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The Journal of Dermatological Treatment Mar 2022Delusional infestation (DI) is a rare delusional disorder in which individuals have a false belief that they are infested with bugs, parasites, or insects, despite the... (Review)
Review
BACKGROUND
Delusional infestation (DI) is a rare delusional disorder in which individuals have a false belief that they are infested with bugs, parasites, or insects, despite the lack of medical evidence that such an infestation exists. Data on the effectiveness of antipsychotics for DI are limited.
METHODS
We conducted a systematic review using EMBASE, MEDLINE, PsycINFO, and Cochrane Central Register of Controlled Trials from inception of the databases up until July 20, 2018. Studies examining typical or atypical antipsychotics for primary DI were included.
RESULTS
A total of 51 relevant articles were identified, primarily case reports/series. Overall response was favorable for both typical and atypical antipsychotics, but there was no strong evidence to suggest that any one antipsychotic agent was preferable to other agents. Pimozide (1-16 mg/day) and risperidone (0.5-8 mg/day) were the most commonly studied typical and atypical antipsychotics, respectively. Inconsistent reporting of treatment outcomes and variability in study designs limited the overall evaluation of the data.
CONCLUSIONS
There remains a lack of sound data supporting the effectiveness of antipsychotic treatment for primary DI. Further research is required to establish more definitive conclusions about the relative clinical utility of antipsychotic agents for DI.
Topics: Antipsychotic Agents; Humans; Risperidone; Treatment Outcome
PubMed: 32658556
DOI: 10.1080/09546634.2020.1795061 -
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 -
Expert Review of Neurotherapeutics Jun 2024Trigeminal neuralgia is a rare condition that can be effectively treated by carbamazepine or oxcarbazepine but these older drugs are associated with dose-dependent and... (Review)
Review
INTRODUCTION
Trigeminal neuralgia is a rare condition that can be effectively treated by carbamazepine or oxcarbazepine but these older drugs are associated with dose-dependent and potentially treatment-limiting adverse effects. Third-generation anticonvulsants, new calcitonin gene-related peptide blockers for migraine, and older drugs such as ketamine and cannabinoids may be promising adjuvants or monotherapeutic options.
AREAS COVERED
The new drugs, their presumed mechanisms of action, safety and efficacy are discussed herein. There is a paucity of robust clinical evidence in support of these drugs for trigeminal neuralgia. New migraine agents are considered as well although migraines and trigeminal neuralgia are distinct, albeit similar, conditions. No new drugs have been released to market in recent years with the specific indication of trigeminal neuralgia.
EXPERT OPINION
In real-world clinical practice, about half of trigeminal neuralgia patients take more than one agent for prevention and combination therapy may be the optimal approach. Combination therapy might allow for lower doses of carbamazepine or oxcarbazepine, thus reducing the number and severity of potential adverse events but the potential for pharmacokinetic drug-drug interactions must be considered. Drug therapy for trigeminal neuralgia involves acute or abortive treatments, often administered in hospital versus long-term preventive therapy, usually involving oral agents.
PubMed: 38870050
DOI: 10.1080/14737175.2024.2365946 -
Drug Metabolism and Disposition: the... Nov 2020Pimozide is a dopamine receptor antagonist indicated for the treatment of Tourette syndrome. Prior in vitro studies characterized dealkylation of pimozide to...
Pimozide is a dopamine receptor antagonist indicated for the treatment of Tourette syndrome. Prior in vitro studies characterized dealkylation of pimozide to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI) via CYP3A4 and, to a lesser extent, CYP1A2 as the only notable routes of pimozide biotransformation. However, drug-drug interactions between pimozide and CYP2D6 inhibitors and genotype-dependent effects have since been observed. To reconcile these incongruities between the prior in vitro and in vivo studies, we characterized two novel pimozide metabolites: 5-hydroxypimozide and 6-hydroxypimozide. Notably, 5-hydroxypimozide was the major metabolite produced by recombinant CYP2D6 (K ∼82 nM, ∼0.78 pmol/min per picomoles), and DHPBI was the major metabolite produced by recombinant CYP3A4 (apparent K ∼1300 nM, ∼2.6 pmol/min per picomoles). Kinetics in pooled human liver microsomes (HLMs) for the 5-hydroxylation (K ∼2200 nM, ∼59 pmol/min per milligram) and dealkylation (K ∼3900 nM, ∼600 pmol/min per milligram) reactions were also determined. Collectively, formation of DHPBI, 5-hydroxypimozide, and 6-hydroxypimozide accounted for 90% of pimozide depleted in incubations of NADPH-supplemented pooled HLMs. Studies conducted in HLMs isolated from individual donors with specific cytochrome P450 isoform protein abundances determined via mass spectrometry revealed that 5-hydroxypimozide ( = 0.94) and 6-hydroxypimozide ( = 0.86) formation rates were correlated with CYP2D6 abundance, whereas the DHPBI formation rate ( = 0.98) was correlated with CYP3A4 abundance. Furthermore, the HLMs differed with respect to their capacity to form 5-hydroxypimozide relative to DHPBI. Collectively, these data confirm a role for CYP2D6 in pimozide clearance via 5-hydroxylation and provide an explanation for a lack of involvement when only DHPBI formation was monitored in prior in vitro studies. SIGNIFICANCE STATEMENT: Current genotype-guided dosing information in the pimozide label is discordant with available knowledge regarding the primary biotransformation pathways. Herein, we characterize the CYP2D6-dependent biotransformation of pimozide to previously unidentified metabolites. In human liver microsomes, formation rates for the novel metabolites and a previously identified metabolite were determined to be a function of CYP2D6 and CYP3A4 content, respectively. These findings provide a mechanistic basis for observations of genotype-dependent pimozide clearance in vivo.
