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Journal of Clinical Medicine Oct 2023In recent years, numerous approaches have been developed to comprehend the molecular alterations underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic...
In recent years, numerous approaches have been developed to comprehend the molecular alterations underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic strategies for TC. It is now well established that the neurokinin-1 receptor (NK-1R) is overexpressed in cancer cells and that NK-1R is essential for the viability of cancer cells. The binding of substance P (SP) to NK-1R in neoplastic cells plays a pivotal role in cancer progression by promoting neoplastic cell growth, protecting tumor cells from apoptosis, triggering invasion and metastasis through the enhanced migration of cancer cells, and stimulating endothelial cell proliferation for tumor angiogenesis. Remarkably, all types of human TC (papillary, follicular, medullary, anaplastic), as well as metastatic lesions, exhibit the overexpression of SP and NK-1R compared to the normal thyroid gland. TC cells synthesize and release SP, which exerts its multiple functions through autocrine, paracrine, intracrine, and neuroendocrine processes, including the regulation of tumor burden. Consequently, the secretion of SP from TC results in increased SP levels in plasma, which are significantly higher in TC patients compared to controls. Additionally, NK-1R antagonists have demonstrated a dose-dependent antitumor action. They impair cancer cell proliferation on one side and induce apoptosis of tumor cells on the other side. Furthermore, it has been demonstrated that NK-1R antagonists inhibit neoplastic cell migration, thereby impairing both invasiveness and metastatic abilities, as well as angiogenesis. Given the consistent overexpression of NK-1R in all types of TC, targeting this receptor represents a promising therapeutic approach for TC. Therefore, NK-1R antagonists, such as the drug aprepitant, may represent novel drugs for TC treatment.
PubMed: 37835053
DOI: 10.3390/jcm12196409 -
Journal of Cancer Research and Clinical... Sep 2023The aim of this study was to determine the drug profile of patients with non-small cell lung cancer (NSCLC) and to identify potential drug-drug interactions (PDDIs)...
BACKGROUND
The aim of this study was to determine the drug profile of patients with non-small cell lung cancer (NSCLC) and to identify potential drug-drug interactions (PDDIs) during hospitalization. In particular, PDDIs in categories X and D were determined.
METHODS
This retrospective cross-sectional study was conducted in the oncology services of a university hospital between 2018 and 2021. PDDIs were evaluated using Lexicomp Drug Interactions software included in UpToDate.
RESULTS
A total of 199 patients were included in the study. Polypharmacy was present in 92.5% of the patients and the median (min-max) number of drugs used was 8 (2-16). 32% of the patients had D and X PDDIs. A total of 16 PDDIs at risk grade X were found in 15 (7.5%) patients. A total of 81 PDDIs of risk grade D were found in 54 (27.1%) patients and a total of 276 PDDIs of risk grade C were identified in 97 (48.7%) patients. Anticancer drugs (p = 0.008), opioids (p = 0.046), steroids (p = 0.003), 5-HT3 receptor antagonists (p = 0.012), aprepitant (p = 0.025) and antihistamines (p < 0.001) were statistically more frequent among patients with PDDIs than among those without.
CONCLUSION
The results of our study indicated that polypharmacy and PDDIs are common in hospitalized patients with NSCLC cancer. The monitoring of medications is critical for maximizing therapeutic effects and minimizing side effects related to PDDIs. As a part of multidisciplinary team, clinical pharmacists can contribute significantly to preventing, detecting and managing PDDIs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Retrospective Studies; Cross-Sectional Studies; Turkey; Lung Neoplasms; Drug Interactions; Hospitals
PubMed: 37222813
DOI: 10.1007/s00432-023-04890-0 -
BMJ Supportive & Palliative Care Jan 2024Dexamethasone sparing strategies have shown success. The feasibility of a dexamethasone-free antiemetic strategy remains undetermined. A prospective, single-arm, pilot... (Clinical Trial)
Clinical Trial
OBJECTIVES
Dexamethasone sparing strategies have shown success. The feasibility of a dexamethasone-free antiemetic strategy remains undetermined. A prospective, single-arm, pilot study was planned to determine the efficacy of an olanzapine-based, dexamethasone-free, three-drug antiemetic regimen.
METHODS
Chemotherapy naïve, adult patients (≥18 years) who received ondansetron, aprepitant and olanzapine during the first cycle of highly emetogenic chemotherapy were enrolled. The primary endpoint was the rate of complete response (CR: no vomiting and no use of rescue medications) during the overall period (0-120 hours).
