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Frontiers in Oncology 2023The limitations of current cancer therapies, including the increasing prevalence of multidrug resistance, underscore the urgency for more effective treatments. One... (Review)
Review
The limitations of current cancer therapies, including the increasing prevalence of multidrug resistance, underscore the urgency for more effective treatments. One promising avenue lies in the repurposing of existing drugs. This review explores the impact of phenothiazines, primarily used as antipsychotic agents, on key mechanisms driving tumor growth and metastasis. The cationic and amphiphilic nature of phenothiazines allows interaction with the lipid bilayer of cellular membranes, resulting in alterations in lipid composition, modulation of calcium channels, fluidity, thinning, and integrity of the plasma membrane. This is especially significant in the setting of increased metabolic activity, a higher proliferative rate, and the invasiveness of cancer cells, which often rely on plasma membrane repair. Therefore, properties of phenothiazines such as compromising plasma membrane integrity and repair, disturbing calcium regulation, inducing cytosolic K-RAS accumulation, and sphingomyelin accumulation in the plasma membrane might counteract multidrug resistance by sensitizing cancer cells to membrane damage and chemotherapy. This review outlines a comprehensive overview of the mechanisms driving the anticancer activities of phenothiazines derivates such as trifluoperazine, prochlorperazine, chlorpromazine, promethazine, thioridazine, and fluphenazine. The repurposing potential of phenothiazines paves the way for novel approaches to improve future cancer treatment.
PubMed: 38074670
DOI: 10.3389/fonc.2023.1320621 -
Indian Journal of Otolaryngology and... Dec 2023To assess the efficacy and safety of prochlorperazine in Indian patients with acute vertigo.
AIM
To assess the efficacy and safety of prochlorperazine in Indian patients with acute vertigo.
METHODS
In this prospective, multicenter, open-label, post-marketing observational study, patients with acute peripheral vertigo of different etiologies received 5 mg prochlorperazine thrice a day for 5 days. The primary endpoints were percentage of patients with improvement in (1) vertigo symptoms and (2) clinical response as per scale for vestibular vertigo severity level and clinical response evaluation (SVVSLCRE) from baseline to end of treatment (Day 6). The key secondary endpoints were (1) improvement in nystagmus grading, and (2) safety and tolerability Efficacy of prochlorperazine by route of administration of first prochlorperazine dose (oral or intramuscular) was also assessed.
RESULTS
Of 1716 enrolled patients (mean [standard deviation, SD]) age (42.0 [12.95] years; 53.6% men), 57.4% were diagnosed with Meniere's disease, followed by vestibular neuritis (17.4%), labyrinthitis (16.7%), or ear surgery (8.5%). In the overall population, 91.1% of patients showed improvement in clinical response per SVVSLCRE grading at Day 6 (p < 0.0001 vs. non-responders). Nystagmus grading was improved in 99.7% (of patients. No adverse drug reactions events were reported. Tolerability of prochlorperazine was rated as good, very good, and excellent by 43.6%, 32.9% and 20.7% of patients, respectively. Among patients with postoperative vertigo, 80.1% showed improvement in clinical response. In the intramuscular and oral subsets, 85.5% and 92.1% of patients showed improved clinical response, respectively.
CONCLUSION
Prochlorperazine showed improvement in severity of symptoms and clinical response in all subsets of vertigo patients, with a good safety and tolerability profile.
TRIAL REGISTRATION NUMBER
CTRI/2022/01/039287.
DATE OF REGISTRATION
10 January 2022.
PubMed: 38027535
DOI: 10.1007/s12070-023-03831-0 -
Journal of Nuclear Medicine : Official... Dec 2023Glypican-1 (GPC1) is overexpressed in several solid cancers and is associated with tumor progression, whereas its expression is low in normal tissues. This study aimed...
