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Recent developments in the clinical pharmacology of rolapitant: subanalyses in specific populations.Drug Design, Development and Therapy 2017Knowledge of the involvement of the neurokinin substance P in emesis has led to the development of the neurokinin-1 receptor antagonists (NK-1 RAs) for control of... (Comparative Study)
Comparative Study Review
Knowledge of the involvement of the neurokinin substance P in emesis has led to the development of the neurokinin-1 receptor antagonists (NK-1 RAs) for control of chemotherapy-induced nausea and vomiting (CINV), in combination with serotonin type 3 receptor antagonists and corticosteroids. The NK-1 RA rolapitant, recently approved in oral formulation, has nanomolar affinity for the NK-1 receptor, as do the other commercially available NK-1 RAs, aprepitant and netupitant. Rolapitant is rapidly absorbed and has a long half-life in comparison to aprepitant and netupitant. All three NK-1 RAs undergo metabolism by cytochrome P450 (CYP) 3A4, necessitating caution with the concomitant use of CYP3A4 inhibitors, but in contrast to aprepitant and netupitant, rolapitant does not inhibit or induce CYP3A4. However, rolapitant is a moderate inhibitor of CYP2D6, and concomitant use with CYP2D6 substrates with narrow therapeutic indices should be avoided. Aprepitant, netupitant, and rolapitant have all demonstrated efficacy in the control of delayed CINV in patients receiving moderately and highly emetogenic chemotherapy in randomized controlled trials, including over multiple cycles of chemotherapy. We reviewed recent post hoc analyses of clinical trial data demonstrating that rolapitant is efficacious in the control of CINV in patient populations with specific tumor types, namely, breast cancers, gastrointestinal/colorectal cancers, and lung cancers. In addition, we show that rolapitant has efficacy in the control of CINV in specific age groups of patients receiving chemotherapy (<65 and ≥65 years of age). Overall, the safety profile of rolapitant in these specific patient populations was consistent with that observed in primary analyses of phase 3 trials.
Topics: Antiemetics; Antineoplastic Agents; Half-Life; Humans; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Randomized Controlled Trials as Topic; Spiro Compounds; Vomiting
PubMed: 28919712
DOI: 10.2147/DDDT.S133943 -
Neurogastroenterology and Motility Jun 2019This evidence review was conducted to inform the accompanying clinical practice guideline on the management of cyclic vomiting syndrome (CVS) in adults. (Review)
Review
BACKGROUND
This evidence review was conducted to inform the accompanying clinical practice guideline on the management of cyclic vomiting syndrome (CVS) in adults.
METHODS
We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and focused on interventions aimed at prophylactic management and abortive treatment of adults with CVS. Specifically, this evidence review addresses the following clinical questions: (a) Should the following pharmacologic agents be used for prophylaxis of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, or mitochondrial supplements? (b) Should the following pharmacologic agents be used for abortive treatment: triptans or aprepitant?
RESULTS
We found very low-quality evidence to support the use of the following agents for prophylactic and abortive treatment of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, and mitochondrial supplements. We have moderate certainty of evidence for the use of triptans as abortive therapy. We found limited evidence to support the use of ondansetron and the treatment of co-morbid conditions and complementary therapies.
CONCLUSIONS
This evidence review helps inform the accompanying guideline for the management of adults with CVS which is aimed at helping clinicians, patients, and policymakers, and should improve patient outcomes.
Topics: Antiemetics; Humans; Treatment Outcome; Vomiting
PubMed: 31241818
DOI: 10.1111/nmo.13605 -
Biological & Pharmaceutical Bulletin 2024Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in...
Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1-3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.
Topics: Aprepitant; Carboplatin; Humans; Dexamethasone; Palonosetron; Male; Etoposide; Antiemetics; Female; Middle Aged; Vomiting; Aged; Nausea; Retrospective Studies; Adult; Drug Therapy, Combination; Antineoplastic Combined Chemotherapy Protocols; Quinuclidines; Morpholines; Antineoplastic Agents; Isoquinolines; Treatment Outcome
PubMed: 38897969
DOI: 10.1248/bpb.b24-00046 -
European Journal of Pharmacology Sep 2023Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1...
Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1 expression have been identified in the gastrointestinal (GI) tract. GI mucosal functions remain largely undefined for TRPV1 and TRPA1 with side-dependence and regional differences in signalling unclear. Here we investigated TRPV1- and TRPA1-induced vectorial ion transport as changes in short-circuit current (ΔI), in defined segments of mouse colon mucosa (ascending, transverse and descending) under voltage-clamp conditions in Ussing chambers. Drugs were applied basolaterally (bl) or apically (ap). Capsaicin responses were biphasic, with primary secretory and secondary anti-secretory phases, observed with bl application only, which predominated in descending colon. AITC responses were monophasic and secretory, with ΔI dependent on colonic region (ascending vs. descending) and sidedness (bl vs. ap). Aprepitant (neurokinin-1 (NK1) antagonist, bl) and tetrodotoxin (Na channel blocker, bl) significantly inhibited capsaicin primary responses in descending colon, while GW627368 (EP4 receptor antagonist, bl) and piroxicam (cyclooxygenase inhibitor, bl) inhibited AITC responses in ascending and descending colonic mucosae. Antagonism of the calcitonin gene-related peptide (CGRP) receptor had no effect on mucosal TRPV1 signalling, while tetrodotoxin and antagonists of the 5-hydroxytryptamine-3 and 4 receptors, CGRP receptor, and EP1/2/3 receptors had no effect on mucosal TRPA1 signalling. Our data demonstrates the regional-specificity and side-dependence of colonic TRPV1 and TRPA1 signalling, with involvement of submucosal neurons and mediation by epithelial NK1 receptor activation for TRPV1, and endogenous prostaglandins and EP4 receptor activation for TRPA1 mucosal responses.
Topics: Mice; Animals; Transient Receptor Potential Channels; TRPA1 Cation Channel; Capsaicin; Tetrodotoxin; Colon; Mucous Membrane; TRPV Cation Channels
PubMed: 37394028
DOI: 10.1016/j.ejphar.2023.175897 -
Neurokinin-1 Receptor Antagonists as a Potential Novel Therapeutic Option for Osteosarcoma Patients.Journal of Clinical Medicine Mar 2023Osteosarcoma is a bone tumor predominantly affecting children and adolescents with high malignant potential. It is a cause of serious public health challenges due to its... (Review)
Review
Osteosarcoma is a bone tumor predominantly affecting children and adolescents with high malignant potential. It is a cause of serious public health challenges due to its high morbidity rates and metastatic potential. Metastasis in osteosarcoma may manifest either during treatment of the primary tumor, shortly after treatment, or a long time after the end of the treatment. So far, there are no therapeutics that can prevent or treat osteosarcoma metastasis. The peptide substance P (SP) and its high-affinity receptor, Neurokinin-1 (NK-1R), are known to positively correlate with osteosarcoma progression. Osteosarcoma cells overexpress NK-1R. SP is known to elicit the proliferation of osteosarcoma cells and induce angiogenesis and migration, leading to the invasion and metastasis of tumor cells. In contrast, NK-1R antagonists, such as aprepitant, inhibit the proliferation and induce the apoptosis of osteosarcoma cells. Aprepitant is also known to inhibit the migration of osteosarcoma cells, as well as reduce the expression levels and activities of transcriptional regulators of metastasis-related genes such as matrix metalloproteinases (MMP-2 and MMP-9), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB). These preceding studies highlighted the antimetastatic role of aprepitant in osteosarcoma Moreover, combination therapy consisting of chemotherapy and NK-1R antagonist increases the chemosensitization of osteosarcoma cells. Interestingly, this combination therapy in vitro and in vivo decreases the severe side-effects of chemotherapy and produces neuroprotection, hepatoprotection, nephroprotection, and cardioprotection. In this review, we provide an update on existing data and suggest the need to repurpose aprepitant for use as an antitumor drug for treatment of osteosarcoma, and they suggest the need for phase I and II clinical trials for assessment of its safety/efficacy.
PubMed: 36983138
DOI: 10.3390/jcm12062135 -
Biochemical and Biophysical Research... Jan 2022TRAAK (KCNK4, K2P4.1) is a mechanosensitive two-pore domain potassium (K2P) channel. Due to its expression within sensory neurons and genetic link to neuropathic pain it...
