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3.
Gan To Kagaku Ryoho ; 47(10): 1471-1475, 2020 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-33130743

RESUMO

This retrospective study aimed to evaluate the effect of the antiemetic drug olanzapine(OLZ)on blood sugar levels in patients treated with adjuvant or neoadjuvant chemotherapy(AC: doxorubicin plus cyclophosphamide or CEF: cyclophosphamide plus epirubicin plus fluorouracil) for breast cancer. Here, we evaluated the frequency of diabetes(postprandial blood sugar: PBS≥200 mg/dL)and the change in PBS in 149 patients who were prescribed OLZ between September 2016 and August 2017 at our hospital. No diabetic patients were identified during the observation period(median: 3 cycles of chemotherapy). Among the 95 patients with more than 2 PBS readings, no difference was observed in the incidence of increased PBS, regardless of the diabetic risk, before and after OLZ administration. This study therefore found that the short term use of OLZ as an antiemetic had little effect on PBS, suggesting that it can be used safely during treatment with AC or CEF.


Assuntos
Antieméticos , Neoplasias da Mama , Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Glicemia , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Ciclofosfamida/efeitos adversos , Epirubicina/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Terapia Neoadjuvante , Olanzapina , Estudos Retrospectivos , Resultado do Tratamento
5.
Lancet Psychiatry ; 7(11): 945-954, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33069317

RESUMO

BACKGROUND: Amisulpride, aripiprazole, and olanzapine are first-line atypical antipsychotics that have not previously been compared head-to-head in a pragmatic trial. We aimed to compare the efficacy and safety of these agents in a controlled trial. METHODS: This pragmatic, rater-blind, randomised controlled trial was done in three academic centres of psychiatry in Norway, and one in Austria. Eligible patients were aged 18 years or older, met ICD-10 criteria for schizophrenia-spectrum disorders (F20-29), and had symptoms of active psychosis. Eligible patients were randomly assigned to receive oral amisulpride, aripiprazole, or olanzapine. Treatment allocation was open to patients and staff, and starting dose, treatment changes, and adjustments were left to the discretion of the treating physician. Computer-generated randomisation lists for each study centre were prepared by independent statisticians. Patients were followed up for 52 weeks after random assignment, during which assessments were done 8 times by researchers masked to treatment. The primary outcome was reduction of the Positive And Negative Syndrome Scale (PANSS) total score at 52 weeks, and primary analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01446328. FINDINGS: Between Oct 20, 2011, and Dec 30, 2016, we assessed 359 patients for eligibility. 215 patients were excluded (107 did not meet inclusion criteria, 82 declined to participate, 26 other reasons). 144 patients (mean baseline PANSS total estimated score 78·4 [SD 1·4]) were randomly assigned 1:1:1 to receive amisulpride (44 patients), aripiprazole (48 patients) or olanzapine (52 patients). After 52 weeks, the patients allocated to amisulpride had a PANSS total score reduction of 32·7 points (SD 3·1) compared with 21·9 points reduction with aripiprazole (SD 3·9, p=0·027) and 23·3 points with olanzapine (2·9, p=0·025). We observed weight gain and increases of serum lipids and prolactin in all groups. 26 serious adverse events (SAEs) among 20 patients were registered (four [9%] of 44 patients allocated to amisulpride, ten [21%] of 48 patients allocated to aripiprazole, and six [12%] of 52 patients allocated to olanzapine), with no statistically significant differences between the study drugs. 17 (65%) of the 26 SAEs occurred during the use of the study drug, with readmission or protracted hospital admission accounting for 13 SAEs. One death by suicide, one unspecified death, and one life-threatening accident occurred during follow-up, after cessation of treatment. INTERPRETATION: Amisulpride was more efficacious than aripiprazole or olanzapine for reducing the PANSS total scores in adults with schizophrenia-spectrum disorders. Side-effect differences among the groups were generally small. This study supports the notion that clinically relevant efficacy differences exist between antipsychotic drugs. Future research should aim to compare first-line antipsychotics directly in pragmatic clinical trials that reflect everyday clinical practice. FUNDING: The Research Council of Norway, the Western Norway Regional Health Trust, and participating hospitals and universities.


