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Cells Sep 2020Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of...
Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.
Topics: Adenine; Animals; Antineoplastic Agents; Antipsychotic Agents; Autophagy; Autophagy-Related Protein 5; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Repositioning; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Microtubule-Associated Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Pimozide; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; RNA, Small Interfering; STAT3 Transcription Factor; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 32971907
DOI: 10.3390/cells9092141 -
British Medical Journal Sep 1972
Topics: Benzimidazoles; Epilepsy; Humans; Substance Withdrawal Syndrome; Time Factors
PubMed: 5071707
DOI: 10.1136/bmj.3.5827.643-a -
PloS One 2020Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole...
Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy. Here, we investigated the possible involvement of P-glycoprotein (P-gp)-mediated interaction among these drugs, using in vitro methods. ATPase assay confirmed that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The maximum transport rate (Jmax) and half-saturation concentration (Kt) for the carrier-mediated transport estimated by means of pimozide efflux assay using P-gp-overexpressing LLC-GA5-CoL150 cells were 84.9 ± 8.9 pmol/min/mg protein, and 10.6 ± 4.7 μM, respectively. These results indicate that pimozide is a good P-gp substrate, and it appears to have the potential to cause drug-drug interactions in the digestive tract at clinically relevant gastrointestinal concentrations. Moreover, sertraline or aripiprazole significantly decreased the efflux ratio of pimozide in LLC-GA5-CoL150 cells. Transport studies using Caco-2 cell monolayers were consistent with the results in LLC-GA5-CoL150 cells, and indicate that P-gp-mediated drug-drug interaction may occur in the gastrointestinal tract. Thus, P-gp inhibition by sertraline and/or aripiprazole may increase the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which is known to be associated with an increased risk of QT prolongation, a life-threatening side effect.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Aripiprazole; Biological Transport; Caco-2 Cells; Drug Interactions; Gastrointestinal Absorption; Humans; LLC-PK1 Cells; Pimozide; Sertraline; Swine
PubMed: 33119612
DOI: 10.1371/journal.pone.0232438 -
Canadian Journal of Psychiatry. Revue... May 2015It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T... (Review)
Review
OBJECTIVE
It remains unclear whether antipsychotic polypharmacy, a common clinical practice, is related to an increased risk of corrected time between start of Q wave and end of T wave (QTc) interval prolongation. We conducted a systematic review of the literature to address this important issue.
METHOD
A systematic literature search was conducted in October 2014, using MEDLINE, Embase, and PsycINFO. Studies and case reports were included if they reported QTc intervals or QTc interval changes before and after antipsychotic polypharmacy or QTc intervals in both antipsychotic polypharmacy and monotherapy groups.
RESULTS
A total of 21 articles (10 clinical trials, 4 observational studies, and 7 case reports) met inclusion criteria. The clinical trials have shown that a combination treatment with risperidone or pimozide is not obviously related to an increase in QTc interval, whereas ziprasidone or sertindole combined with clozapine may prolong QTc interval. Among the 4 observational studies, antipsychotic polypharmacy was not clearly associated with QTc prolongation in 3 studies, each cross-sectional. In contrast, one prospective study showed a significant increase in QTc interval following antipsychotic coadministration. The case reports indicated an increased risk of QTc prolongation in at least some patients receiving antipsychotic polypharmacy.
CONCLUSIONS
Currently available evidence fails to confirm that antipsychotic polypharmacy worsens QTc prolongation in general, although the evidence is scarce and inconsistent. Clinicians are advised to remain conservative in resorting to antipsychotic polypharmacy, as a combination of some QTc-prolongation liable antipsychotics may further prolong QTc interval, and efficacy supporting the clinical benefits of antipsychotic polypharmacy is equivocal, at best.
Topics: Antipsychotic Agents; Heart Rate; Humans; Polypharmacy
PubMed: 26174525
DOI: 10.1177/070674371506000503 -
Cell Death & Disease Sep 2022Ubiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2....
Ubiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2. Because USP1 is highly expressed in many cancers, dysregulation of USP1 contributes to cancer therapy. However, the role of USP1 and the mechanisms underlying chemotherapy remain unclear. In this study, we found high USP1 expression in tumor tissues and that it correlated with poor prognosis in RCC. Mechanistically, USP1 enhanced survivin stabilization by removing ubiquitin. Pharmacological inhibitors (ML23 and pimozide) and siRNA targeting USP1 induced downregulation of survivin expression. In addition, ML323 upregulated DR5 expression by decreasing miR-216a-5p expression at the post-transcriptional level, and miR-216a-5p mimics suppressed the upregulation of DR5 by ML323. Inhibition of USP1 sensitized cancer cells. Overexpression of survivin or knockdown of DR5 markedly prevented the co-treatment with ML323 and TRAIL-induced apoptosis. These results of in vitro were proved in a mouse xenograft model, in which combined treatment significantly reduced tumor size and induced survivin downregulation and DR5 upregulation. Furthermore, USP1 and survivin protein expression showed a positive correlation, whereas miR-216a-5p and DR5 were inversely correlated in RCC tumor tissues. Taken together, our results suggest two target substrates of USP1 and demonstrate the involvement of survivin and DR5 in USP1-targeted chemotherapy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Deubiquitinating Enzymes; Down-Regulation; Humans; Kidney Neoplasms; Mice; MicroRNAs; Pimozide; Proliferating Cell Nuclear Antigen; RNA, Small Interfering; Receptors, TNF-Related Apoptosis-Inducing Ligand; Survivin; Ubiquitin-Specific Proteases; Ubiquitins; Up-Regulation
PubMed: 36153316
DOI: 10.1038/s41419-022-05271-0 -
Cureus Feb 2022Tourette's Syndrome (TS), in which patients have sudden, repeated, involuntary twitches and movements, called tics, is a condition of the nervous system. They can be... (Review)
Review
Tourette's Syndrome (TS), in which patients have sudden, repeated, involuntary twitches and movements, called tics, is a condition of the nervous system. They can be motor, vocal, simple, or complex tics. It can be physically, emotionally, mentally, and socially distressing and challenging for those suffering from it. Usually, it is accompanied by various comorbidities like attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and sleep disorders. A variety of environmental and genetic factors are also associated with tics in TS like the first-degree relatives are more at risk of developing TS.TS is heterogeneous with complicated patterns of inheritance and phenotypic manifestations. There is a strong association between common single nucleotide polymorphisms (SNP, s) in the SLITRK1 gene and TS. Environmental factors like prenatal, postnatal, and perinatal factors directly influence tics in TS. These factors are low birth weight, intrauterine growth retardation (IGR), and various infections. The treatment of TS can be broadly classified into non-pharmacological and pharmacological treatment. Non-pharmacological therapy includes various behavioural interventions that can be helpful in situations when patients are tolerant of medical treatments. Psychoeducation and counselling play an essential role in the treatment of TS. It is vital to give a proper understanding to the patient and their family about the disease. Cognitive-behavioral intervention for tics, cognitive-behavioral therapy, exposure and response prevention, relaxation techniques, deep brain stimulation, and habit reversal training are the commonly used therapies for tics. These therapies have shown good efficacy because it improves the Yale Global Tic Severity Scale score (YGTSS) significantly. And they show effectiveness in patients who are irresponsive to medical treatment. The main lines of medical treatment are antipsychotics and alpha agonists. Typical (haloperidol, pimozide) or atypical (aripiprazole, risperidone, olanzapine) Antipsychotics differ in their side effects, efficacy, and tolerance in different age groups of children. Haloperidol was the first drug approved by the Food and Drug Administration for tics, but later on, new developments and improvements were made as far as drug therapy is concerned. The alpha-agonist most commonly used is clonidine which is also available in the form of adhesive patches. Another alpha agonist which is also widely used is guanfacine. Botulinum toxin and baclofen have also shown efficacy in dealing with tics in TS with other comorbidities. We will review in this article all the main lines of treatment and their effectiveness in TS.
PubMed: 35345730
DOI: 10.7759/cureus.22449 -
Journal of Psychiatry & Neuroscience :... Mar 2000Recently, antipsychotic medications of the novel or atypical classes have received increased attention because of concerns with respect to potential lengthening of the... (Review)
Review
Recently, antipsychotic medications of the novel or atypical classes have received increased attention because of concerns with respect to potential lengthening of the QT interval, yet the currently available and commonly prescribed conventional antipsychotics are significantly more cardiotoxic, particularly agents in the butyrophenone and phenothiazine classes. Lengthening of the QT interval can be associated with a fatal paroxysmal ventricular arrhythmia known as torsades de pointes. The specific duration of the QT interval at which the risk of an adverse cardiac event is greatest, is not established. There is not only significant variation in the applied definition of an abnormal interval, but the maximal QT interval in healthy volunteers is greater than the currently accepted standards. The QT interval is influenced by normal physiological and pathologic factors, but the mechanisms remain unclear. Using recombinant technology, haloperidol and sertindole have been demonstrated to be high-affinity antagonists of a human cardiac potassium channel encoded by the human ether-a-go-go-related gene. Pimozide, however, has been shown to act principally through calcium channel antagonism, and chlorpromazine may affect sodium channels. Nevertheless, it is possible that these effects are significant only in the presence of predisposing factors, either genetic or acquired. Despite proven efficacy in clinical trials and subsequent supervised use in Europe, a number of recently developed antipsychotic medications are not available to patients in North America. Yet, conventional antipsychotic medications that would not be approved by current safety standards continue to be widely used.
Topics: Animals; Antipsychotic Agents; Electrocardiography; Heart Rate; Humans; Torsades de Pointes
PubMed: 10740988
DOI: No ID Found -
BMC Gastroenterology May 2013Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of... (Review)
Review
BACKGROUND
Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy. Therefore, the impact of DAAs on the management of co-morbid psychiatric illness and neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions (DDIs) between DAAs and psychiatric medications.
