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Frontiers in Pharmacology 2023analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor...
analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor metabolizer status. This precautionary measure aims to prevent the occurrence of serious adverse drug reactions. This study presents a case of a patient diagnosed with schizophrenia spectrum disorder. The patient suffered re-admission in the psychiatry ward because of severe secondary symptoms due to the antipsychotic drug pimozide, previously prescribed on a first admission. In order to assess the patient's medication profile, real-time PCR was performed to analyze the main genes responsible for its metabolization, namely, and . The pharmacogenetic study revealed that the patient is a poor metabolizer for , presenting deletion of both copies of the gene (diplotype *5/*5). Fortunately, the symptomatology disappeared after the withdrawal of the responsible drug. In conclusion, abiding by the pharmacogenetic clinical practice guidelines and the pharmacogenetic analysis of when prescribing pimozide would have probably saved the patient from the consequences of severe side effects and the health system expenditure. There is an important need for more training in the pharmacogenetic field for specialists in psychiatry.
PubMed: 37637419
DOI: 10.3389/fphar.2023.1237446 -
International Journal of Molecular... Jul 2023Chromatin regulators (CRs) are essential upstream regulatory factors of epigenetic modification. The role of CRs in the pathogenesis of renal ischemia-reperfusion injury...
Chromatin regulators (CRs) are essential upstream regulatory factors of epigenetic modification. The role of CRs in the pathogenesis of renal ischemia-reperfusion injury (IRI) remains unclear. We analyzed a bioinformatic analysis on the differentially expressed chromatin regulator genes in renal IRI patients using data from public domains. The hub CRs identified were used to develop a risk prediction model for renal IRI, and their expressions were also validated using Western blot, qRT-PCR, and immunohistochemistry in a murine renal IRI model. We also examined the relationships between hub CRs and infiltrating immune cells in renal IRI and used network analysis to explore drugs that target hub CRs and their relevant downstream microRNAs. The results of machine learning methods showed that five genes (, , , , ) were upregulated in renal IRI, with key roles in the cell cycle, p38 MAPK signaling pathway, p53 signaling pathway, FoxO signaling pathway, and NF-κB signaling pathway. Two genes from the network, and (growth arrest and DNA damage-inducible protein 45 alpha and beta), were chosen for the renal IRI risk prediction model. They all showed good performance in the testing and validation cohorts. Mice with renal IRI showed significantly upregulated and expression within kidneys compared to sham-operated mice. and showed correlations with plasmacytoid dendritic cells (pDCs) in infiltrating immune cell analysis and enrichment in the MAPK pathway based on the weighted gene co-expression network analysis (WGCNA) method. Candidate drugs that target and include beta-escin, sertraline, primaquine, pimozide, and azacyclonol. The dysregulation of and is related to renal IRI and the infiltration of pDCs, and drugs that target and may have therapeutic potential for renal IRI.
Topics: Animals; Mice; Biomarkers; Cell Cycle Proteins; Chromatin; Kidney; Reperfusion Injury
PubMed: 37511062
DOI: 10.3390/ijms241411304 -
Journal of Experimental & Clinical... Jul 2023After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression....
BACKGROUND
After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression. However, systematic study about the relationship between depression and GBM progression is still lacking.
METHODS
Chronic unpredictable mild stress and chronic restrain stress were used to mimic human depression in mice. Human GBM cells and intracranial GBM model were used to assess the effects of chronic stress on GBM growth. Targeted neurotransmitter sequencing, RNA-seq, immunoblotting and immunohistochemistry were used to detect the related molecular mechanism.
RESULTS
Chronic stress promoted GBM progression and up-regulated the level of dopamine (DA) and its receptor type 2 (DRD2) in tumor tissues. Down-regulation or inhibition of DRD2 abolished the promoting effect of chronic stress on GBM progression. Mechanistically, the elevated DA and DRD2 activated ERK1/2 and consequently inhibited GSK3β activity, leading to β-catenin activation. Meanwhile, the activated ERK1/2 up-regulated tyrosine hydroxylase (TH) level in GBM cells and then promoted DA secretion, forming an autocrine positive feedback loop. Remarkably, patients with high-depression exhibited high DRD2 and β-catenin levels, which showed poor prognosis. Additionally, DRD2 specific inhibitor pimozide combined with temozolomide synergistically inhibited GBM growth.