Assuntos
Amissulprida/uso terapêutico , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Olanzapina/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Amissulprida/efeitos adversos , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Olanzapina/efeitos adversos , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Ganho de Peso/efeitos dos fármacos , Adulto Jovem
6.
Sci Rep ; 10(1): 17028, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046806

RESUMO

Olanzapine-induced dyslipidemia significantly increases the risk of cardiovascular disease in patients with schizophrenia. However, the clinical features of olanzapine-induced dyslipidemia remain hitherto unclear because of inconsistencies in the literature. This meta-analysis thus investigated the effects of olanzapine treatment on lipid profiles among patients with schizophrenia. Studies of the effects of olanzapine on lipids were obtained through the PubMed, Web of science, The Cochrane Library and Embase databases (up to January 1, 2020). Twenty-one studies and 1790 schizophrenia patients who received olanzapine therapy were included in our analysis. An olanzapine-induced increase was observed in plasma triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels in patients with schizophrenia (all P < 0.05). Moreover, the time points analyzed included the following: baseline, 4 weeks, 6 weeks, 8 weeks, 12 weeks, and ≥ 24 weeks (data of ≥ 24 weeks were integrated). The significant elevation of TG, TC, and LDL-C was observed in patients with schizophrenia already by 4 weeks of olanzapine therapy (all P < 0.05), with no obvious changes observed in high-density lipoprotein cholesterol (HDL-C) (P > 0.05). In conclusion, olanzapine-induced dyslipidemia, characterized by increased TG, TC, and LDL-C levels, was observed in patients with schizophrenia already by 4 weeks of olanzapine treatment.


Assuntos
Antipsicóticos/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Olanzapina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacologia , Humanos , Olanzapina/farmacologia , Esquizofrenia/sangue
8.
Am J Physiol Endocrinol Metab ; 319(6): E1101-E1111, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017220

RESUMO

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing psychoses, acute olanzapine treatment causes hyperglycemia. Pharmacological agonists of the glucagon-like peptide 1 (GLP1) receptor have been shown to offset weight gain associated with chronic SGA administration. It is not known whether GLP1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine whether pharmacological targeting of the GLP1 receptor would be sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine and/or the GLP1 receptor agonists liraglutide and exendin 4, and the blood glucose response was measured. We found that liraglutide or exendin 4 completely protected male mice against olanzapine-induced hyperglycemia in parallel with increases in circulating insulin (liraglutide, exendin 4) and reductions in glucagon (liraglutide only). In additional experiments, female mice, which are protected from acute olanzapine-induced hyperglycemia, displayed hyperglycemia, increases in glucagon, and reductions in insulin when treated with olanzapine and the GLP1 receptor antagonist exendin 9-39 compared with olanzapine treatment alone. Although in some instances the pharmacological targeting of the GLP1 receptor attenuated indexes of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signaling through the GLP1 receptor can remarkably influence acute olanzapine-induced hyperglycemia, and from the standpoint of protecting against acute excursions in blood glucose, GLP1 receptor agonists should be considered as an adjunct treatment approach.NEW & NOTEWORTHY Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hiperglicemia/induzido quimicamente , Hiperglicemia/prevenção & controle , Olanzapina , Inibidores de Captação de Serotonina , Animais , Exenatida/uso terapêutico , Feminino , Teste de Tolerância a Glucose , Hipoglicemiantes/uso terapêutico , Lipólise/efeitos dos fármacos , Liraglutida/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismo
9.
Toxicol Appl Pharmacol ; 406: 115214, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866524