METHODS
We conducted a Pubmed search using relevant search terms and hand searched reference lists of related review articles. In addition, we searched abstracts for major hepatology conferences and contacted respective pharmaceutical companies for additional studies.
RESULTS
Limited data is available on the neuropsychiatric adverse effects of DAAs; however, data from major clinical trials suggest that DAAs have minimal neuropsychiatric risk. DAAs can potentially interact with a variety of psychotropic agents via cytochrome P450 and p-glycoprotein interactions. Triazolam, oral midazolam, St. John's Wort, carbamazepine and pimozide, are contraindicated with DAAs. DDIs between DAAs and antidepressants, anxiolytics, hypnotics, mood stabilizers, antipsychotics and treatments for opioid dependence are summarized.
CONCLUSIONS
Although DAAs do not add significant neuropsychiatric risk, the potential for DDIs is high. Consideration of DDIs is paramount to improving medication adherence and mitigating adverse effects during HCV therapy.
Topics: Antiviral Agents; Contraindications; Drug Interactions; Hepatitis C; Humans; Medication Adherence; Mental Disorders; Oligopeptides; Proline; Psychotropic Drugs
PubMed: 23672254
DOI: 10.1186/1471-230X-13-86 -
European Journal of Pharmacology Aug 2010Accumulating evidence suggests that antipsychotics affect dopamine release from dopaminergic neurons, but the precise mechanisms are not fully understood. Besides, there...
Haloperidol, spiperone, pimozide and aripiprazole reduce intracellular dopamine content in PC12 cells and rat mesencephalic cultures: Implication of inhibition of vesicular transport.
Accumulating evidence suggests that antipsychotics affect dopamine release from dopaminergic neurons, but the precise mechanisms are not fully understood. Besides, there are few studies on the effects of antipsychotics on intracellular dopamine content. In this study, the effects of 8 antipsychotics on dopamine release and intracellular dopamine content in PC12 cells were investigated. Pretreatment with haloperidol, spiperone, pimozide, aripiprazole and risperidone markedly inhibited high potassium-evoked dopamine release. By contrast, pretreatment with chlorpromazine slightly increased high potassium-evoked dopamine release, while pretreatment with sulpiride and olanzapine had no effect. Haloperidol, spiperone, pimozide, chlorpromazine, aripiprazole and olanzapine evoked dopamine release, while sulpiride and risperidone had no effect. In addition, haloperidol, spiperone, pimozide, aripiprazole and risperidone reduced intracellular dopamine content in a concentration-dependent manner. These results suggest that the reduction in high potassium-evoked dopamine release by pretreatment with antipsychotics results from the reduction in vesicular dopamine content. Treatment with the 8 antipsychotics did not affect the expression of total or phosphorylated tyrosine hydroxylase. Instead, haloperidol, spiperone, pimozide and aripiprazole as well as reserpine transiently increased extracellular levels of dopamine metabolites. In addition, haloperidol, spiperone, pimozide, aripiprazole and risperidone reduced vesicular [3H]dopamine transport. These results suggest that the inhibition of vesicular dopamine transport by haloperidol, spiperone, pimozide and aripiprazole results in a reduction in vesicular dopamine content.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antipsychotic Agents; Aripiprazole; Ascorbic Acid; Biological Transport; Dopamine; Extracellular Space; Gene Expression Regulation, Enzymologic; Haloperidol; Homovanillic Acid; Mesencephalon; Neurons; PC12 Cells; Pargyline; Pimozide; Piperazines; Quinolones; Rats; Spiperone; Transport Vesicles; Tyrosine 3-Monooxygenase
PubMed: 20460122
DOI: 10.1016/j.ejphar.2010.04.043 -
Antioxidants (Basel, Switzerland) Jun 2021Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to...
Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has provided new hope for refractory AML patients. While generally not efficacious as monotherapy, BH3 mimetics are very effective in combination with chemotherapy agents. With this in mind, we further explored novel BH3 mimetic drug combinations and showed that pimozide cooperates with mTOR inhibitors and BH3 mimetics in AML cells. The three-drug combination was able to reach cells that were not as responsive to single or double drug combinations. In Flt3-internal tandem duplication (ITD)-positive cells, we previously showed pimozide to be highly effective when combined with imipramine blue (IB). Here, we show that Flt3-ITD cells are sensitive to an IB-induced dynamin 1-like (Drp1)-p38-ROS pathway. Pimozide contributes important calcium channel blocker activity converging with IB on mitochondrial oxidative metabolism. Overall, these data support the concept that antioxidants are a double-edged sword. Rationally designed combination therapies have significant promise for further pre-clinical development and may ultimately lead to improved responses.
PubMed: 34203664
DOI: 10.3390/antiox10060956