akagi, Emi Noguchi, Tatsunori Shimoi, Akihiko Shimomura, Mayu Yunokawa, Chikako Shimizu, Yasuhiro Fujiwara, Yoshinori MakinoAbstract:Background To determine the feasibility and efficacy of olanzapine, which is approved by the Pharmaceuticals and Medical Devices Agency as multi acting receptor targeted antipsychotic agent of the Thienobenzodiazepine class, for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients undergoing continuous five-day chemotherapy. Patients and methods This study was a prospective dose escalation study at a single center (UMIN ID: UMIN000015386). Patients received a combination of adriamycin and ifosfamide (AI) or a combination of bleomycin, etoposide, and cisplatin (BEP). On days 1–5, all patients received intravenous granisetron (1 mg) and intravenous dexamethasone sodium phosphate (24 mg). Olanzapine was administrated on day-1 to day5 at bedtime. The dose of olanzapine followed a dose-escalation scheme, with monitoring of safety and tolerability at each dose. A 3 + 3 cohort design was used, with three to six patients per cohort. Results Nine patients were enrolled (three for each cohort). No patients experienced dose-limiting toxicity (DLT). The most frequent adverse events were dry mouth and constipation. In each cohort, the maximum severity of nausea was Grade 2, and no patients experienced a vomiting episode. Conclusion A 2.5 mg/day dosage of olanzapine is sufficient to prevent from CINV in Japanese patients receiving continuous five-day chemotherapy. A dose of 10 mg/day, which is recommended by international CINV guidelines, is also tolerated. If CINV is not controlled by an initial dose of 2.5 mg/day of olanzapine, dosage escalation is encouraged. Future studies should compare olanzapine with aprepitant.
F J B Mendonca - One of the best experts on this subject based on the ideXlab platform.
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benzo and thienobenzo diazepines multi target drugs for cns disorders
Mini-reviews in Medicinal Chemistry, 2015Co-Authors: F J B Mendonca, Luciana Scotti, Hamilton Mitsugu Ishiki, S P S Botelho, M S Da Silva, Marcus Tullius ScottiAbstract:Benzodiazepines (BZ or BZD) are a class of gabaminergic psychoactive chemicals used in hypnotics, sedation, in the treatment of anxiety, and in other CNS disorders. These drugs include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and others. There are two distinct types of pharmacological binding sites for benzodiazepines in the brain (BZ1 and BZ2), these sites are on GABA-A receptors, and are classified as short, intermediate, or long-acting. From the Thienobenzodiazepine class (TBZ), Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) (Zyprexa) was used as an example to demonstrate the antagonism of this class of compounds for multiples receptors including: dopamine D1-D5, α-adrenoreceptor, histamine H1, muscarinic M1-M5 and 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT6 receptors. Olanzapine is an atypical antipsychotic agent, structurally related to clozapine, and extensively used for the treatment of schizophrenia, bipolar disorder-associated mania, and the behavioral symptoms of Alzheimer's disease. The functional blockade of these multiple receptors contributes to the wide range of its pharmacologic and therapeutic activities, having relatively few side effects when compared to other antipsychotics agents. Thienobenzodiazepines (such as Olanzapine) are characterized as multi- receptor- targeted- acting- agents. This mini-review discusses these 2 drug classes that act on the central nervous system, the main active compounds used, and the various receptors with which they interact. In addition, we propose 12 olanzapine analogues, and generated Random Forest models, from a data set obtained from the ChEMBL database, to classify the structures as active or inactive against 5 dopamine receptors (D1, D2, D3, D4, D5 and D6), and dopamine transporter.
Ellen C Fisher - One of the best experts on this subject based on the ideXlab platform.
