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1.
Int J Mol Sci ; 24(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36674761

RESUMO

The risk of idiosyncratic drug-induced agranulocytosis (IDIAG) markedly constrains the use of clozapine, a neuroleptic with unparalleled efficacy. Most clozapine patients experience an early inflammatory response, likely a necessary step in IDIAG onset. However, most patients do not progress to IDIAG, presumably because of the requirement of specific human leukocyte antigen (HLA) haplotypes, T cell receptors, and other unknown factors. We established that clozapine activates inflammasomes and that myeloperoxidase bioactivation of clozapine generates neoantigens, but the connection between these early mechanistic events remained unknown and, thus, was the aim of this work. We found that the myeloperoxidase inhibitor PF-1355 attenuated myeloperoxidase activity in phorbol myristate acetate (PMA)-differentiated THP-1 macrophages, and it also attenuated clozapine-induced release of inflammatory mediators (e.g., IL-1ß, CXCL1, and C-reactive protein). In vivo, pretreatment of Sprague Dawley rats with PF-1355 significantly attenuated clozapine-induced increases in neutrophil mobilization from the bone marrow to the blood and spleen, as determined using differential blood counts and flow cytometry. Moreover, the clozapine-triggered release of inflammatory mediators (e.g., IL-1ß, calprotectin, CXCL1, and α-1-acid glycoprotein) from the liver, spleen, and bone marrow was dampened by myeloperoxidase inhibition. These data support the working hypothesis that oxidation of clozapine to a reactive metabolite by myeloperoxidase is critical for induction of the inflammatory response to clozapine. Ultimately, a better mechanistic understanding of the early events involved in the immune response to clozapine may elucidate ways to prevent IDIAG, enabling safer, more frequent therapeutic use of this and potentially other highly efficacious drugs.


Assuntos
Antipsicóticos , Clozapina , Neutropenia , Humanos , Ratos , Animais , Clozapina/efeitos adversos , Peroxidase/metabolismo , Ratos Sprague-Dawley , Antipsicóticos/efeitos adversos , Inflamação/tratamento farmacológico , Corantes , Mediadores da Inflamação
2.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674542

RESUMO

Schizophrenia (SZ) is a heterogeneous mental disorder, affecting ~1% of the worldwide population. One of the main pathophysiological theories of SZ is the imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This may lead to local glutamate storms coupled with excessive dendritic pruning and subsequent cellular stress, including nitrosative stress, during a critical period of neurodevelopment, such as adolescence. Nitrosative stress is mediated by nitric oxide (NO), which is released by NO synthases (NOS) and has emerged as a key signaling molecule implicated in SZ. Regarding glutamatergic models of SZ, the administration of NMDAr antagonists has been found to increase NOS levels in the prefrontal cortex (PFC) and ventral hippocampus (HPC). We hypothesized that suboptimal NOS function in adolescence could be a target for early treatments, including clozapine (CLZ) and the novel metabotropic glutamate receptor modulator JNJ-46356479 (JNJ). We analyzed the protein levels of NOS isoforms in adult PFC and HPC of a postnatal ketamine induced murine model of SZ receiving CLZ or JNJ during adolescence by western blot. Endothelial NOS and neuronal NOS increased under ketamine administration in PFC and decreased in CLZ or JNJ treatments. The same trends were found in the HPC in neuronal NOS. In contrast, inducible NOS was increased under JNJ treatment with respect to ketamine induction in the HPC, and the same trends were found in the PFC. Taken together, our findings suggest a misbalance of the NOS system following NMDAr antagonist administration, which was then modulated under early CLZ and JNJ treatments.


