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Biochimica Et Biophysica Acta. Reviews... Apr 2021The natural history of adenoid cystic carcinoma (ACC) is relentless, defined by treatment failure heralded by locoregional recurrence and distant metastatic disease. In... (Review)
Review
The natural history of adenoid cystic carcinoma (ACC) is relentless, defined by treatment failure heralded by locoregional recurrence and distant metastatic disease. In this review, we present an update of clinical features, molecular classification, current targeted therapies, immune landscapes and novel treatment targets with their respective clinical trials. The presented results are defined by a lack of overall response rate and limited progression free survival, with restriction to stable disease. In addition, ACC is resistant to immune checkpoint inhibition due to low tumour immunogenicity and lack of PD-L1 expression. Here we present a new prospective research paradigm for ACC, including the potential to target prostate specific membrane antigen (PSMA) and the potential for manipulation of target receptors in the clinic. The presentation of this review aims to promote future research to improve response rates and outcomes for therapeutics undergoing clinical trial in ACC.
Topics: Antibodies, Monoclonal; Carcinoma, Adenoid Cystic; Clinical Trials as Topic; Disease Progression; Humans; Immunotherapy; Prospective Studies; Signal Transduction; Survival Analysis
PubMed: 33600823
DOI: 10.1016/j.bbcan.2021.188523 -
Therapeutic Advances in... 2021Antipsychotic agents (APS) are widely used drugs to treat psychotic symptoms and can effectively reduce both positive and negative symptoms of schizophrenia. For...
BACKGROUND
Antipsychotic agents (APS) are widely used drugs to treat psychotic symptoms and can effectively reduce both positive and negative symptoms of schizophrenia. For decades, some studies suggested that there is a relationship between using APS and the risk of venous thromboembolism (VTE) and pulmonary embolism (PE). However, results remain inconclusive.
METHOD
This review has been registered in International Prospective Register of Systematic Reviews (PROSPERO, ID: CDR42020155620). Relevant studies were identified among observational studies published up to 1 October 2019 in the databases MEDLINE, EMBASE, and Cochrane Library. Random or fixed-effects models were used to calculate the pooled odds ratio (OR).
RESULTS
In total, 28 observational studies were included. The results showed that compared with non-users, current APS users have significantly increased risks of VTE [OR 1.55 95% confidence interval (CI) 1.36, 1.76] and PE (OR 3.68, 95% CI 1.23, 11.05). Subgroup analyses suggested that new users were associated with a higher risk of VTE (OR 2.06, 95% CI 1.81, 2.35). For individual drugs, increased risk of VTE and PE was observed in taking haloperidol, risperidone, olanzapine, prochlorperazine but not in chlorpromazine, quetiapine or aripiprazole. However, careful interpretation is needed because of high heterogeneity among studies and scarce data.
CONCLUSION
The present comprehensive meta-analysis further indicates a significantly increased risk of VTE and PE in current APS users compared with non-users. Subgroup analyses suggest that new users are more likely to develop VTE. However, due to significant heterogeneity among studies, conclusions should be considered with caution.
PubMed: 33505665
DOI: 10.1177/2045125320982720 -
Pediatric Neurology Mar 2021A combination of parenteral medications (often referred to as standard combination therapy) is frequently used in the treatment of acute migraine in the pediatric... (Observational Study)
Observational Study
BACKGROUND
A combination of parenteral medications (often referred to as standard combination therapy) is frequently used in the treatment of acute migraine in the pediatric emergency department (PED). The primary aim of this study was to evaluate the two-hour, 24-hour, and seven-day impact of one such regimen on pain in children who present to the PED. Standard combination therapy for purposes of our study is defined as a bolus of intravenous saline, and a combination of intravenous ketorolac, prochlorperazine, and diphenhydramine.
METHODS
This prospective observational study included 120 children between the ages seven and 18 years who presented to the PED with migraine, whose parents could read and understand the consent form in English, and who were treated with standard combination therapy. The primary outcome measure for this study was the change in severity of pain as noted by the child using the Faces Pain Scale-Revised. We analyzed normally distributed continuous variables by mean and standard deviation, whereas non-normally distributed continuous variables are reported by median and interquartile range.
RESULTS
Nonparametric Friedman testing on the entire cohort (n = 120) noted that there was a statistically significant change in the Faces pain scale from before administration of standard combination therapy to the two-hour, 24-hour, and one-week time point with a reduction in pain score of 87.5%, 100%, and 50%, respectively, at the three time points.
CONCLUSIONS
This study noted moderate relief of pain after administration of standard combination therapy, which persisted at one-week after administration.
Topics: Acute Disease; Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Child; Diphenhydramine; Dopamine Antagonists; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Ketorolac; Male; Migraine Disorders; Outcome Assessment, Health Care; Prochlorperazine; Prospective Studies; Saline Solution
PubMed: 33493999
DOI: 10.1016/j.pediatrneurol.2020.12.004 -
The Medical Letter on Drugs and... Dec 2020
Topics: Administration, Intravesical; Amisulpride; Antiemetics; Double-Blind Method; Humans; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic
PubMed: 33451177
DOI: No ID Found -
The Medical Letter on Drugs and... Oct 2020
Topics: Acupuncture Therapy; Adult; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Antiemetics; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Interactions; Ergot Alkaloids; Female; Humans; Migraine Disorders; Pregnancy; Serotonin 5-HT1 Receptor Antagonists; Tryptamines
PubMed: 33434187
DOI: No ID Found -
Frontiers in Oncology 2020T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive subtype of leukemia for which important progress in treatment efficiency have been made in the past decades...