RESULTS
Out of the total of 101 patients enrolled, most were women (82%) and received anthracycline cyclophosphamide (73%) combination therapy. The rate of CR for the overall period was 65% (95% CI 55.2% to 74.5%). The rate of CR for the acute and delayed period was 79% (95% CI 70% to 86.7%) and 76% (95% CI 66.7% to 84.1%). The rate of nausea control rates for the acute, delayed and overall periods were 34%, 29% and 24%, respectively. The grade I, II and III sedation rates over the 5 days were 8%, 5% and 1%, respectively.
CONCLUSIONS
The dexamethasone-free antiemetic strategy showed modest efficacy with low incidence of clinically significant somnolence. There is a need to prospectively investigate the role of dexamethasone in the era of newer potent antiemetics in a randomised fashion.
TRIAL REGISTRATION NUMBER
CTRI/2021/07/034813.
Topics: Adult; Female; Humans; Male; Antiemetics; Antineoplastic Agents; Dexamethasone; Olanzapine; Pilot Projects; Prospective Studies
PubMed: 36927873
DOI: 10.1136/spcare-2022-003864 -
Journal of Clinical Medicine Feb 2024Prior speculation suggests that selective 5-hydroxytryptamine-3 receptors and neurokinin-1 receptor antagonists may increase arrhythmia risk and induce...
Effect of Selective 5-Hydroxytryptamine-3 Receptor and Neurokinin-1 Receptor Antagonists on Hemodynamic Changes and Arrhythmogenic Potential in Patients Receiving Chemotherapy: A Retrospective, Observational Study.
Prior speculation suggests that selective 5-hydroxytryptamine-3 receptors and neurokinin-1 receptor antagonists may increase arrhythmia risk and induce electrocardiographic changes. This study examined the effect of anti-emetic medications on arrhythmogenic potential and hemodynamic alterations. We considered patients aged 18 or above receiving chemotherapy between June 2013 and December 2013. Patients were grouped by anti-emetic medication: intravenous granisetron (Group G), oral aprepitant plus IV granisetron (Group AG), IV palonosetron (Group P), and oral aprepitant plus IV palonosetron (Group AP). We recorded blood pressure and electrocardiography initially and at the thirtieth minute post-medication, focusing on P dispersion, QTc dispersion, and systolic/diastolic blood pressure alterations. The study included 80 patients (20 per group). Baseline systolic/diastolic blood pressure and P dispersion showed no significant variance. However, the baseline QTc dispersion was significantly lower in Groups P and AP than G and AG. The thirtieth-minute systolic/diastolic blood pressures were significantly lower than the baseline for Groups AG and AP, and the heart rates decreased in all groups. Group P showed significantly fewer blood pressure changes. We found no arrhythmogenic potential linked to granisetron, palonosetron, and aprepitant. Hypotension was more frequent at 30 min post-medication in granisetron or aprepitant recipients. Considering no hypotension occurred when using palonosetron alone, this treatment was deemed safer.
PubMed: 38337537
DOI: 10.3390/jcm13030843 -
International Journal of Systematic and... Jan 2024The practice of naming elements from the natural world after notable individuals stretches back to ancient times. This practice of creating eponyms-terms derived from... (Review)
Review
Formation of prokaryote names from personal names: a review of current practice and a proposal to emend Appendix 9 of the International Code of Nomenclature of Prokaryotes.
The practice of naming elements from the natural world after notable individuals stretches back to ancient times. This practice of creating eponyms-terms derived from personal names-has been carried forward into prokaryotic nomenclature, where the International Code of Nomenclature of Prokaryotes (ICNP) sets guidelines for creating scientific names from personal names. However, these guidelines can be seen as culturally biased, disjointed and, on occasion, misguided. Here, with the goal of modernizing these recommendations to render them more user-friendly, coherent and inclusive, I review current practice in the light of precedents and key linguistic and cultural principles, while questioning the applicability of the first-name/last-name paradigm for many cultural traditions. Procedural challenges include romanization of the personal name (including handling of diacritics), creation of a short and agreeable latinized stem, assignment of the stem to a declension and addition of suffixes or compound word components to create genus names or species epithets, customizing the approach for names and stems that end in a vowel. I review the pros and cons of stem augmentation, which involves addition of an extra 'i' to the original stem. Next, I formulate a coherent workflow, which I incorporate into a Python script to enable computer-based automation of name creation. Rather than following the ICNP in limiting discussion to a few dozen mainly European names, I examine how these principles work out when applied to the tens of thousands of last names under which scientists publish in the PubMed database, focusing on edge cases where conventional approaches fail, particularly very short and very long names. Drawing on these explorations and analyses, I propose emendations to the advice currently presented in the ICNP to usher in a modern, consistent, pragmatic and globally inclusive approach to the creation of prokaryotic eponyms.