RESUMO

Mortality in psychiatric patients with severe mental illnesses reaches a 2-3 times higher mortality rate compared to the general population, primarily due to somatic comorbidities. A high prevalence of cardiovascular morbidity can be attributed to the adverse metabolic effects of atypical antipsychotics (atypical APs), but also to metabolic dysregulation present in drug-naïve patients. The metabolic aspects of neurodevelopmental schizophrenia-like models are understudied. This study evaluated the metabolic phenotype of a methylazoxymethanol (MAM) schizophrenia-like model together with the metabolic effects of three APs [olanzapine (OLA), risperidone (RIS) and haloperidol (HAL)] administered via long-acting formulations for 8 weeks in female rats. Body weight, feed efficiency, serum lipid profile, gastrointestinal and adipose tissue-derived hormones (leptin, ghrelin, glucagon and glucagon-like peptide 1) were determined. The lipid profile was assessed in APs-naïve MAM and control cohorts of both sexes. Body weight was not altered by the MAM model, though cumulative food intake and feed efficiency was lowered in the MAM compared to CTR animals. The effect of the APs was also present; body weight gain was increased by OLA and RIS, while OLA induced lower weight gain in the MAM rats. Further, the MAM model showed lower abdominal adiposity, while OLA increased it. Serum lipid profile revealed MAM model-induced alterations in both sexes; total, HDL and LDL cholesterol levels were increased. The MAM model did not exert significant alterations in hormonal parameters except for elevation in leptin level. The results support intrinsic metabolic dysregulation in the MAM model in both sexes, but the MAM model did not manifest higher sensitivity to metabolic effects induced by antipsychotic treatment.


Assuntos
Modelos Animais de Doenças , Acetato de Metilazoximetanol/análogos & derivados , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Feminino , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Olanzapina/farmacologia , Olanzapina/uso terapêutico , Ratos Sprague-Dawley , Risperidona/farmacologia , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico
10.
Psychiatry Res ; 293: 113470, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32992097

RESUMO

Olanzapine is an atypical antipsychotic drug that has been increasingly used for treatment in schizophrenia. It has been observed that olanzapine responses in schizophrenia patients vary individually, but the reason has not been elucidated. In the study, we aimed to comprehensively explore the relationships between olanzapine responses and genetic polymorphisms of drug metabolizing enzymes, transporters and target receptors, and so as to interpret the reason of good and poor responses of olanzapine. A total of 241 Chinese Han paranoid schizophrenia who treated with olanzapine alone for 4 weeks were recruited. The positive and negative symptom scale (PANSS) was used to evaluate the efficacy of olanzapine. The genetic polymorphisms were detected by improved multiple ligase detection reaction (iMLDR). Multivariate logistic regression analysis suggested that the genetic polymorphisms of CYP1A2 rs762551, UGT1A4 rs2011425, ABCB1 rs1045642, DRD2 rs1799732 and rs1799978, 5-HTR2A rs6311 were significantly associated with olanzapine response. Multifactor dimensionality reduction (MDR) analysis showed that there was a negative interaction between CYP1A2 rs762551, ABCB1 rs1045642, DRD2 rs1799978, 5-HTR2A rs6311 and the interaction model was the optimal model. Our findings could partially explain the different olanzapine outcome and provided evidence for clarifying the predictive indicators of olanzapine response in further.


Assuntos
Antipsicóticos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Citocromo P-450 CYP1A2/genética , Olanzapina/uso terapêutico , Esquizofrenia Paranoide/tratamento farmacológico , Adulto , Feminino , Genótipo , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Polimorfismo Genético , Esquizofrenia Paranoide/etnologia , Esquizofrenia Paranoide/genética , Resultado do Tratamento
11.
Am J Psychiatry ; 177(12): 1168-1178, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791894

RESUMO

OBJECTIVE: A combination of olanzapine and the opioid receptor antagonist samidorphan is under development for the treatment of schizophrenia and bipolar I disorder. The single-tablet combination treatment is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. In this phase 3 double-blind trial, the authors evaluated the weight profile of combined olanzapine/samidorphan compared with olanzapine in patients with schizophrenia. METHODS: Adults (ages 18‒55 years) with schizophrenia were randomly assigned to receive either combination treatment with olanzapine and samidorphan or olanzapine treatment for 24 weeks. Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. The key secondary endpoint was the proportion of patients with ≥7% weight gain. Waist circumference and fasting metabolic laboratory parameters were also measured. RESULTS: Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of -2.38% [SE=0.76] was significant). Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50). Increases in waist circumference were smaller in the olanzapine/samidorphan combination group compared with the olanzapine group. Schizophrenia symptom improvement was similar between treatment groups. Adverse events (in ≥10% of the groups) in the olanzapine/samidorphan and olanzapine groups included weight gain (24.8% and 36.2%), somnolence (21.2% and 18.1%), dry mouth (12.8% and 8.0%), and increased appetite (10.9% and 12.3%). Metabolic changes were small and similar between treatments. CONCLUSIONS: Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine and was well tolerated. The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy.