Assuntos
Clozapina , Ketamina , Esquizofrenia , Humanos , Adulto , Camundongos , Animais , Clozapina/farmacologia , Ketamina/farmacologia , Ketamina/metabolismo , Esquizofrenia/metabolismo , Ácido Glutâmico/metabolismo , Estresse Nitrosativo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
4.
Int. j. clin. health psychol. (Internet) ; 23(1): 1-5, ene.-abr. 2023. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-213102

RESUMO

Background: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a therapeutic solution in patients with treatment-resistant auditory verbal hallucinations. However, the optimal stimulation parameters remain unclear, especially for patients with clozapine-resistant symptoms. Method: In an open label retrospective study, we investigated whether parameters of stimulation that were useful in patients with major depressive disorder would help schizophrenia patients with treatment-resistant auditory verbal hallucinations. Fourteen participants, including 9 under clozapine, received 30 sessions of 1 Hz rTMS over 3 weeks (360 pulses per sessions delivered with 60 s ‘on’ and 30 s ‘off’ at 110% of the resting motor threshold, 2 sessions per day). Stimulations were applied over the left temporoparietal junction (T3-P3 according to 10/20 system). Results: After rTMS, a significant decrease of auditory verbal hallucinations was observed (−38.7% ± 31.8, p = 0.003) on the Auditory Hallucination Rating Scale. The beneficial effects were also significant in the 9 patients who were also receiving clozapine (−34.9% ± 28.4, p = 0.01). Conclusions: Low frequency rTMS, 30 sessions over 3 weeks, appears to be a suitable approach to decrease treatment-resistant auditory verbal hallucinations, including in patients with clozapine-resistant symptoms. Results from the current retrospective study in the clinical settings need to be confirmed by large-scale randomized sham-controlled trials. (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Esquizofrenia , Alucinações/tratamento farmacológico , Estimulação Magnética Transcraniana , Estudos Retrospectivos , França , Clozapina
5.
Eur. j. psychiatry ; 37(1): 1-7, enero 2023.
Artigo em Inglês | IBECS | ID: ibc-213935

RESUMO

Background and objectivesThe potential role of antipsychotics in increasing cardiovascular risk of mortality is still debated. The aim of this study was to assess the death risk associated with sequences of first-generation antipsychotic (FGA) and second-generation antipsychotic (SGA) prescriptions, including clozapine and lithium, and drugs for cardiometabolic diseases.MethodsWe conducted a retrospective longitudinal analysis involving 84,881 patients who received antipsychotics between 2008 and 2012. Data on deaths were collected from the National Death Registry. The sequence creation was performed according to an algorithm that iterates prescriptions in chronological order and appends them to the end of the patient's prescription sequence. Fuzzy set qualitative comparative analysis (FsQCA) was also used to produce causal combinations of conditions that best lead to survival.ResultsThere were 1,095,518 antipsychotic prescriptions and 16,010 deaths among antipsychotic users. Among the reimbursement data, 85,272 drug sequences were identified. The most prevalent sequence consisted of FGA (69.1%). Subsequent groups consisted of FGA, followed by SGA (13.1%) and SGA-only (12.3%) sequences. The highest occurrence of death and cardiometabolic drug use after introducing antipsychotic treatment was observed for clozapine. The FsQCA analysis revealed the highest coverage for combinations of young age with FGA (40.6%) or with no cardiometabolic risk factors drug therapy (39.5%).ConclusionThe sequence analysis suggests that clozapine is associated with an increased death risk compared to FGA and SGA. (AU)


Assuntos
Humanos , Antipsicóticos , Mortalidade , Clozapina , Lítio
8.
Biomed Pharmacother ; 158: 114079, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36521250

RESUMO

Positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), may mitigate the glutamate storm during the early stages of schizophrenia (SZ), which could be especially useful in the treatment of cognitive and negative symptoms. We evaluated the efficacy of early treatment with JNJ or clozapine (CLZ) in reversing behavioral and neuropathological deficits induced in a postnatal ketamine (KET) mouse model of SZ. Mice exposed to KET (30 mg/kg) on postnatal days (PND) 7, 9, and 11 received JNJ or CLZ (10 mg/kg) daily in the adolescent period (PND 35-60). Mice exposed to KET did not show the expected preference for a novel object or for social novelty, but they recovered this preference with JNJ treatment. Similarly, KET group did not show the expected dishabituation in the fifth trial, but mice treated with JNJ or CLZ recovered an interest in the novel animal. Neuronal immunoreactivity also differed between treatment groups with mice exposed to KET showing a reduction in parvalbumin positive cells in the prefrontal cortex and decreased c-Fos expression in the hippocampus, which was normalized with the pharmacological treatment. JNJ-46356479 treatment in early stages may help improve the cognitive and negative symptoms, as well as certain neuropathological deficits, and may even obtain a better response than CLZ treatment. This may have relevant clinical translational applications since early treatment with mGluR2 modulators that inhibit glutamate release at the onset of critical phases of SZ may prevent or slow down the clinical deterioration of the disease.