Topics: Adult; Aged; Antipsychotic Agents; Biotransformation; Child; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Drug Interactions; Female; Humans; Male; Microsomes, Liver; Middle Aged; Pimozide; Recombinant Proteins; Tourette Syndrome; Young Adult
PubMed: 32847865
DOI: 10.1124/dmd.120.000188 -
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 -
International Immunopharmacology Jul 2020Mast cells (MCs) mediate a key role in allergic diseases. Detailed studies of how the neuroleptic drug pimozide affects MC activity are lacking. The aim of this study...
BACKGROUND
Mast cells (MCs) mediate a key role in allergic diseases. Detailed studies of how the neuroleptic drug pimozide affects MC activity are lacking. The aim of this study was to investigate pimozide inhibition of immunoglobulin E (IgE)-mediated MC activation and MC-mediated allergic responses.
METHOD
MCs were stimulated with anti-dinitrophenyl (DNP) IgE antibodies and DNP-horse serum albumin (HSA) antigen (Ag), and anti-allergic pimozide effects were detected by measuring β-hexosaminidase levels. Morphological changes were observed histologically. In vivo pimozide effects were assessed in passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-sensitized active systemic anaphylaxis mouse (ASA) model experiments. Levels of phosphorylated (p-) SYK (spleen tyrosine kinase) and MAPKs (mitogen-activated protein kinases) were detected in western blots.
RESULTS
We found that pimozide inhibited MC degranulation, reduced MC release of β-hexosaminidase dose-dependently in activated RBL-2H3 (IC: 13.52 μM) and bone marrow derived MC (BMMC) (IC: 42.42 μM), and reduced MC morphological changes. The IgE/Ag-induced migration effect was suppressed by pimozide treatment dose-dependently. Pimozide down-regulated IgE/Ag-induced phosphorylation of SYK and MAPKs in activated MCs. Moreover, pimozide attenuated allergic reactions in PCA and ASA model mice, and decreased MC populations among splenic cells.
CONCLUSIONS
The antipsychotic drug pimozide can suppress IgE-mediated MC activation in vitro and in vivo and should be considered for repurposing to suppress MC-mediated diseases.
Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Cell Degranulation; Cell Line; Cell Movement; Disease Models, Animal; Female; Immunoglobulin E; Mast Cells; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Passive Cutaneous Anaphylaxis; Pimozide; Rats; Syk Kinase
PubMed: 32311669
DOI: 10.1016/j.intimp.2020.106500 -
Biological & Pharmaceutical Bulletin 2021T-Type Ca channels (T-channels), particularly Ca3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing...
T-Type Ca channels (T-channels), particularly Ca3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing medicines, bepridil, a multi-channel blocker, used for treatment of arrhythmia and angina, and pimozide, a dopamine D receptor antagonist, known as a typical antipsychotic, have potent T-channel blocking activity. We thus tested whether bepridil and pimozide could suppress visceral pain in mice. Colonic and bladder pain were induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and systemic administration of cyclophosphamide (CPA), respectively. Referred hyperalgesia was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load with intracolonic water injection and spontaneous bladder pain were evaluated by observing nociceptive behaviors in conscious mice. The mice exhibited referred hyperalgesia and colonic hypersensitivity to distension on day 6 after TNBS treatment. Systemic administration of bepridil at 10-20 mg/kg or pimozide at 0.1-0.5 mg/kg strongly reduced the referred hyperalgesia on the TNBS-induced referred hyperalgesia and colonic hypersensitivity to distension. CPA treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia, which were reversed by bepridil at 10-20 mg/kg or pimozide at 0.5-1 mg/kg. Our data thus suggest that bepridil and pimozide, existing medicines capable of blocking T-channels, are useful for treatment of colonic and bladder pain, and serve as seeds for the development of new medicines for visceral pain treatment.