Assuntos
Naltrexona/análogos & derivados , Olanzapina/efeitos adversos , Olanzapina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Ganho de Peso/efeitos dos fármacos , Adolescente , Adulto , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Adulto Jovem
12.
J Affect Disord ; 277: 337-340, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858315

RESUMO

BACKGROUND: In December 2019, the novel coronavirus (SARS-CoV-2) infection was first reported in Wuhan city, central China, which has spread rapidly. The common clinical features of patients with SARS-CoV-2 infection included fever, fatigue, and damage to the respiratory or digestive system. However, it is still unclear whether SARS-CoV-2 infection could cause damage to the central nervous system (CNS) inducing psychiatric symptoms. CASE REPORT: Herein, we present the first case of SARS-CoV-2 infection with manic-like symptoms and describe the diagnosis, clinical course, and treatment of the case, focusing on the identifications of SARS-CoV-2 in the specimen of cerebrospinal fluid (CSF). The patient developed manic-like symptoms when his vital signs recovered on illness day 17. After manic-like attack, the detection of SARS-CoV-2 specific IgG antibody in CSF was positive, while the reverse transcriptase-polymerase chain reaction (RT-PCR) on CSF for the SARS-CoV-2 was negative. The patient received Olanzapine for treatment and his mood problems concurrently improved as indicated by scores of Young Manic Rating Scale (YMRS). LIMITATION: This is a single case report only, and the RT-PCR test for SARS-CoV-2 in CSF was not performed simultaneously when SARS-CoV-2 was positive in samples of sputum and stool. CONCLUSION: This first case of COVID-19 patient with manic-like symptoms highlights the importance of evaluation of mental health status and may contribute to our understanding of potential risk of CNS impairments by SARS-CoV-2 infection.


Assuntos
Transtorno Bipolar/etiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Anticorpos Antivirais/líquido cefalorraquidiano , Antipsicóticos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Transtorno Bipolar/líquido cefalorraquidiano , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Dor no Peito , China , Técnicas de Laboratório Clínico , Cobicistat/uso terapêutico , Infecções por Coronavirus/líquido cefalorraquidiano , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Darunavir/uso terapêutico , Dispneia , Febre , Glucocorticoides/uso terapêutico , Humanos , Indóis/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Moxifloxacina/uso terapêutico , Olanzapina/uso terapêutico , Pandemias , Faringite , Pneumonia Viral/líquido cefalorraquidiano , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
J Anal Toxicol ; 44(8): 915-922, 2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-32780823

RESUMO

Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.


Assuntos
Antipsicóticos/sangue , Detecção do Abuso de Substâncias/métodos , Adulto , Amissulprida/sangue , Aripiprazol/sangue , Benzodiazepinas/sangue , Cromatografia Líquida , Clozapina/sangue , Dibenzotiazepinas/sangue , Feminino , Toxicologia Forense , Humanos , Masculino , Olanzapina/sangue , Palmitato de Paliperidona/sangue , Piperazinas/sangue , Fumarato de Quetiapina/sangue , Estudos Retrospectivos , Risperidona/sangue , Esquizofrenia/tratamento farmacológico , Suicídio , Sulpirida/sangue , Espectrometria de Massas em Tandem , Tiazóis/sangue
14.
Expert Opin Pharmacother ; 21(12): 1455-1466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32633577

RESUMO

INTRODUCTION: Currently conceptualized as an obsessive compulsive and related disorder, trichotillomania, or hair-pulling disorder, is a common illness that causes significant distress or functional impairments in various life domains. Most individuals with trichotillomania also have other comorbid diagnoses. Treating trichotillomania with pharmacotherapy is complicated since there are currently no FDA-approved drugs for its treatment. AREAS COVERED: The databases PubMed, PsychINFO, CINAHL, Evidence-based Medicine Reviews, and Cochrane Database of Systematic Reviews were searched, yielding a total of 10 open trials and 10 controlled trials selected. This review aims to examine pharmacotherapeutic options for the treatment of trichotillomania in adults and makes recommendations for the assessment and management of the disorder. EXPERT OPINION: There is preliminary evidence that clomipramine, olanzapine, and N-acetylcysteine may be effective in cases of trichotillomania, however, given the paucity of controlled studies with large sample sizes, decisions regarding the use of drugs should be made on a case-by-case basis taking into account the severity of trichotillomania and the nature of psychiatric comorbidity.