Topics: Humans; Aprepitant; Phylogeny; Sequence Analysis, DNA; RNA, Ribosomal, 16S; DNA, Bacterial; Bacterial Typing Techniques; Base Composition; Fatty Acids
PubMed: 38226641
DOI: 10.1099/ijsem.0.006233 -
BMJ Supportive & Palliative Care Jan 2024To assess the cost-effectiveness of addition of olanzapine to a prophylactic antiemetic regimen containing aprepitant, dexamethasone and ondansetron among children...
OBJECTIVES
To assess the cost-effectiveness of addition of olanzapine to a prophylactic antiemetic regimen containing aprepitant, dexamethasone and ondansetron among children receiving highly emetogenic chemotherapy (HEC) in India, Bangladesh, Indonesia, the UK and the USA.
METHODS
Health states were estimated using individual patient-level outcome data from a randomised trial. The incremental cost-utility ratio (ICUR), incremental cost-effectiveness ratio and net monetary benefit (NMB) were calculated from the patient perspective for India, Bangladesh, Indonesia, the UK and the USA. One-way sensitivity analysis was done by varying the cost of olanzapine, cost of hospitalisation and utility values by ±25%.
RESULTS
The olanzapine arm had an increment of 0.0018 quality-adjusted life-years (QALY) over the control arm. The mean total expenditure in the olanzapine arm was greater by US$0.51, US$0.43, US$6.73, US$11.05 and US$12.35 in India, Bangladesh, Indonesia, the UK and the USA, respectively. The ICUR($/QALY) was US$282.60 in India, US$241.42 in Bangladesh, US$3755.93 in Indonesia, US$6161.83 in the UK and US$6887.41 in the USA. The NMB was US$9.86, US$10.12, US$14.08, US$44.74 and US$98.79 for India, Bangladesh, Indonesia, the UK and the USA, respectively. The ICUR estimates of the base case and sensitivity analysis were below the willingness-to-pay threshold in all scenarios.
CONCLUSION
The addition of olanzapine as a fourth agent for antiemetic prophylaxis is cost-effective despite an increase in overall expenditure. Olanzapine should be uniformly considered for children receiving HEC.
Topics: Adolescent; Child; Humans; Antiemetics; Antineoplastic Agents; Cost-Benefit Analysis; Dexamethasone; Nausea; Olanzapine; Vomiting; Randomized Controlled Trials as Topic
PubMed: 36813535
DOI: 10.1136/spcare-2022-004069 -
Chemico-biological Interactions Aug 2023Regulation of the interplay between autophagy and oxidative stress is vital in maintaining neuronal homeostasis during neurotoxicity. The interesting involvement of NK1...
Regulation of the interplay between autophagy and oxidative stress is vital in maintaining neuronal homeostasis during neurotoxicity. The interesting involvement of NK1 receptor (NK1R) in neurodegeneration has highlighted the value of investigating the neuroprotective effect of aprepitant (Aprep), an NK1R antagonist in Parkinson's disease (PD). This study was conducted to disclose Aprep's ability to modulate extracellular signal-regulated kinase 5/Krüppel-like factor 4 (ERK5/KLF4) cue as molecular signaling implicated in regulating autophagy and redox signaling in response to rotenone neurotoxicity. Rotenone (1.5 mg/kg) was administered on alternate days, and rats were given Aprep simultaneously with or without PD98059, an ERK inhibitor, for 21 days. Aprep ameliorated motor deficits as verified by restored histological features, and intact neurons count in SN and striata along with tyrosine hydroxylase immunoreactivity in SN. The molecular signaling of Aprep was illustrated by the expression of KLF4 following the phosphorylation of its upstream target, ERK5. Nuclear factor erythroid 2-related factor 2 (Nrf2) was up-regulated, shifting the oxidant/antioxidant balance towards the antioxidant side, as evidenced by elevated GSH and suppressed MDA levels. In parallel, Aprep noticeably reduced phosphorylated α-synuclein aggregates due to autophagy induction as emphasized by marked LC3II/LC3I elevation and p62 level reduction. These effects were diminished upon PD98059 pre-administration. In conclusion, Aprep showed neuroprotective effects against rotenone-induced PD, which may be partially attributed to the activation of the ERK5/KLF4 signaling pathway. It modulated p62-mediated autophagy and Nrf2 axis which act cooperatively to counter rotenone-associated neurotoxicity pointing to Aprep's prospect as a curious candidate in PD research.