CONCLUSIONS
Our study revealed that chronic stress accelerates GBM progression via DRD2/ERK/β-catenin axis and Dopamine/ERK/TH positive feedback loop. DRD2 together with β-catenin may serve as a potential predictive biomarker for worse prognosis as well as therapeutic target of GBM patients with depression.
Topics: Humans; Animals; Mice; Glioblastoma; Dopamine; Tyrosine 3-Monooxygenase; beta Catenin; Feedback; Cell Line, Tumor; Brain Neoplasms; Cell Proliferation; Receptors, Dopamine D2
PubMed: 37415171
DOI: 10.1186/s13046-023-02728-8 -
Biomedicines Feb 2023Pimozide is a conventional antipsychotic drug largely used in the therapy for schizophrenia and Tourette's syndrome. Pimozide is assumed to inhibit synaptic transmission...
Pimozide is a conventional antipsychotic drug largely used in the therapy for schizophrenia and Tourette's syndrome. Pimozide is assumed to inhibit synaptic transmission at the CNS by acting as a dopaminergic D receptor antagonist. Moreover, pimozide has been shown to block voltage-gated Ca and K channels in different cells. Despite its widespread clinical use, pimozide can cause several adverse effects, including extrapyramidal symptoms and cardiac arrhythmias. Dizziness and loss of balance are among the most common side effects of pimozide. By using the patch-clamp whole-cell technique, we investigated the effect of pimozide [3 μM] on K channels expressed by chicken embryo vestibular type-II hair cells. We found that pimozide slightly blocks a transient outward rectifying A-type K current but substantially increases a delayed outward rectifying K current. The net result was a significant hyperpolarization of type-II hair cells at rest and a strong reduction of their response to depolarizing stimuli. Our findings are consistent with an inhibitory effect of pimozide on the afferent synaptic transmission by type-II hair cells. Moreover, they provide an additional key to understanding the beneficial/collateral pharmacological effects of pimozide. The finding that pimozide can act as a K channel opener provides a new perspective for the use of this drug.
PubMed: 36831024
DOI: 10.3390/biomedicines11020488 -
Biomolecules Jan 2023Treatment of tremors, such as in essential tremor (ET) and Parkinson's disease (PD) is mostly ineffective. Exact tremor pathomechanisms are unknown and relevant animal...
Treatment of tremors, such as in essential tremor (ET) and Parkinson's disease (PD) is mostly ineffective. Exact tremor pathomechanisms are unknown and relevant animal models are missing. GABA-A receptor is a target for tremorolytic medications, but current non-selective drugs produce side effects and have safety liabilities. The aim of this study was a search for GABA-A subunit-specific tremorolytics using different tremor-generating mechanisms. Two selective positive allosteric modulators (PAMs) were tested. Zolpidem, targeting GABA-A α1, was not effective in models of harmaline-induced ET, pimozide- or tetrabenazine-induced tremulous jaw movements (TJMs), while the novel GABA-A α2/3 selective MP-III-024 significantly reduced both the harmaline-induced ET tremor and pimozide-induced TJMs. While zolpidem decreased the locomotor activity of the rats, MP-III-024 produced small increases. These results provide important new clues into tremor suppression mechanisms initiated by the enhancement of GABA-driven inhibition in pathways controlled by α2/3 but not α1 containing GABA-A receptors. Tremor suppression by MP-III-024 provides a compelling reason to consider selective PAMs targeting α2/3-containing GABA-A receptors as novel therapeutic drug targets for ET and PD-associated tremor. The possibility of the improved tolerability and safety of this mechanism over non-selective GABA potentiation provides an additional rationale to further pursue the selective α2/3 hypothesis.
Topics: Rats; Animals; Tremor; Pimozide; Zolpidem; Harmaline; Receptors, GABA-A; Rats, Sprague-Dawley; Ligands; Essential Tremor; gamma-Aminobutyric Acid
PubMed: 36830567
DOI: 10.3390/biom13020197 -
Journal of Cutaneous Medicine and... 2023The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to... (Review)
Review
BACKGROUND
The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to identify, appraise, and summarize the currently available evidence about the safety and effectiveness of pharmacological management of PPDs through randomized controlled trials (RCTs).