Assuntos
Acetilcisteína/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Antipsicóticos/uso terapêutico , Clomipramina/uso terapêutico , Olanzapina/uso terapêutico , Tricotilomania/tratamento farmacológico , Adulto , Ensaios Clínicos como Assunto , Comorbidade , Feminino , Humanos , Resultado do Tratamento , Tricotilomania/epidemiologia , Tricotilomania/psicologia
15.
J Clin Psychiatry ; 81(4)2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32609960

RESUMO

OBJECTIVE: INP105 is a drug-device combination of olanzapine and technology that delivers a powder formulation of olanzapine to the vascular-rich upper nasal space. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single ascending doses of INP105, olanzapine intramuscular (OLZ IM), and olanzapine oral disintegrating tablet (OLZ ODT). METHODS: This was a phase 1, active and double-blind placebo comparator-controlled, ascending-dose, 2-period, incomplete-block, 1-way crossover study in 40 healthy subjects, randomized to single doses of OLZ IM (5 or 10 mg) or OLZ ODT (10 mg) in Period 1 and then 1 of 3 doses (5 mg, 10 mg, or 15 mg) of INP105 or placebo in Period 2 between July and October 2018. Sedation and attention were evaluated by visual analog scale (VAS), the Agitation/Calmness Evaluation Scale (ACES), and the Digit Symbol Substitution Test (DSST). RESULTS: At equivalent doses, INP105 provided similar area under the drug concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity, and maximum observed concentration (Cmax) as OLZ IM and greater Cmax than but similar AUCs to OLZ ODT. Median time to maximum concentration was less for INP105 (15, 10, and 9.5 min for 5 mg, 10 mg, and 15 mg, respectively) than for OLZ IM (20 and 15 min for 5 mg and 10 mg, respectively) or OLZ ODT (120 min). Effects as measured with the VAS, ACES, and DSST with INP105 5 mg were comparable to those with OLZ IM 5 mg, with earlier onset for INP105 10 mg and 15 mg and greater effects than placebo and OLZ ODT. The incidence of treatment-emergent adverse events with INP105 5 mg, 10 mg, and 15 mg was 80%, 66.7%, and 75%, respectively, compared to 90% and 100% for OLZ IM 5 mg and 10 mg, respectively, and 83.3% for OLZ ODT; most common were dizziness, hypotension, and orthostatic symptoms. CONCLUSIONS: INP105 has rapid absorption and pharmacodynamic effects and may represent an effective, convenient, noninvasive, and well-tolerated alternative for treating acutely agitated patients by self- or caregiver administration in the home, community, or hospital environments. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03624322.


Assuntos
Olanzapina/efeitos adversos , Olanzapina/farmacocinética , Administração Intranasal , Administração Oral , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Atenção/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/farmacologia , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Olanzapina/administração & dosagem , Olanzapina/farmacologia , Adulto Jovem
16.
Rinsho Shinkeigaku ; 60(8): 520-526, 2020 Aug 07.
Artigo em Japonês | MEDLINE | ID: mdl-32641633