Topics: Analgesics; Animals; Bepridil; Calcium Channel Blockers; Calcium Channels, T-Type; Colitis; Cyclophosphamide; Cystitis; Dopamine D2 Receptor Antagonists; Female; Male; Mice; Pimozide; Trinitrobenzenesulfonic Acid; Visceral Pain
PubMed: 33642557
DOI: 10.1248/bpb.b20-00742 -
Frontiers in Oncology 2021Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in...
Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance . Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.
PubMed: 34336684
DOI: 10.3389/fonc.2021.697950 -
Journal of Structural Biology Sep 2023Of the two putative amino acid binding periplasmic receptors of ABC transporter family in Candidatus Liberibacter asiaticus (CLas), cystine binding receptor (CLasTcyA)...
Of the two putative amino acid binding periplasmic receptors of ABC transporter family in Candidatus Liberibacter asiaticus (CLas), cystine binding receptor (CLasTcyA) has been shown to mainly express in phloem of citrus plant and is a target for inhibitor development. The crystal structure of CLasTcyA in complex with substrates has been reported earlier. The present work reports the identification and evaluation of potential candidates for their inhibitory potential against CLasTcyA. Among many compounds, selected through virtual screening, and MD simulation, pimozide, clidinium, sulfasalazine and folic acid showed significantly higher affinities and stability in complex with CLasTcyA. The SPR studies with CLasTcyA revealed significantly higher binding affinities for pimozide and clidinium (Kd, 2.73 nM and 70 nM, respectively) as compared to cystine (Kd, 1.26 µM). The higher binding affinities could be attributed to significantly increased number of interactions in the binding pocket as evident from the crystal structures of CLasTcyA in complex with pimozide and clidinium as compared to cystine. The CLasTcyA possess relatively large binding pocket where bulkier inhibitors fit quite well. In planta studies, carried out to assess the effect of inhibitors on HLB infected Mosambi plants, showed significant reduction in CLas titre in plants treated with inhibitors as compared to control plants. The results showed that pimozide exhibited higher efficiency as compared to clidinium in reducing CLas titre in treated plants. Our results showed that the inhibitor development against critical proteins like CLasTcyA can be an important strategy in management of HLB.
Topics: Rhizobiaceae; Cystine; Pimozide; Plant Diseases
PubMed: 37394197
DOI: 10.1016/j.jsb.2023.107992 -
European Journal of Pharmacology Oct 2021Patients with adult T-cell leukemia (ATL), caused by the human T-cell leukemia virus type 1 (HTLV-1), exhibit poor prognosis owing to drug resistance. Pimozide is a...
Patients with adult T-cell leukemia (ATL), caused by the human T-cell leukemia virus type 1 (HTLV-1), exhibit poor prognosis owing to drug resistance. Pimozide is a dopamine D2 receptor antagonist and antipsychotic shown to exhibit anticancer activity. Herein, we investigated whether pimozide exerts anti-ATL effects and explored the mechanisms underlying these effects. Pimozide inhibited cell growth and survival in HTLV-1-infected T cells but not in the uninfected T cells. The dopamine D2 receptor subfamily mRNA expression levels in HTLV-1-infected T cells were high. Pimozide induced G1 cell cycle arrest concomitant with the upregulation of p21/p27/p53, and suppression of cyclin D2/E, cyclin-dependent kinase 2/4/6 and c-Myc expression, and pRb phosphorylation. Pimozide also induced apoptosis by activating caspases, upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins. Additionally, it promoted reactive oxygen species (ROS) generation and increased the expression of the endoplasmic reticulum stress marker activating transcription factor 4 and the DNA damage-inducible protein GADD45α and the phosphorylation of the DNA damage marker H2AX. Furthermore, pimozide-induced cytotoxicity was partially inhibited by a ROS scavenger, and pan-caspase and necroptosis inhibitors, indicating the involvement of caspase-dependent and -independent lethal pathways. The activities of the nuclear factor-κB, Akt, STAT3/5 and AP-1 signaling pathways were inhibited via the dephosphorylation of IκBα, IκB kinase α/β, Akt and STAT3/5, in addition to reduced JunB and JunD expression in HTLV-1-infected T cells. Pimozide also exhibited potent anti-ATL activity in the xenograft mouse model. These findings demonstrated the efficacy of pimozide as a potential therapeutic agent for ATL.
Topics: Animals; Antipsychotic Agents; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; Mice; Pimozide
PubMed: 34303663
DOI: 10.1016/j.ejphar.2021.174373