T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive subtype of leukemia for which important progress in treatment efficiency have been made in the past decades to reach a cure rate of 75%-80% nowadays. It is nevertheless mandatory to find new targets and active molecules for innovative therapeutic strategies as relapse is associated with a very dismal outcome. We designed an experimental workflow to highlight the conserved core pathways associated with leukemogenesis by confronting the gene expression profiles (GEPs) of human T-ALL cases to the GEP of a murine T-ALL representative model, generated by the conditional deletion of the tumor suppressor gene in T cell precursors (tPTEN-/-). We identified 844 differentially expressed genes, common GEPs (cGEP) that were conserved between human T-ALL and murine signatures, and also similarly differentially expressed, compared to normal T cells. Using bioinformatic tools we highlighted in cGEPan upregulation of E2F, MYC and mTORC1. Next, using Connectivity Map (CMAP) and CMAPViz a visualization procedure for CMAP data that we developed, we selected three FDA-approved, bioactive molecule candidates: α-estradiol (α-E), nordihydroguaiaretic acid (NDGA) and prochlorperazine dimaleate (PCZ). At a biological level, we showed that the three drugs triggered an apoptotic cell death in a panel of T-ALL cell lines, activated a DNA damage response and interfered with constitutive mTORC1 activation and c-MYC expression. This analysis shows that the investigation of conserved leukemogenesis pathways could be a strategy to reveal new avenues for pharmacological intervention.
PubMed: 33240808
DOI: 10.3389/fonc.2020.557643 -
Journal of Gastroenterology and... Feb 2021
Topics: Antiemetics; COVID-19; Humans; Nausea; Prochlorperazine; Vomiting
PubMed: 33068035
DOI: 10.1111/jgh.15301 -
The American Journal of Emergency... Jan 2021Due to the healthcare burden associated with migraines, prompt and effective treatment is vital to improve patient outcomes and ED workflow. This was a prospective,... (Randomized Controlled Trial)
Randomized Controlled Trial
Due to the healthcare burden associated with migraines, prompt and effective treatment is vital to improve patient outcomes and ED workflow. This was a prospective, randomized, double-blind trial. Adults who presented to the ED with a diagnosis of migraine from August of 2019 to March of 2020 were included. Pregnant patients, or with renal impairment were excluded. Patients were randomized to receive intravenous magnesium, prochlorperazine, or metoclopramide. The primary outcome was change in pain from baseline on a numeric rating scale (NRS) evaluated at 30 min after initiation of infusion of study drug. Secondary outcomes included NRS at 60 and 120 min, ED length of stay, necessity for rescue analgesia, and adverse effects. A total of 157 patients were analyzed in this study. Sixty-one patients received magnesium, 52 received prochlorperazine, and 44 received metoclopramide. Most patients were white females, and the median age was 36 years. Hypertension and migraines were the most common comorbidities, with a third of the patients reporting an aura. There was a median decrease in NRS at 30 min of three points across all three treatment arms. The median decrease in NRS (IQR) at 60 min was -4 (2-6) in the magnesium group, -3 (2-5) in the metoclopramide group, and -4.5 (2-7) in the prochlorperazine group (p = 0.27). There were no statistically significant differences in ED length of stay, rescue analgesia, or adverse effects. Reported adverse effects were dizziness, anxiety, and akathisia. No significant difference was observed in NRS at 30 min between magnesium, metoclopramide and prochlorperazine.
Topics: Administration, Intravenous; Adult; Double-Blind Method; Female; Humans; Magnesium; Male; Metoclopramide; Middle Aged; Migraine Disorders; Patient Satisfaction; Prochlorperazine; Prospective Studies; Severity of Illness Index; Time Factors
PubMed: 33041146
DOI: 10.1016/j.ajem.2020.09.033 -
Computational and Structural... 2020The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination...
The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination therapies are fast becoming untenable. Combining antibiotics with various FDA-approved non-antibiotic drugs has emerged as a novel strategy against otherwise untreatable multi-drug resistant (MDR) pathogens. The apex of this study was to investigate the mechanisms of antibacterial synergy of the combination of polymyxin B with the phenothiazines against the MDR Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The synergistic antibacterial effects were tested using checkerboard and static time-kill assays. Electron microscopy (EM) and untargeted metabolomics were used to ascertain the mechanism(s) of the antibacterial synergy. The combination of polymyxin B and the phenothiazines showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. EM revealed that the polymyxin B-prochlorperazine combination resulted in greater damage to the bacterial cell compared to each drug monotherapy. In metabolomics, at 0.5 h, polymyxin B monotherapy and the combination (to a greatest extent) disorganised the bacterial cell envelope as manifested by a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan and lipopolysaccharide (LPS) biosynthesis. At the late time exposure (4 h), the aforementioned effects (except LPS biosynthesis) perpetuated mainly with the combination therapy, indicating the disorganising bacterial membrane biogenesis is potentially behind the mechanisms of antibacterial synergy. In conclusion, the study highlights the potential usefulness of the combination of polymyxin B with phenothiazines for the treatment of polymyxin-resistant Gram-negative infections (e.g. CNS infections).
PubMed: 32952938
DOI: 10.1016/j.csbj.2020.08.008 -
European Journal of Pharmacology Nov 2020In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not... (Review)
Review
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
Topics: Animals; Antipsychotic Agents; Antiviral Agents; Betacoronavirus; COVID-19; Chlorpromazine; Coronavirus Infections; Fluphenazine; Humans; Pandemics; Perphenazine; Phenothiazines; Pneumonia, Viral; Prochlorperazine; RNA Viruses; SARS-CoV-2; Thioridazine; COVID-19 Drug Treatment
PubMed: 32949606
DOI: 10.1016/j.ejphar.2020.173553