RESUMO

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. His parents were not consanguineous, and there was no family history of neuropsychiatric diseases. On neurological examination, he showed mild cognitive impairment, saccadic eye pursuit with horizontal gaze nystagmus, mild dysarthria, dystonic posture and movement of the neck, incoordination of both hands, and an ataxic gait. Deep tendon reflexes were normal except for the patellar tendon reflex, which was exaggerated bilaterally. Pathological reflexes were negative and there was no sign of rigidity, sensory disturbance or autonomic dysfunction. Ophthalmological examinations detected thinning of the outer macula lutea in both eyes, indicative of macular dystrophy. After admission, all anti-psychotic drugs were ceased, but his dystonia was unchanged. Levodopa and trihexyphenidyl hydrochloride were not effective. General blood, urine and cerebrospinal fluid examinations showed no abnormalities. Brain MRI showed cerebellar atrophy and bilateral symmetrical thalamic lesions without brainstem atrophy or abnormal signals in the basal ganglia. I123-IMP SPECT also revealed a decreased blood flow in the cerebellum. Genetic screening, including whole exome sequencing conducted by the Initiative on Rare and Undiagnosed Disease identified no possible disease-causing variants. The patient's dystonia worsened and choreic movements manifested on his right hand and foot. We suspected dystonia with marked cerebellar atrophy (DYTCA), but could not exclude drug-induced dystonia. Macular dystrophy and bilateral thalamic lesions on brain MRI have not been previously described in DYTCA. Whether these features might be primarily associated with dystonia or cerebellar ataxia now remains to be determined.


Assuntos
Antipsicóticos/efeitos adversos , Ataxia Cerebelar/etiologia , Cerebelo/patologia , Distonia Muscular Deformante/etiologia , Distonia/etiologia , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Atrofia/diagnóstico por imagem , Atrofia/etiologia , Biperideno/efeitos adversos , Ataxia Cerebelar/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Distonia/diagnóstico por imagem , Distonia Muscular Deformante/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pescoço , Olanzapina/efeitos adversos
18.
Toxicol Appl Pharmacol ; 402: 115124, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32652086

RESUMO

Atypical antipsychotics (AAPs) have the tendency of inducing severe metabolic alterations like obesity, diabetes mellitus, insulin resistance, dyslipidemia and cardiovascular complications. These alterations have been attributed to altered hypothalamic appetite regulation, energy sensing, insulin/leptin signaling, inflammatory reactions and active reward anticipation. Line of evidence suggests that transient receptor potential vanilloid type 1 and 3 (TRPV1 and TRPV3) channels are emerging targets in treatment of obesity, diabetes mellitus and could modulate feed intake. The present study was aimed to investigate the putative role TRPV1/TRPV3 in olanzapine-induced metabolic alterations in mice. Female BALB/c mice were treated with olanzapine for six weeks to induce metabolic alterations. Non-selective TRPV1/TRPV3 antagonist (ruthenium red) and selective TRPV1 (capsazepine) and TRPV3 antagonists (2,2-diphenyltetrahydrofuran or DPTHF) were used to investigate the involvement of TRPV1/TRPV3 in chronic olanzapine-induced metabolic alterations. These metabolic alterations were differentially reversed by ruthenium red and capsazepine, while DPTHF didn't show any significant effect. Olanzapine treatment also altered the mRNA expression of hypothalamic appetite-regulating and nutrient-sensing factors, inflammatory genes and TRPV1/TRPV3, which were reversed with ruthenium red and capsazepine treatment. Furthermore, olanzapine treatment also increased expression of TRPV1/TRPV3 in nucleus accumbens (NAc), TRPV3 expression in ventral tegmental area (VTA), which were reversed by the respective antagonists. However, DPTHF treatment showed reduced feed intake in olanzapine treated mice, which might be due to TRPV3 specific antagonism and reduced hedonic feed intake. In conclusion, our results suggested the putative role TRPV1 in hypothalamic dysregulations and TRPV3 in the mesolimbic pathway; both regulate feeding in olanzapine treated mice.


Assuntos
Regulação do Apetite/efeitos dos fármacos , Inflamação/metabolismo , Olanzapina/farmacologia , Canais de Cátion TRPV/metabolismo , Animais , Capsaicina/administração & dosagem , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Corantes/administração & dosagem , Corantes/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Furanos/administração & dosagem , Furanos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipotálamo/efeitos dos fármacos , Inflamação/genética , Metformina/administração & dosagem , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora , Rutênio Vermelho/administração & dosagem , Rutênio Vermelho/farmacologia , Fármacos do Sistema Sensorial/administração & dosagem , Fármacos do Sistema Sensorial/farmacologia , Canais de Cátion TRPV/genética
19.
BMJ Case Rep ; 13(6)2020 Jun 14.
Artigo em Inglês | MEDLINE | ID: covidwho-599775