Glypican-1 (GPC1) is overexpressed in several solid cancers and is associated with tumor progression, whereas its expression is low in normal tissues. This study aimed to evaluate the potential of an anti-GPC1 monoclonal antibody (GPC1 mAb) labeled with Zr or At as a theranostic target in pancreatic ductal adenocarcinoma. GPC1 mAb clone 01a033 was labeled with Zr or At with a deferoxamine or decaborane linker, respectively. The internalization ability of GPC1 mAb was evaluated by fluorescence conjugation using a confocal microscope. PANC-1 xenograft mice ( = 6) were intravenously administered [Zr]GPC1 mAb (0.91 ± 0.10 MBq), and PET/CT scanning was performed for 7 d. Uptake specificity was confirmed through a comparative study using GPC1-positive (BxPC-3) and GPC1-negative (BxPC-3 GPC1-knockout) xenografts (each = 3) and a blocking study. DNA double-strand breaks were evaluated using the γH2AX antibody. The antitumor effect was evaluated by administering [At]GPC1 mAb (∼100 kBq) to PANC-1 xenograft mice ( = 10). GPC1 mAb clone 01a033 showed increased internalization ratios over time. One day after administration, a high accumulation of [Zr]GPC1 mAb was observed in the PANC-1 xenograft (SUV, 3.85 ± 0.10), which gradually decreased until day 7 (SUV, 2.16 ± 0.30). The uptake in the BxPC-3 xenograft was significantly higher than in the BxPC-3 GPC1-knockout xenograft (SUV, 4.66 ± 0.40 and 2.36 ± 0.36, respectively; = 0.05). The uptake was significantly inhibited in the blocking group compared with the nonblocking group (percentage injected dose per gram, 7.3 ± 1.3 and 12.4 ± 3.0, respectively; = 0.05). DNA double-strand breaks were observed by adding 150 kBq of [At]GPC1 and were significantly suppressed by the internalization inhibitor (dynasore), suggesting a substantial contribution of the internalization ability to the antitumor effect. Tumor growth suppression was observed in PANC-1 mice after the administration of [At]GPC1 mAb. Internalization inhibitors (prochlorperazine) significantly inhibited the therapeutic effect of [At]GPC1 mAb, suggesting an essential role in targeted α-therapy. [Zr]GPC1 mAb PET showed high tumoral uptake in the early phase after administration, and targeted α-therapy using [At]GPC1 mAb showed tumor growth suppression. GPC1 is a promising target for future applications for the precise diagnosis of pancreatic ductal adenocarcinoma and GPC1-targeted theranostics.
Topics: Humans; Animals; Mice; Glypicans; Positron-Emission Tomography; Precision Medicine; Positron Emission Tomography Computed Tomography; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; DNA; Zirconium
PubMed: 37827841
DOI: 10.2967/jnumed.123.266313 -
Frontiers in Cellular and Infection... 2023The coronavirus disease 2019 (COVID-19) pandemic, stemming from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has persistently threatened the global...
INTRODUCTION
The coronavirus disease 2019 (COVID-19) pandemic, stemming from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has persistently threatened the global health system. Meanwhile, tuberculosis (TB) caused by () still continues to be endemic in various regions of the world. There is a certain degree of similarity between the clinical features of COVID-19 and TB, but the underlying common pathogenetic processes between COVID-19 and TB are not well understood.
METHODS
To elucidate the common pathogenetic processes between COVID-19 and TB, we implemented bioinformatics and systematic research to obtain shared pathways and molecular biomarkers. Here, the RNA-seq datasets (GSE196822 and GSE126614) are used to extract shared differentially expressed genes (DEGs) of COVID-19 and TB. The common DEGs were used to identify common pathways, hub genes, transcriptional regulatory networks, and potential drugs.
RESULTS
A total of 96 common DEGs were selected for subsequent analyses. Functional enrichment analyses showed that viral genome replication and immune-related pathways collectively contributed to the development and progression of TB and COVID-19. Based on the protein-protein interaction (PPI) network analysis, we identified 10 hub genes, including IFI44L, ISG15, MX1, IFI44, OASL, RSAD2, GBP1, OAS1, IFI6, and HERC5. Subsequently, the transcription factor (TF)-gene interaction and microRNA (miRNA)-gene coregulatory network identified 61 TFs and 29 miRNAs. Notably, we identified 10 potential drugs to treat TB and COVID-19, namely suloctidil, prenylamine, acetohexamide, terfenadine, prochlorperazine, 3'-azido-3'-deoxythymidine, chlorophyllin, etoposide, clioquinol, and propofol.
CONCLUSION
This research provides novel strategies and valuable references for the treatment of tuberculosis and COVID-19.
Topics: Humans; COVID-19; SARS-CoV-2; Computational Biology; Genes, Regulator; Tuberculosis; Mycobacterium tuberculosis; Gene Expression Profiling; MicroRNAs
PubMed: 38162574
DOI: 10.3389/fcimb.2023.1280223 -
Fujita Medical Journal Nov 2023Antiemetics have been widely recommended for treating opioid-induced nausea and vomiting (OINV). According to a previous study, the use of prophylactic prochlorperazine...
