-
Biochemical Pharmacology Mar 2024Olanzapine-induced metabolic syndrome (MS) is a primary risk factor for insulin resistance, hepatorenal damage, and polycystic ovarian syndrome. The objective of the...
Aprepitant boasted a protective effect against olanzapine-induced metabolic syndrome and its subsequent hepatic, renal, and ovarian dysfunction; Role of IGF/p-AKT/FOXO and NFκB/IL-1β/TNF-α signaling pathways in female Wistar albino rats.
Olanzapine-induced metabolic syndrome (MS) is a primary risk factor for insulin resistance, hepatorenal damage, and polycystic ovarian syndrome. The objective of the current study was to assess the protective effects of aprepitant (AP) against MS caused by olanzapine and the associated ovarian, renal, and liver dysfunction via modulation of IGF/p-AKT/FOXO and NFκB/IL-1β/TNF-α signaling pathways. AP mitigated all biochemical and histopathological abnormalities induced by olanzapine and resulted in a significant reduction of serum HOMA-IR, lipid profile parameters, and a substantial decrease in hepatic, renal, and ovarian MDA, IL-6, IL-1β, TNF-α, NFκB, and caspase 3. Serum AST, ALT, urea, creatinine, FSH, LH, and testosterone also decreased significantly by AP administration. The FOXO 1 signaling pathway was downregulated in the AP-treated group, while GSH, SOD, and HDL cholesterol levels were elevated.
Topics: Female; Rats; Animals; Metabolic Syndrome; Aprepitant; Olanzapine; Proto-Oncogene Proteins c-akt; Tumor Necrosis Factor-alpha; Interleukin-1beta
PubMed: 38237301
DOI: 10.1016/j.bcp.2024.116020 -
The Ocular Surface Apr 2024
PubMed: 38286217
DOI: 10.1016/j.jtos.2024.01.011 -
Naunyn-Schmiedeberg's Archives of... Feb 2024Substance P (SP), an important neuropeptide, has a crucial role in the progression of several cancers, including prostate cancer, through interacting with the...
Substance P (SP), an important neuropeptide, has a crucial role in the progression of several cancers, including prostate cancer, through interacting with the neurokinin-1 receptor (NK1R). Oxidative stress is also involved in the onset and progression of prostate cancer. However, no studies have been performed on the cross-talk between the SP/NK1R system and cellular redox balance in prostate cancer, and how it is involved in tumorogenesis. We aimed to investigate the effect of the SP/NK1R system and the blockage of NK1R with its specific antagonist (aprepitant) on the cellular redox status of the prostate cancer cell line (PC3 and LNCaP). We performed the resazurin assay to evaluate the toxicity of the aprepitant on the PC3 and LNCaP cell lines. The intracellular reactive oxygen species (ROS) level was measured after SP and aprepitant treatment. The alterations of expression and activity of two crucial cellular oxidoreductases, glutaredoxin, and thioredoxin were evaluated by qRT-PCR and commercial kits (ZellBio GmbH), respectively. Our results revealed that SP increased ROS production and decreased the expression and activity of glutaredoxin and thioredoxin. On the other hand, treatment of cells with aprepitant showed reverse results. In conclusion, we found that the SP/NK1R system could promote prostate cancer progression by inducing oxidative stress. In addition, the inhibition of NK1R by aprepitant modulated the effect of the SP/NK1R system on the cellular redox system. Aprepitant might therefore be introduced as a candidate for the treatment of prostate cancer; however, more studies are required to confirm the validation of this hypothesis.
PubMed: 38334824
DOI: 10.1007/s00210-024-02996-x -
Obesity Surgery Jun 2024This study aims to evaluate the effectiveness of aprepitant in preventing postoperative nausea and vomiting (PONV) following metabolic bariatric surgery (MBS).
INTRODUCTION
This study aims to evaluate the effectiveness of aprepitant in preventing postoperative nausea and vomiting (PONV) following metabolic bariatric surgery (MBS).