RESUMO

A 41-year-old man with no significant medical history presented with acute behavioural disruption on the background of a 1-day history of severe headache and a 10-day history of dry cough and fever. He was sexually disinhibited with pressured speech and grandiose ideas. His behaviour worsened, necessitating heavy sedation and transfer to intensive care for mechanical ventilation despite no respiratory indication. Investigations confirmed that he was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neuroimaging and a lumbar puncture were normal. Initial screening for SARS-CoV-2 in the cerebrospinal fluid was negative although no validated assay was available. The patient's mental state remained abnormal following stepdown from intensive care. Psychiatric assessment found features consistent with acute mania, and he was detained under the Mental Health Act. This case indicates the need to consider COVID-19 in a wider series of clinical presentations and to develop a validated assay for SARS-CoV-2 in the cerebrospinal fluid.


Assuntos
Sintomas Afetivos , Betacoronavirus/isolamento & purificação , Clonazepam/administração & dosagem , Infecções por Coronavirus , Olanzapina/administração & dosagem , Pandemias , Pneumonia Viral , Agitação Psicomotora , Transtornos Psicóticos/diagnóstico , Adulto , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/tratamento farmacológico , Sintomas Afetivos/etiologia , Betacoronavirus/patogenicidade , Líquido Cefalorraquidiano/virologia , Infecções por Coronavirus/líquido cefalorraquidiano , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/psicologia , Infecções por Coronavirus/terapia , Diagnóstico Diferencial , Serviços Médicos de Emergência/métodos , Cefaleia/etiologia , Cefaleia/virologia , Humanos , Masculino , Neuroimagem/métodos , Pneumonia Viral/líquido cefalorraquidiano , Pneumonia Viral/diagnóstico , Pneumonia Viral/psicologia , Pneumonia Viral/terapia , Escalas de Graduação Psiquiátrica , Agitação Psicomotora/diagnóstico , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/etiologia , Psicotrópicos/administração & dosagem , Resultado do Tratamento
20.
BMJ Case Rep ; 13(6)2020 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-32540882

RESUMO

A 41-year-old man with no significant medical history presented with acute behavioural disruption on the background of a 1-day history of severe headache and a 10-day history of dry cough and fever. He was sexually disinhibited with pressured speech and grandiose ideas. His behaviour worsened, necessitating heavy sedation and transfer to intensive care for mechanical ventilation despite no respiratory indication. Investigations confirmed that he was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neuroimaging and a lumbar puncture were normal. Initial screening for SARS-CoV-2 in the cerebrospinal fluid was negative although no validated assay was available. The patient's mental state remained abnormal following stepdown from intensive care. Psychiatric assessment found features consistent with acute mania, and he was detained under the Mental Health Act. This case indicates the need to consider COVID-19 in a wider series of clinical presentations and to develop a validated assay for SARS-CoV-2 in the cerebrospinal fluid.


Assuntos
Sintomas Afetivos , Betacoronavirus/isolamento & purificação , Clonazepam/administração & dosagem , Infecções por Coronavirus , Olanzapina/administração & dosagem , Pandemias , Pneumonia Viral , Agitação Psicomotora , Transtornos Psicóticos/diagnóstico , Adulto , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/tratamento farmacológico , Sintomas Afetivos/etiologia , Betacoronavirus/patogenicidade , Líquido Cefalorraquidiano/virologia , Infecções por Coronavirus/líquido cefalorraquidiano , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/psicologia , Infecções por Coronavirus/terapia , Diagnóstico Diferencial , Serviços Médicos de Emergência/métodos , Cefaleia/etiologia , Cefaleia/virologia , Humanos , Masculino , Neuroimagem/métodos , Pneumonia Viral/líquido cefalorraquidiano , Pneumonia Viral/diagnóstico , Pneumonia Viral/psicologia , Pneumonia Viral/terapia , Escalas de Graduação Psiquiátrica , Agitação Psicomotora/diagnóstico , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/etiologia , Psicotrópicos/administração & dosagem , Resultado do Tratamento
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