The efficacy of prophylactic prochlorperazine injections at the initiation of opioid injections in preventing opioid-induced nausea and vomiting among patients with end-stage cancer.
OBJECTIVES
Antiemetics have been widely recommended for treating opioid-induced nausea and vomiting (OINV). According to a previous study, the use of prophylactic prochlorperazine at the initiation of treatment with oral oxycodone was ineffective in preventing OINV. This study examined whether prochlorperazine injection prevents OINV and induces drowsiness in patients with end-stage cancer (a different patient population from the previous study).
METHODS
Patients with end-stage cancer who received opioid injections for more than 5 days between April 2017 and March 2020 were classified into two groups: the opioid and prochlorperazine injection group and opioid alone group. Their systemic conditions were evaluated on the basis of the performance status and the palliative performance scale, a prognostic indicator.
RESULTS
Of 325 patients who received opioid treatment during the study period, 156 patients met the inclusion criteria. Of these, 103 patients and 53 patients were classified into the opioid and prochlorperazine injection group (prochlorperazine) and opioid alone groups (placebo) , respectively. There was no significant difference in characteristics, age, gender, performance status, or palliative performance scale results between the 2 groups. OINV developed in 4 patients in the opioid and prochlorperazine injection groups and in 1 patient in the opioid alone group. Given that sleep disturbance develops in many patients with end-stage cancer who had a specific condition, it is difficult to conclude regarding the relationship between prochlorperazine injection and drowsiness, although this study examined this relationship.
CONCLUSIONS
As with the previous study, prophylactic prochlorperazine injection was ineffective in preventing OINV in patients who received opioid injections.
PubMed: 38077960
DOI: 10.20407/fmj.2022-034 -
Medicina (Kaunas, Lithuania) Jul 2023: There is scarce data about the epidemiology, clinical features, investigations, diagnosis, treatment, and outcome in patients attending Singapore emergency departments... (Observational Study)
Observational Study
: There is scarce data about the epidemiology, clinical features, investigations, diagnosis, treatment, and outcome in patients attending Singapore emergency departments (EDs) with nontraumatic headache. We sought to describe these characteristics of adult patients presenting to the ED with a primary complaint of headache. : We performed a cross-sectional study on adult patients with nontraumatic headache over 4 consecutive weeks from 18 March 2019 to 14 April 2019 across four EDs in Singapore. Exclusion criteria were history of head trauma within 48 h of presentation, missing records, interhospital transfers, representation with the same headache as a recent previous visit and headache as an associated symptom. : During the study period, 579 patients (representing 1.8% of the total ED census) comprising 55.3% males and with a median age of 36 years presented to the four Singapore EDs with a primary complaint of nontraumatic headache. Paracetamol (41.5%), non-steroidal anti-inflammatory drugs (34.4%) and tramadol (31.5%) were the three commonest analgesics used either singly or in combination. Prochlorperazine (22.9%) and metoclopramide (17.4%) were frequent anti-emetic adjuncts. One-third of patients had computed tomography of the brain performed, which found abnormalities among 20.9% of them. ED diagnoses of primary headache conditions were made in 73.6% of patients. : Primary headaches constituted most ED headache diagnoses. ED imaging of selected patients yielded a relatively high pick-up rate for significant intracranial abnormalities. Opioid use for symptomatic relief of headaches in the ED was found to be high, underscoring the need for improvement in headache analgesia relief practices in the ED.
Topics: Adult; Male; Humans; Female; Singapore; Cross-Sectional Studies; Headache; Metoclopramide; Emergency Service, Hospital
PubMed: 37512151
DOI: 10.3390/medicina59071340 -
Current Issues in Molecular Biology Jun 2023Skeletal muscle disuse leads to pathological muscle activity as well as to slow-to-fast fiber-type transformation. Fast-type fibers are more fatigable than slow-type, so...
Skeletal muscle disuse leads to pathological muscle activity as well as to slow-to-fast fiber-type transformation. Fast-type fibers are more fatigable than slow-type, so this transformation leads to a decline in muscle function. Prochlorperazine injections previously were shown to attenuate autonomous rat soleus muscle electrical activity under unloading conditions. In this study, we found that prochlorperazine blocks slow-to-fast fiber-type transformation in disused skeletal muscles of rats, possibly through affecting calcium and ROS-related signaling.
PubMed: 37504270
DOI: 10.3390/cimb45070354