-
Bioorganic Chemistry Jun 2023Glioblastoma multiform (GBM) is one of the most aggressive tumors of the central nervous system in humans. GBM overexpresses serotonin-7 receptors (5-HTRs); hence, this...
Glioblastoma multiform (GBM) is one of the most aggressive tumors of the central nervous system in humans. GBM overexpresses serotonin-7 receptors (5-HTRs); hence, this study aims to develop 5-HTR targeted radiotracers. Aryl piperazine derivatives can act as ligands for 5-HTR. Therefore, compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were synthesized and radiolabeled with TcN core. Radiolabeled 6 and 7 (TcN-[6] and TcN-[7]) were prepared with high radiochemical purity (RCP > 96%). They displayed high affinity toward U-87 MG cell line 5-HTR. The calculated K for TcN-[7] was lower than that of TcN-[6] (14.85 ± 0.32 vs 22.57 ± 0.73 nM) which indicates the higher affinity of TcN-[7] toward 5-HTR. A molecular docking study also confirmed the binding of these radiotracers to 5-HTR. The biodistribution study in normal mice revealed that TcN-[7] has the highest brain accumulation at 30 min post-injection (0.54 ± 0.12 %ID/g) while the uptake of TcN-[6] is much lower (0.14 ± 0.02 %ID/g). The biodistribution study in the xenograft model confirms that the radiotracers recognize the tumor site. TcN-[6], and TcN-[7] showed the highest tumor uptake at 1-hour post-injection (5.44 ± 0.58 vs 4.94 ± 1.65 %ID/g) and tumor-to-muscle ratios were (4.61 vs. 5.61). The injection of pimozide blocks the receptors and significantly reduces the tumor-to-muscle ratios at 1-hour post-injection to 0.81 and 0.31, respectively. In correlation with in vitro study, TcN-[6] and TcN-[7] visualize the tumor site in U-87 MG glioma xenografted nude mice and display the tumor-to-muscle ratios of 7.05 and 6.03.
Topics: Humans; Mice; Animals; Organotechnetium Compounds; Tissue Distribution; Mice, Nude; Molecular Docking Simulation; Serotonin; Glioma; Piperazines; Cell Line, Tumor
PubMed: 36965286
DOI: 10.1016/j.bioorg.2023.106486 -
Clinics in Dermatology 2023Eating disorders (EDs) such as anorexia nervosa and bulimia nervosa have a plethora of skin manifestations. They can be categorized into skin signs of self-purging, skin...
Eating disorders (EDs) such as anorexia nervosa and bulimia nervosa have a plethora of skin manifestations. They can be categorized into skin signs of self-purging, skin signs of starvation, skin signs related to drug abuse, skin signs of psychiatric comorbidity, and miscellaneous signs. "Guiding signs" are valuable because they are pointers to the diagnosis of an ED. They include hypertrichosis (lanugo-like hair), Russell's sign (knuckle calluses), self-induced dermatitis, and perimylolysis (tooth enamel erosion). Practitioners should recognize such skin signs promptly, as this helps to diagnose early, which may improve the prognosis of ED. Management requires a multidisciplinary approach that focuses on psychotherapy combined with attention to medical complications, nutritional needs, and nonpsychiatric findings such as cutaneous manifestations. Psychotropic medications that are currently used in EDs include pimozide and atypical antipsychotic agents, such as aripiprazole and olanzapine, fluoxetine, and lisdexamfetamine.
Topics: Humans; Skin; Feeding and Eating Disorders; Anorexia Nervosa; Skin Diseases; Fluoxetine
PubMed: 36878454
DOI: 10.1016/j.clindermatol.2023.03.005 -
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 -
Current Topics in Medicinal Chemistry 2023Glioblastoma Multiforme (GBM) is a debilitating type of brain cancer with a high mortality rate. Despite current treatment options such as surgery, radiotherapy, and the... (Review)
Review
Glioblastoma Multiforme (GBM) is a debilitating type of brain cancer with a high mortality rate. Despite current treatment options such as surgery, radiotherapy, and the use of temozolomide and bevacizumab, it is considered incurable. Various methods, such as drug repositioning, have been used to increase the number of available treatments. Drug repositioning is the use of FDA-approved drugs to treat other diseases. This is possible because the drugs used for this purpose have polypharmacological effects. This means that these medications can bind to multiple targets, resulting in multiple mechanisms of action. Antipsychotics are one type of drug used to treat GBM. Antipsychotics are a broad class of drugs that can be further subdivided into typical and atypical classes. Typical antipsychotics include chlorpromazine, trifluoperazine, and pimozide. This class of antipsychotics was developed early on and primarily works on dopamine D2 receptors, though it can also work on others. Olanzapine and Quetiapine are examples of atypical antipsychotics, a category that was created later. These medications have a high affinity for serotonin receptors such as 5- HT2, but they can also act on dopamine and H1 receptors. Antipsychotic medications, in the case of GBM, also have other effects that can affect multiple pathways due to their polypharmacological effects. These include NF-B suppression, cyclin deregulation, and -catenin phosphorylation, among others. This review will delve deeper into the polypharmacological, the multiple effects of antipsychotics in the treatment of GBM, and an outlook for the field's future progression.