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persistent choreoathetosis in a fatal olanzapine overdose drug kinetics neuroimaging and neuropathology
American Journal of Psychiatry, 2005Co-Authors: Larry E Davis, Mark W Becher, Wieslawa Tlomak, Blaine E Benson, Roland R Lee, Ellen C FisherAbstract:Atypical antipsychotics are a relatively new group of medications for the management of psychosis. Currently approved medications of this category include clozapine, risperidone, quetiapine, and olanzapine. Olanzapine was first marketed in 1996 in the United States as an atypical antipsychotic medication similar to clozapine for schizophrenia. By 2002, olanzapine was widely used and in the top 20 drugs by sales (1). Olanzapine belongs to the Thienobenzodiazepine drug class and is known to have a high affinity for dopamine D2, D3, and D4 receptors, all five serotonin HT2 receptor subtypes, the 5-HT6 receptor, acetylcholine muscarinic receptors, and α1-adrenergic and histamine H1 receptors (2). The drug is well absorbed from the gut and reaches maximum plasma concentration about 6 hours after an oral dose (3). In plasma, 93% of the drug is bound to serum proteins, especially albumin (3). The drug is extensively eliminated by first-pass metabolism in the liver and has a mean elimination half-life of 30 hours, with a range of 21–54 hours (3). Olanzapine is considered to have a good overall safety profile at therapeutic doses (4). Adverse effects of olanzapine that affect the nervous system include mental status deterioration and extrapyramidal signs and, rarely, delirium, mutism, confusion, aggression, and lethargy that can progress to coma. Seizures, status epilepticus, and hypersalivation occasionally develop (5, 6). Extrapyramidal signs may include dystonia, parkinsonism, akathisia, choreoathetosis, and neuroleptic malignant syndrome (7– 9). Serious systemic complications include diabetes mellitus, tachycardia and supraventricular tachycardia, arrhythmias, and cardiopulmonary arrest (10, 11). Overdoses can lead to deaths. The American Association of Poison Control Centers Toxic Exposure Surveillance System reported the number of deaths associated with olanzapine to be six in 2000 (12), 10 in 2001 (13), and 10 in 2002 (14). Before some of these deaths, concomitant agents were ingested. The majority of deaths occurred within 12 hours of overdose, and the results of autopsies, when available, were often unremarkable (15–17). We report here a patient who survived the early phase of an overdose. He then developed coma with persistent choreoathetosis and hypersalivation, and neuroimaging and autopsy findings suggested damage to the basal ganglia.
Seiko Bun - One of the best experts on this subject based on the ideXlab platform.
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feasibility of olanzapine multi acting receptor targeted antipsychotic agent for the prevention of emesis caused by continuous cisplatin or ifosfamide based chemotherapy
Investigational New Drugs, 2018Co-Authors: Seiko Bun, Kan Yonemori, Toru Akagi, Emi Noguchi, Tatsunori Shimoi, Akihiko Shimomura, Mayu Yunokawa, Chikako Shimizu, Yasuhiro Fujiwara, Yoshinori MakinoAbstract:Background To determine the feasibility and efficacy of olanzapine, which is approved by the Pharmaceuticals and Medical Devices Agency as multi acting receptor targeted antipsychotic agent of the Thienobenzodiazepine class, for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients undergoing continuous five-day chemotherapy. Patients and methods This study was a prospective dose escalation study at a single center (UMIN ID: UMIN000015386). Patients received a combination of adriamycin and ifosfamide (AI) or a combination of bleomycin, etoposide, and cisplatin (BEP). On days 1–5, all patients received intravenous granisetron (1 mg) and intravenous dexamethasone sodium phosphate (24 mg). Olanzapine was administrated on day-1 to day5 at bedtime. The dose of olanzapine followed a dose-escalation scheme, with monitoring of safety and tolerability at each dose. A 3 + 3 cohort design was used, with three to six patients per cohort. Results Nine patients were enrolled (three for each cohort). No patients experienced dose-limiting toxicity (DLT). The most frequent adverse events were dry mouth and constipation. In each cohort, the maximum severity of nausea was Grade 2, and no patients experienced a vomiting episode. Conclusion A 2.5 mg/day dosage of olanzapine is sufficient to prevent from CINV in Japanese patients receiving continuous five-day chemotherapy. A dose of 10 mg/day, which is recommended by international CINV guidelines, is also tolerated. If CINV is not controlled by an initial dose of 2.5 mg/day of olanzapine, dosage escalation is encouraged. Future studies should compare olanzapine with aprepitant.