METHODS
The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRIMSA) statement and the Global Evidence Mapping Initiative guidance were followed. Medline, Embase, PsycInfo, Cochrane and Scopus were searched, and two reviewers independently completed article review, data extraction, and quality assessment.
RESULTS
Among 2618 unique studies, full texts of 83 were reviewed and 21 RCTs were included. Five PDDs were identified: trichotillomania ( = 12), pathologic skin picking ( = 5), nail biting ( = 2), delusional parasitosis ( = 1), and dermatitis from compulsive hand washing ( = 1). Seven different classes of medications were investigated: SSRIs (i.e., fluoxetine, sertraline, and citalopram), tricyclic antidepressants (i.e., clomipramine and desipramine), antipsychotics (i.e., olanzapine and pimozide), anticonvulsant (i.e., lamotrigine), N-acetylcysteine, inositol, and milk thistle. RCT-derived evidence supports the use of antidepressants in trichotillomania (sertraline and clomipramine), pathologic skin picking (fluoxetine), pathologic nail biting and dermatitis from compulsive hand washing (clomipramine or desipramine); antipsychotics in trichotillomania (olanzapine) and delusional parasitosis (pimozide); N-acetyl cysteine in trichotillomania and skin picking.
CONCLUSION
Few pharmacotherapies for primary psychodermatologic disorders are assessed through controlled trials in the literature. This review serves as a roadmap for researchers and clinicians to reach informed decisions with current evidence, and to build on it to establish guidelines in the future.
Topics: Humans; Sertraline; Fluoxetine; Clomipramine; Olanzapine; Antipsychotic Agents; Desipramine; Pimozide; Randomized Controlled Trials as Topic; Acetylcysteine; Dermatitis
PubMed: 36802832
DOI: 10.1177/12034754231155888 -
Frontiers in Immunology 2022Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the...
BACKGROUND
Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease.
METHODS
Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of (EC = 0.4 μM) and models, we show that methotrexate is able to inhibit COVID-19 multiple mechanisms.
RESULTS
Our studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals.
CONCLUSIONS
We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.
Topics: Animals; Cricetinae; SARS-CoV-2; COVID-19; Methotrexate; Antiviral Agents; Inflammation; Computational Biology
PubMed: 36618412
DOI: 10.3389/fimmu.2022.1080897 -
Biomedicines Dec 2022For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment.... (Review)
Review
For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment. It is possible that the discovery of the right drug could turn treatment resistance into treatment response. The goal of this narrative review is to provide a historical perspective of the treatment of DD since the introduction of antipsychotics 70 years ago. The following search terms were used to scan the literature: antipsychotics AND "delusional disorder". Findings were that therapy for DD symptoms has changed over time. Initial reports suggested that the drug of choice was the antipsychotic pimozide, and that this drug was especially effective for the somatic subtype of DD. Subsequent studies demonstrated that other antipsychotics, for instance, risperidone and olanzapine, were also highly effective. Treatment response may vary according to the presence or absence of specific symptoms, such as cognitive defect and depression. Clozapine, partial D2 agonists, and long-acting injectable drugs may be more effective than other drugs, but the evidence is not yet in. Because of the absence of robust evidence, treatment guidelines for the optimal management of DD are not yet available.
PubMed: 36552037
DOI: 10.3390/biomedicines10123281 -
Biomedicines Dec 2022Evidence about the use of pharmacologic agents in the treatment of Anorexia Nervosa (AN) is lacking, especially in childhood and adolescence. A systematic scoping review... (Review)
Review
Evidence about the use of pharmacologic agents in the treatment of Anorexia Nervosa (AN) is lacking, especially in childhood and adolescence. A systematic scoping review was conducted to outline current literature evidence about the use of antipsychotics in this population. A total of 499 studies were identified with the initial search, and 28 of these studies were selected regarding the use of olanzapine (n = 13), risperidone (n = 4), aripiprazole (n = 3), chlorpromazine (n = 3), pimozide (n = 1) clotiapine (n = 1) and multiple antipsychotics (n = 3) in these patients. Overall, major side effects were reported infrequently; improvements in psychopathology and weight measures have been suggested in the majority of the considered studies. Nonetheless, the lack of RCT or good-quality studies strongly limits the generalizability of results in clinical practice.
PubMed: 36551922
DOI: 10.3390/biomedicines10123167