Topics: Humans; Antipsychotic Agents; Glioblastoma; Quetiapine Fumarate; Dopamine; Receptors, Serotonin
PubMed: 36593538
DOI: 10.2174/1568026623666230102095836 -
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 -
The Lancet. Child & Adolescent Health Feb 2023In clinical practice guidelines there is no consensus about the medications that should be initially offered to children and young people with Tourette's syndrome. To... (Meta-Analysis)
Meta-Analysis
Comparative efficacy, tolerability, and acceptability of pharmacological interventions for the treatment of children, adolescents, and young adults with Tourette's syndrome: a systematic review and network meta-analysis.
BACKGROUND
In clinical practice guidelines there is no consensus about the medications that should be initially offered to children and young people with Tourette's syndrome. To provide a rigorous evidence base that could help guide decision making and guideline development, we aimed to compare the efficacy, tolerability, and acceptability of pharmacological interventions for Tourette's syndrome.
METHODS
For this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, Embase, PsycINFO, PubMed, Web of Science, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov, for published and unpublished studies from database inception to Nov 19, 2021. We included double-blind randomised controlled trials of any medication administered as a monotherapy for at least 1 week against another medication or placebo in children and adolescents (aged ≥4 years and ≤18 years), adults (>18 years), or both, diagnosed with Tourette's syndrome according to standardised criteria. We excluded studies that exclusively recruited participants with comorbid attention-deficit hyperactivity disorder or obsessive-compulsive disorder. The primary outcome was change in severity of tic symptoms (efficacy). Secondary outcomes were treatment discontinuations due to adverse events (tolerability) and for any reason (acceptability). Pharmacological interventions were examined considering medication categories and medications individually in separate analyses. Summary data were extracted and pooled with a random-effects network meta-analysis to calculate standardised mean differences for efficacy and odds ratios for tolerability and acceptability, with 95% CIs. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was pre-registered in PROSPERO (CRD42022296975).
FINDINGS
Of the 12 088 records identified through the database search, 88 records representing 39 randomised controlled trials were included in the network meta-analysis; these 39 randomised controlled trials comprised 4578 participants (mean age 11·8 [SD 4·5] years; 3676 [80·8%] male participants) and evaluated 23 individual medications distributed across six medication categories. When considering medication categories, first-generation (standardised mean difference [SMD] -0·65 [95% CI -0·79 to -0·51]; low certainty of evidence) and second-generation (-0·71 [-0·88 to -0·54]; moderate certainty of evidence) antipsychotic drugs, as well as α-2 agonists (-0·21 [-0·39 to -0·03]; moderate certainty of evidence), were more efficacious than placebo. First-generation and second-generation antipsychotic drugs did not differ from each other (SMD 0·06 [95% CI -0·14 to 0·25]; low certainty of evidence). However, both first-generation (SMD 0·44 [95% CI 0·21 to 0·66]) and second-generation (0·49 [0·25 to 0·74]) antipsychotic drugs outperformed α-2 agonists, with moderate certainty of evidence. Similar findings were observed when individual medications were considered: aripiprazole (SMD -0·60 [95% CI -0·83 to -0·38]), haloperidol (-0·51 [-0·88 to -0·14]), olanzapine (-0·83 [-1·49 to -0·18]), pimozide (-0·48 [-0·84 to -0·12]), risperidone (-0·66 [-0·98 to -0·34]), and clonidine (-0·20 [-0·37 to -0·02]) all outperformed placebo, with moderate certainty of evidence. Antipsychotic medications did not differ from each other, but there was low to very low certainty of evidence for these comparisons. However, aripiprazole (SMD -0·40 [95% CI -0·69 to -0·12]) and risperidone (-0·46 [-0·82 to -0·11]) outperformed clonidine, with moderate certainty of evidence. Heterogeneity or inconsistency only emerged for a few comparisons. In terms of tolerability and acceptability, there were no relevant findings for any of the efficacious medication categories or individual medications against each other or placebo, but there was low to very low certainty of evidence associated with these comparisons.
INTERPRETATION
Our analyses show that antipsychotic drugs are the most efficacious intervention for Tourette's syndrome, while α-2 agonists are also more efficacious than placebo and could be chosen by those who elect not to take antipsychotic drugs. Shared decision making about the degree of tic-related severity and distress or impairment, the trade-offs of efficacy and safety between antipsychotic drugs and α-2 agonists, and other highly relevant individual factors that could not be addressed in the present analysis, should guide the choice of medication for children and young people with Tourette's syndrome.
FUNDING
None.
Topics: Male; Adolescent; Child; Young Adult; Humans; Female; Tourette Syndrome; Antipsychotic Agents; Clonidine; Aripiprazole; Risperidone; Network Meta-Analysis; Tics; Adrenergic alpha-2 Receptor Agonists; Randomized Controlled Trials as Topic
PubMed: 36528030
DOI: 10.1016/S2352-4642(22)00316-9