Topics: Rats; Animals; Rotenone; NF-E2-Related Factor 2; Aprepitant; Antioxidants; Mitogen-Activated Protein Kinase 7; Receptors, Neurokinin-1; Kruppel-Like Factor 4; Parkinsonian Disorders; Parkinson Disease; Signal Transduction; Neuroprotective Agents; Oxidative Stress
PubMed: 37224993
DOI: 10.1016/j.cbi.2023.110562 -
Expert Opinion on Pharmacotherapy 2023Chemotherapy-induced nausea and vomiting (CINV) is an ongoing problem. While effectiveness of triplet antiemetic regimens in the delayed CINV phase (24-120 hours after... (Observational Study)
Observational Study
BACKGROUND
Chemotherapy-induced nausea and vomiting (CINV) is an ongoing problem. While effectiveness of triplet antiemetic regimens in the delayed CINV phase (24-120 hours after administration of chemotherapy) has been studied, their effectiveness in the long-delayed phase (120-168 hours post-administration) is unknown. We compared the efficacy of 3- and 5-day courses of a triplet antiemetic prophylaxis containing aprepitant (APR) in controlling long-delayed CINV after cisplatin (CDDP)-based chemotherapy.
RESEARCH DESIGN AND METHODS
We obtained patient-level data from a nationwide, multicenter, prospective observational study in Japan. The incidence and timing of CINV after 3- and 5-day APR-containing regimens were compared using inverse probability treatment weighting.
RESULTS
The analysis included 380 patients. The incidence rates of long-delayed nausea and vomiting were significantly reduced for the 5-day compared with the 3-day regimen (29.1% vs. 22.2%, = 0.0042; 6.7% vs. 0%, < 0.0001, respectively). Among those without CINV, vomiting was not reported after day 2 in the 5-day APR group but increased after day 4 in the 3-day APR group.
CONCLUSION
A 5-day regimen triplet antiemetic prophylaxis with APR decreased long-delayed vomiting compared with a 3-day regimen in patients receiving CDDP-based chemotherapy. However, the 5-day regimen showed no advantage over the 3-day regimen against long-delayed nausea.
Topics: Humans; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Nausea; Vomiting
PubMed: 38009903
DOI: 10.1080/14656566.2023.2288288 -
Biological & Pharmaceutical Bulletin Mar 2024Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory... (Observational Study)
Observational Study
Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0-24 h), delayed (24-120 h), overall (0-120 h), and beyond-delayed (120-168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0-168 and 120-168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.
Topics: Humans; Aprepitant; Cisplatin; Antiemetics; Emetics; Retrospective Studies; Case-Control Studies; Vomiting; Neurokinin-1 Receptor Antagonists; Neoplasms; Gastrointestinal Agents; Antineoplastic Agents; Morpholines
PubMed: 38417893
DOI: 10.1248/bpb.b23-00819 -
Biotechnology and Applied Biochemistry Feb 2024Neurokinin/tachykinin receptors are classified as the G-protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues....
Neurokinin/tachykinin receptors are classified as the G-protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues. NK2R is associated with a range of biological events, such as inflammation, smooth muscle contraction, intestinal motor functions, and asthma. Despite these diverse activities, no approved drugs targeting NK2R have been developed yet. Our study focuses on finding potential inhibitors for NK2R using virtual screening, molecular docking, and ADME (absorption, distribution, metabolism, and excretion) approaches. We used a homology modeling approach and AlphaFold DB to obtain the three-dimensional structure of mouse and human NK2R proteins, respectively. The homology model of NK2R was predicted using MODELLER v10.3 and further refined and validated using the 3Drefine tool and RAMPAGE server, respectively. Molecular docking was performed using a library of 910 structurally similar molecules to four NK1R antagonists: aprepitant, casopitant, fosaprepitant, and rolapitant. Molecular docking revealed six small molecules that displayed high Chemscore fitness scores, and binding energies with desirable ligand-NK2R interactions. The evaluation of the in silico ADME profile, solubility, and permeability of the ligand molecules has revealed that the small molecules are potentially nontoxic and have the chance of exhibiting biological activity after oral administration. Further experimental studies (in vitro and in vivo assays) are required to evaluate the effectiveness of these inhibitors as therapeutic targets.
Topics: Humans; Receptors, Neurokinin-2; Molecular Docking Simulation; Ligands; Molecular Dynamics Simulation; Asthma
PubMed: 37904319
DOI: 10.1002/bab.2533