METHODS
Clinical trials meeting the inclusion criteria were identified through searches of PubMed, Embase, and the Cochrane Library databases, as well as clinical trials registered at clinicaltrials. gov. These trials compared aprepitant with the control or placebo groups among patients who underwent MBS. Meta-analysis was performed using StataSE 17.0 software to calculate the pooled risk ratio (RR) and its 95% confidence interval (CI) to assess the effectiveness of aprepitant in preventing PONV following MBS.
RESULTS
A total of five articles comprising six studies including 929 patients undergoing MBS were included. Meta-analysis revealed a significant reduction in the incidence of PONV among patients receiving aprepitant (pooled RR = 0.51, 95% CI: 0.38-0.68, P < 0.05). Subgroup analysis indicated that aprepitant effectively reduced PONV incidence at 0, 6, and 12 h postoperatively in patients with MBS, but did not decrease PONV occurrence at 24 and 48 h postoperatively.
CONCLUSION
Aprepitant demonstrated significant clinical efficacy in preventing PONV following MBS, effectively reducing patient discomfort, and improving postoperative recovery. Therefore, aprepitant should be considered a preventive measure in patients undergoing MBS to enhance patient satisfaction and recovery rates. Additionally, to maintain an effective drug concentration, aprepitant should be administered within the first 24 h postoperatively.
PROSPERO REGISTRATION
CRD 42024528154.
PubMed: 38858295
DOI: 10.1007/s11695-024-07338-7 -
Rejuvenation Research Jun 2024Elevated substance P can be utilized to predict early mortality during the first week of cerebral infarction. Whether aprepitant, a substance P receptor blocker could be...
Elevated substance P can be utilized to predict early mortality during the first week of cerebral infarction. Whether aprepitant, a substance P receptor blocker could be utilized to alleviate poststroke pneumonia which is investigated in this study. Intraluminal monofilament model of middle cerebral artery occlusion (MCAO) was constructed in C57BL/6J male mice, and the relative expression of substance P was detected in collected bronchoalveolar lavage fluid (BALF) and lung tissue homogenate at 24 hours, 48 hours, and 72 hours poststroke. On the other hand, different concentrations of aprepitant (0.5, 1, and 2 mg/kg) were atomized and inhaled into MCAO mice. Inflammation cytokines and bacterial load were detected in collected BALF and lung tissue homogenate at 72-hour poststroke, and lung injury was revealed by histological examination. Aprepitant administration decreased total proteins, total cells, neutrophils, and macrophages in BALF. The concentrations of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, interferon γ, monocyte chemoattractant protein-1, and IL-10 in lung tissue homogenates were also diminished by the administration of aprepitant. In conclusion, aprepitant could attenuate poststroke pneumonia in mice suggesting its potential therapeutic use in the clinic.
Topics: Animals; Aprepitant; Male; Infarction, Middle Cerebral Artery; Mice, Inbred C57BL; Disease Models, Animal; Pneumonia; Bronchoalveolar Lavage Fluid; Cytokines; Stroke; Substance P; Lung; Mice; Morpholines
PubMed: 38666697
DOI: 10.1089/rej.2024.0011 -
Clinical Pharmacology and Therapeutics Jan 2024All patients treated with anticancer agents should receive the most effective anti-emetic regimen. Anti-emetic guidelines provide recommendations but do not take into... (Observational Study)
Observational Study
Effect of Aprepitant on Etoposide Pharmacokinetics in Patients with Testicular Cancer: A Pharmacokinetic Study to Determine the Absence of a Clinically Relevant Interaction.
All patients treated with anticancer agents should receive the most effective anti-emetic regimen. Anti-emetic guidelines provide recommendations but do not take into account possible drug-drug interactions between anti-emetics and anticancer drugs. This study determines the clinical relevance of the potential drug-drug interaction of the neurokinin-1 receptor antagonist, aprepitant, on the pharmacokinetics of etoposide. Aprepitant is a moderate CYP3A4 inhibitor and may increase the systemic exposure of etoposide which is partly metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). In this prospective observational study, the pharmacokinetics of etoposide with and without concomitant use of aprepitant was determined in 12 patients receiving first-line chemotherapy for testicular cancer. The geometric mean (95% confidence interval (CI)) area under the plasma concentration-time curve 0-24 hour (AUC ) of etoposide with aprepitant was 86.2 (79.7-93.2) mg/L*hour vs. 83.7 (75.8-92.4) mg/L*hour without aprepitant. Geometric mean ratios (90% CIs) of AUC and maximum plasma concentration (C ) for etoposide with and without aprepitant were 1.03 (0.96-1.10) and 0.96 (0.89-1.03), respectively. This study confirms the absence of a clinically relevant interaction between etoposide and aprepitant. Both drugs can be safely combined without affecting etoposide exposure.
