Olanzapine

Olanzapine(LY170053) is a high affinity for 5-HT2 serotonin and D2 dopamine receptor antagonist.

Non-medical use of olanzapine by people on methadone treatment.[Pubmed:28377810]

BJPsych Bull. 2016 Dec;40(6):314-317.

Aims and method We examined non-medical use (NMU) of Olanzapine among adults on methadone treatment. Information was collected on patient demographics and NMU of Olanzapine. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) was administered to assess risk among current users of Olanzapine. Results Ninety-two clients participated and 30% reported lifetime history of NMU of Olanzapine. Nine people reported doses of 30 mg or higher on a typical day of use, with three typically using 100 mg. The most common reasons for use were to relieve anxiety and to aid sleep, but a quarter used it to 'get stoned'. Eleven participants (12%) reported NMU of Olanzapine in the preceding month. Eight completed the ASSIST with four scoring in the high-risk zone. Clinical implications Self-medication is the dominant motivator for NMU of Olanzapine, but hedonic motivations also occur. A small minority show features of dependency. All doctors should be aware of the potential NMU of Olanzapine, especially among patients with history of addiction.

Reducing the rehospitalization risk after a manic episode: A population based cohort study of lithium, valproate, olanzapine, quetiapine and aripiprazole in monotherapy and combinations.[Pubmed:28364619]

J Affect Disord. 2017 Aug 1;217:16-23.

BACKGROUND: Data on real-world rehospitalization risks in patients using different drugs and combination therapies for relapse prevention after a manic episode is limited. METHODS: We conducted a nationwide population based cohort study using data from Swedish national registers. Swedish residents aged 18-75 years who were hospitalized for a manic episode between July 1, 2006 and December 2, 2014 were included. Prescription fills of lithium, valproate, Olanzapine, quetiapine and aripiprazole were recorded throughout the first four weeks after hospital discharge, after which the patients were followed for up to one year. General and treatment specific rehospitalization risks were determined and results were adjusted for clinical and sociodemographic factors. RESULTS: The study included follow-up data from 6 502 hospitalizations for mania. Pharmacologic relapse prevention was used after 78% of these hospitalizations. Monotherapies and combination therapies were equally common. The average one-year rehospitalization risk for patients who did versus did not initiate prophylactic treatment was 39% and 46%, respectively. The lowest rehospitalization risks were seen in patients on combination therapy with Olanzapine and valproate or Olanzapine and lithium, experiencing one year rehospitalization risks of 32% and 34% (adjusted hazard ratios 0.76 (95% confidence interval [CI] 0.62-0.93) and 0.83 (95% CI 0.70-0.98), compared to lithium monotherapy). LIMITATIONS: Register data does not provide information on all clinical parameters affecting treatment choices. CONCLUSIONS: One-year rehospitalization rates after a manic episode are considerable also for patients who initiate prophylactic treatment. Combination therapies including Olanzapine and a classic mood-stabilizer may be beneficial for reducing rehospitalization risks after a manic episode.

Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.[Pubmed:28377074]

Eur Neuropsychopharmacol. 2017 Jul;27(7):667-678.

Weight gain is an important side effect of most atypical antipsychotic drugs such as Olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with Olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of Olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with Olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of Olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by Olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by Olanzapine.

Sulpiride, Amisulpride, Thioridazine, and Olanzapine: Interaction with Model Membranes. Thermodynamic and Structural Aspects.[Pubmed:28375612]

ACS Chem Neurosci. 2017 Jul 19;8(7):1543-1553.

Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, Olanzapine, sulpiride, and amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and zeta potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and Olanzapine, which bind to both neutral and negatively charged membranes, amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of Olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.

Radioreceptor binding profile of the atypical antipsychotic olanzapine.[Pubmed:8822531]

Neuropsychopharmacology. 1996 Feb;14(2):87-96.

The affinities of Olanzapine, clozapine, haloperidol, and four potential antipsychotics were compared on binding to the neuronal receptors of a number of neurotransmitters. In both rat tissues and cell lines transfected with human receptors Olanzapine had high affinity for dopamine D1, D2, D4, serotonin (5HT)2A, 5HT2C, 5HT3, alpha 1-adrenergic, histamine H1, and five muscarinic receptor subtypes. Olanzapine had lower affinity for alpha 2-adrenergic receptors and relatively low affinity for 5HT1 subtypes, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The receptor binding affinities for Olanzapine was quite similar in tissues from rat and human brain. The binding profile of Olanzapine was comparable to the atypical antipsychotic clozapine, while the binding profiles for haloperidol, resperidone, remoxipride, Org 5222, and seroquel were substantially different from that of clozapine. The receptor binding profile of Olanzapine is consistent with the antidopaminergic, antiserotonergic, and antimuscarinic activity observed in animal models and predicts atypical antipsychotic activity in man.

The behavioral pharmacology of olanzapine, a novel "atypical" antipsychotic agent.[Pubmed:1354253]

J Pharmacol Exp Ther. 1992 Aug;262(2):545-51.

Olanzapine (LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine) is a novel "atypical" antipsychotic agent with 5-hydroxytryptamine2.dopamine D1/D2 antagonist activity and anticholinergic properties. In behavioral studies, Olanzapine (1.25-10 mg/kg, p.o.) antagonizes apomorphine-induced climbing behavior in mice, demonstrating that the compound possesses D1/D2 antagonist activity in vivo. Olanzapine (0.3-20 mg/kg, p.o.) antagonizes 5-hydroxytryptophan-induced head twitches in mice at doses much lower than those required to block the climbing response, confirming that in vivo, the compound is a more potent 5-hydroxytryptamine2 antagonist than dopamine antagonist. Olanzapine (2.5-10 mg/kg, p.o.) also antagonized oxotremorine-induced tremor in mice. In a conditioned avoidance paradigm in rats, Olanzapine inhibits the avoidance response with an ED50 of 4.7 mg/kg p.o; however, unlike other antipsychotic agents, catalepsy is only observed at much higher doses (ED50 39.4 mg/kg, p.o.). These data would suggest that the compound will be less likely to produce undesirable extrapyramidal symptoms. Unlike "typical" antipsychotics, Olanzapine (1.25-5 mg/kg p.o.) increases responding during the conflict component of a modified Geller Seifter test, demonstrating that the compound may also possess anxiolytic activity. In another series of experiments, Olanzapine (1.25 mg/kg, i.p.) produced clozapine-appropriate responding in a drug discrimination model in which animals had been trained to discriminate clozapine (5 mg/kg, i.p.) from vehicle. On the basis of these results, it would therefore be predicted that Olanzapine will have an atypical profile and will be less likely to induce undesirable extrapyramidal symptoms than currently available drugs.

Olanzapine is a selective monoaminergic antagonist with high affinity binding to serotonin H1, 5HT2A/2C, 5HT3, 5HT6 (Ki=7, 4, 11, 57, and 5 nM, respectively), dopamine D1-4 (Ki=11 to 31 nM), muscarinic M1-5 (Ki=1.9-25 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is an atypical antipsychotic.

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