Assuntos
Clozapina , Ketamina , Receptores de Glutamato Metabotrópico , Esquizofrenia , Camundongos , Animais , Ketamina/farmacologia , Ketamina/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/uso terapêutico , Clozapina/uso terapêutico
9.
Asian J Psychiatr ; 79: 103353, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36493690

RESUMO

BACKGROUND: Although clozapine is much researched in western literature, a review on Indian research on clozapine published in 2010 reported limited data and need for further research in this area. AIM: We aimed to conduct a systematic review of research on clozapine from India from 2010 to mid-2022 and also compare the same with research output before 2010. METHODOLOGY: A systematic various search engines, i.e., PUBMED, Medknow, Hinari and Google Scholar was done using the key words clozapine and India. Published articles with clozapine in the title and having an author from India, published during 2010 to July 2022 were included. RESULTS: Initial Internet and hand searches yielded 280 articles, out of which 126 articles were excluded due to various reasons and 154 articles, were included for the review. This included 84 case reports, 49 original articles, 11 review articles and 10 letters to the editor as comments. We found an increase in the number of publications during the period of 2010-2022 compared to 1997-2009 in all types of publications. Over the years a significant proportion of the articles focused on various side effects of clozapine, factors associated with response and non-response to clozapine and evaluation of outcomes other than efficacy/effectiveness. However, all the studies were limited to a single centre with no multicentric studies on clozapine. CONCLUSION: Over the last 12 years or so, there is increase in the number of publications on clozapine. However, there is lack of multicentric studies.


Assuntos
Clozapina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Clozapina/efeitos adversos , PubMed , Publicações , Índia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico
10.
Psychopharmacology (Berl) ; 240(1): 203-211, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36538098

RESUMO

RATIONALE: Clozapine has proven to be superior to other antipsychotic drugs in the treatment of schizophrenia but is under-prescribed due to its potentially severe side effects. Clozapine-induced sialorrhea (CIS) is a frequent and extremely uncomfortable side effect, which remains understudied. OBJECTIVES: To examine the prevalence of diurnal and nocturnal CIS in a sample of patients treated with clozapine, and to evaluate its impact on quality of life. METHODS: We conducted a cross-sectional, observational study of 130 patients with schizophrenia spectrum disorders treated with clozapine. The prevalence of CIS was evaluated via specific sialorrhea scales. None of the patients included in the study was receiving a specific treatment for hypersalivation during the study period. Possible associations between sialorrhea and clinical and quality of life variables were analyzed. RESULTS: Of 130 subjects, 120 (92.3%) suffered from CIS. Eighty-one (62.31%) suffered from diurnal CIS, 115 (88.56%) from nocturnal CIS, and 85 (65.38%) suffered from both. Significant positive associations between quality of life and diurnal CIS (B = 0.417; p = 2.1e - 6, R2 = 0.156) and nocturnal CIS (B = 0.411; p = 7.7e - 6, R2 = 0.139) were detected. Thirty per cent of the subjects reported a moderate to severe negative impact of sialorrhea on their quality of life. CONCLUSIONS: The present study suggests that CIS is highly prevalent in patients with schizophrenia and has an important impact on quality of life in one-third of our sample. Therefore, the inclusion of a systematic evaluation and treatment of CIS in standard clinical practice is highly recommended. TRIAL REGISTRATION: Clinical Trials ( https://clinicaltrials.gov ) under reference NCT04197037.