Topics: Male; Humans; Aprepitant; Antiemetics; Etoposide; Testicular Neoplasms; Morpholines; Antineoplastic Agents
PubMed: 37867292
DOI: 10.1002/cpt.3081 -
International Journal of Molecular... Oct 2023As things stand in 2023, metastatic osteosarcoma commonly results in death. There has been little treatment progress in recent decades. To redress the poor prognosis of... (Review)
Review
As things stand in 2023, metastatic osteosarcoma commonly results in death. There has been little treatment progress in recent decades. To redress the poor prognosis of metastatic osteosarcoma, the present regimen, OSR9, uses nine already marketed drugs as adjuncts to current treatments. The nine drugs in OSR9 are: (1) the antinausea drug aprepitant, (2) the analgesic drug celecoxib, (3) the anti-malaria drug chloroquine, (4) the antibiotic dapsone, (5) the alcoholism treatment drug disulfiram, (6) the antifungal drug itraconazole, (7) the diabetes treatment drug linagliptin, (8) the hypertension drug propranolol, and (9) the psychiatric drug quetiapine. Although none are traditionally used to treat cancer, all nine have attributes that have been shown to inhibit growth-promoting physiological systems active in osteosarcoma. In their general medicinal uses, all nine drugs in OSR9 have low side-effect risks. The current paper reviews the collected data supporting the role of OSR9.
Topics: Humans; Osteosarcoma; Celecoxib; Aprepitant; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms
PubMed: 37895152
DOI: 10.3390/ijms242015474 -
Daru : Journal of Faculty of Pharmacy,... Dec 2023Chemotherapy-induced nausea and vomiting are commonly experienced side effects in breast cancer (BCa) patients. Antiemetic drugs used in BCa treatment are either...
BACKGROUND
Chemotherapy-induced nausea and vomiting are commonly experienced side effects in breast cancer (BCa) patients. Antiemetic drugs used in BCa treatment are either inhibitors or inducers of cytochrome P450 (CYP) enzymes, while anticancer drugs are metabolized by CYPs.
OBJECTIVES
The purpose of the present work was to evaluate in silico drug-drug interaction (DDI) potential between BCa chemotherapeutic drugs and antiemetic agents.
METHODS
The Drug-Drug Interaction™ module of GastroPlus™ was employed to assess CYP-related interactions between antiemetic and anticancer therapy combinations. The CYP inhibitory or inducing parameters (IC, K, EC) used in simulations were obtained from the literature.
RESULTS
Analyses of twenty-three BCa drugs indicated that 22% of the chemotherapeutic drugs do not need an antiemetic agent due to their low emetogenicity, whereas 30% of the anticancer drugs are not metabolized by CYPs. The remaining eleven anticancer drugs metabolized by CYPs generated ninety-nine combinations with nine antiemetics. Simulation of DDIs suggest that about half of the pairs did not demonstrate any potential for DDI, whereas 30%, 10%, and 9% of the pairs showed weak, moderate, and strong interaction potential, respectively. In the present study, netupitant was the only antiemetic that showed strong inhibitory interactions (predicted AUC ratio > 5) with CYP3A4-metabolzied anticancer therapies (e.g., docetaxel, ribociclib, olaparib). Moderate to no interactions were observed with ondansetron, aprepitant, rolapitant, and dexamethasone in combination with anticancer agents.
CONCLUSION
It is critical to recognize that these interactions can get amplified in cancer patients because of the severity of the disease and chemotherapy toxicities. Clinicians need to be aware of the DDI likelihood of the drug combinations used in BCa treatment.
Topics: Humans; Female; Antiemetics; Breast Neoplasms; Antineoplastic Agents; Aprepitant; Drug Interactions
PubMed: 37223851
DOI: 10.1007/s40199-023-00463-1 -
Journal of Pharmaceutical Health Care... Dec 2023Dexamethasone (DEX) induces CYP3A activity in a concentration-dependent manner. However, no study has examined changes in the blood concentration of CYP3A substrate...
BACKGROUND
Dexamethasone (DEX) induces CYP3A activity in a concentration-dependent manner. However, no study has examined changes in the blood concentration of CYP3A substrate drugs when DEX is administered at high doses. Herein, we present a case in which tacrolimus (TAC), a typical CYP3A substrate drug, was co-administered with a chemotherapy regimen that included high-dose DEX.
CASE PRESENTATION
A 71-year-old woman underwent liver transplantation for hepatocellular carcinoma 18 years prior to her inclusion in this case study. She was receiving TAC orally at 2 mg/day and had a stable trough blood concentration of approximately 4 ng/mL and a trough blood concentration/dose (C/D) ratio of approximately 2. The patient was diagnosed with post-transplant lymphoproliferative disease (histological type: Burkitt's lymphoma) after admission. Thereafter, the patient received cyclophosphamide-prednisolone (CP), followed by two courses of R-HyperCVAD (rituximab, cyclophosphamide, doxorubicin, vincristine, and DEX) and R-MA (rituximab, methotrexate, and cytarabine) replacement therapy. DEX (33 mg/day) was administered intravenously on days 1-4 and days 11-14 of R-HyperCVAD treatment, and aprepitant (APR) was administered on days 1-5 in both courses. The TAC C/D ratio decreased to approximately 1 on day 11 during both courses, and then increased. Furthermore, a decreasing trend in the TAC C/D ratio was observed after R-MA therapy. The decrease in the TAC C/D ratio was attributed to APR administration rather than to DEX.
CONCLUSION
The induction of CYP3A activity by a high dose of DEX may not be strong. The pharmacokinetic information on DEX and in vitro enzyme activity induction studies also suggested that CYP3A activity induction is not prominent under high-dose DEX treatment.
PubMed: 38044431
DOI: 10.1186/s40780-023-00310-0 -
Yonago Acta Medica Feb 2024Voriconazole is an antifungal drug for which therapeutic monitoring is recommended to prevent side effects. Temporary administration of the antiemetic drug fosaprepitant...
BACKGROUND
Voriconazole is an antifungal drug for which therapeutic monitoring is recommended to prevent side effects. Temporary administration of the antiemetic drug fosaprepitant remarkably decreases the plasma concentration of voriconazole from the therapeutic range. The ratio of the major metabolite voriconazole -oxide to voriconazole exceeded that at any other time for a patient who started chemotherapy during voriconazole therapy. We attributed this unpredictable result to cytochrome P450 3A4 induced by aprepitant that was converted from fosaprepitant in vivo.
METHODS
Concentrations of voriconazole and voriconazole -oxide were measured using liquid chromatography-mass spectrometry/mass spectrometry in primary human hepatocytes after incubation with aprepitant. Aprepitant suppressed voriconazole -oxide formation within 24 h, followed by a continuous increase. Levels of drug-metabolizing cytochrome P450 mRNA were measured using real-time PCR in primary human hepatocytes incubated with aprepitant.
RESULTS
Cytochrome P450 3A4 and 2C9 mRNA levels increased ~4- and 2-fold, respectively, over time. Cytochrome P450 3A4 induction was confirmed using reporter assays. We also assessed L-755446, a major metabolite of aprepitant that lacks a triazole ring. Both compounds dose-dependently increased reporter activity; however, induction by L-755446 was stronger than that by aprepitant.
CONCLUSION
These results indicate that aprepitant initially inhibited voriconazole metabolism via its triazole ring and increased cytochrome P450 3A4 induction following L-755446 formation. The decrease in plasma voriconazole concentration 7 days after fosaprepitant administration was mainly attributed to cytochrome P450 3A4 induction by L-755446.
PubMed: 38371278
DOI: 10.33160/yam.2024.02.004