Assuntos
Antipsicóticos , Clozapina , Sialorreia , Humanos , Clozapina/efeitos adversos , Sialorreia/induzido quimicamente , Sialorreia/epidemiologia , Sialorreia/tratamento farmacológico , Prevalência , Qualidade de Vida , Estudos Transversais , Antipsicóticos/efeitos adversos
11.
Int J Mol Sci ; 23(24)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36555774

RESUMO

Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host's eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018-2022) and identified twenty two eligible cases, restricted only to human patients' experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains (Lactobacillus and Bifidobacterium), or those combined with vitamin D and selenium, maintain the integrity of the gut flora, preventing antagonistic effects including inflammation, antipsychotic-related body weight gain (olanzapine) and other metabolic dysfunctionalities. However, there are multiple antipsychotics that exert a potent effect upon gut flora, influencing a plethora of pathways and creating a dysbalance ratio between beneficial and opportunistic pathogens. Risperidone, amisulpride, and clozapine are just a few examples, but the current literature is unfortunately inconsistent and reported data is contradictory, which is why we support additional studies in this context. Moreover, we further argue the utility of studying how distinct controlled substances influence microbial communities, considering that ketamine is proved to alleviate depressive-like behavior as opposed to amphetamine and phencyclidine, which are known substances to trigger SCZ-like symptoms in experimental models. Probiotics may be regarded as the most consequential vehicle through which the gut flora can be successfully influenced, in adequate doses exerting a beneficial role as an alternative approach to alleviate SCZ symptoms.


Assuntos
Antipsicóticos , Clozapina , Microbioma Gastrointestinal , Probióticos , Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Antipsicóticos/uso terapêutico , Olanzapina , Clozapina/uso terapêutico , Probióticos/uso terapêutico , Prebióticos
15.
Rev Psiquiatr Salud Ment (Engl Ed) ; 15(4): 238-250, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36513400

RESUMO

INTRODUCTION: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. METHODS: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. RESULTS: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005-IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. CONCLUSIONS: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.


Assuntos
Antipsicóticos , Clozapina , Miocardite , Humanos , Clozapina/efeitos adversos , Farmacovigilância , Miocardite/induzido quimicamente , Miocardite/diagnóstico , Miocardite/epidemiologia , Antipsicóticos/efeitos adversos , Organização Mundial da Saúde
16.
Rev Psiquiatr Salud Ment (Engl Ed) ; 15(4): 230-237, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36513399

RESUMO

INTRODUCTION: Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety. METHODS: 31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11). For DBS sample collection, 25µl of capillary blood were placed in the spot of a FTA™DMPK-C-card. After completely dryness, antipsychotics were extracted and analyzed by a validated UHPLC-MS/MS-method. DBS antipsychotic results were compared with those obtained in venous blood/plasma. RESULTS: Aripiprazole, paliperidone and clozapine showed from good to excellent correlations between concentrations in venous blood and DBS capillary blood (r2, from 0.500 to 0.721). The correlation between conventional plasma and DBS concentrations for paliperidone, aripiprazole, clozapine, and their metabolites were moderate, suggesting that optimal drug target concentrations should be established for DBS. CONCLUSIONS: In this study, for aripiprazole, dehydroaripiprazole, paliperidone, clozapine and desmethylclozapine, DBS has provided good analytical performance for TDM. Thus, DBS sampling can offer a great alternative over conventional sampling for plasma measurement. The assay provides good analytical performances for TDM and clinical research applicability, suggesting that DBS is a promising clinical application in TDM in psychiatry.


Assuntos
Antipsicóticos , Clozapina , Humanos , Aripiprazol/uso terapêutico , Clozapina/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Antipsicóticos/uso terapêutico , Espectrometria de Massas em Tandem/métodos
17.
Rev Psiquiatr Salud Ment (Engl Ed) ; 15(4): 281-286, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36513403

RESUMO

INTRODUCTION: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. METHODS: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. RESULTS: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. CONCLUSIONS: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.


Assuntos
Antipsicóticos , Clozapina , Miocardite , Humanos , Clozapina/efeitos adversos , Ácido Valproico/efeitos adversos , Miocardite/induzido quimicamente , Miocardite/diagnóstico , Antipsicóticos/efeitos adversos , Obesidade/induzido quimicamente , Inflamação
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