TRAAK (KCNK4, K2P4.1) is a mechanosensitive two-pore domain potassium (K2P) channel. Due to its expression within sensory neurons and genetic link to neuropathic pain it represents a promising potential target for novel analgesics. In common with many other channels in the wider K2P sub-family, there remains a paucity of small molecule pharmacological tools. Specifically, there is a lack of molecules selective for TRAAK over the other members of the TREK subfamily of K2P channels. We developed a thallium flux assay to allow high throughput screening of compounds and facilitate the identification of novel TRAAK activators. Using a library of ∼1200 drug like molecules we identified Aprepitant as a small molecule activator of TRAAK. Aprepitant is an NK-1 antagonist used to treat nausea and vomiting. Close structural analogues of Aprepitant and a range of NK-1 antagonists were also selected or designed for purchase or brief chemical synthesis and screened for their ability to activate TRAAK. Electrophysiology experiments confirmed that Aprepitant activates both the 'long' and 'short' transcript variants of TRAAK. We also demonstrated that Aprepitant is selective and does not activate other members of the K2P superfamily. This work describes the development of a high throughput assay to identify potential TRAAK activators and subsequent identification and confirmation of the novel TRAAK activator Aprepitant. This discovery identifies a useful tool compound which can be used to further probe the function of TRAAK K2P channels.
Topics: Aprepitant; Cell Line; Humans; Ion Channel Gating; Neurokinin-1 Receptor Antagonists; Patch-Clamp Techniques; Potassium Channels; Receptors, Neurokinin-1; Structure-Activity Relationship; Thallium
PubMed: 34942533
DOI: 10.1016/j.bbrc.2021.12.031 -
Supportive Care in Cancer : Official... Dec 2023This review is an update of the MASCC/ESMO 2015 recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy,... (Review)
Review
2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.
PURPOSE
This review is an update of the MASCC/ESMO 2015 recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting.
METHODS
A systematic literature search was conducted using PubMed from June 1, 2015, through February 1, 2023.
RESULTS
We identified 56 references (16 were duplications or invalid), leaving 40 manuscripts for this search. The panel classified level I evidence (three manuscripts) and level II evidence (14 manuscripts). High-dose chemotherapy and stem cell transplant were discussed in four of these manuscripts, and multiple-day chemotherapy treatment in 15. Some manuscripts covered both topics. Additionally, a search for breakthrough nausea and vomiting resulted in 12 "hits." No new relevant studies were identified.
CONCLUSIONS
The recommendations for patients receiving high-dose chemotherapy with stem cell transplants and patients undergoing multiple-day cisplatin were updated. For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT receptor antagonist with dexamethasone and aprepitant is recommended. Olanzapine could be considered part of the antiemetic regimen. Patients receiving multiple-day cisplatin should receive a 5-HT receptor antagonist plus dexamethasone plus aprepitant plus olanzapine. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests using a single dose of olanzapine daily for 3 days.
Topics: Humans; Aprepitant; Olanzapine; Cisplatin; Consensus; Serotonin; Antineoplastic Agents; Vomiting; Nausea; Antiemetics; Dexamethasone
PubMed: 38105286
DOI: 10.1007/s00520-023-08224-1 -
BMC Anesthesiology Dec 2023Postoperative nausea and vomiting (PONV) is a common side effect associated with general anesthesia. Both ondansetron and aprepitant been effectively used to prevent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Postoperative nausea and vomiting (PONV) is a common side effect associated with general anesthesia. Both ondansetron and aprepitant been effectively used to prevent PONV. However, there is a disagreement of opinions regarding the superiority of these two drugs. This study aims to compare the efficacy of aprepitant with ondansetron in preventing PONV following orthognathic surgeries.
METHODS
In this double-blinded clinical trial, 80 patients scheduled for orthognathic surgery at Imam Hossein Hospital, Tehran, Iran, were randomly assigned to two groups. A standardized anesthesia protocol was used for all patients. The first group received a placebo capsule administered one hour before the surgical procedure along with 4 mg (2 ml) of ondansetron intravenously after anesthesia induction. The second group was given 80 mg aprepitant capsules one hour before the surgery, followed by an injection of 2 ml intravenous distilled water after anesthesia induction. The occurrence and severity of PONV, the amount of rescue medication required, and the complete response of patients assessed within 24 h after the surgery.
RESULTS
There were no significant differences in demographic data between the two groups. Patients in the aprepitant group had a significantly lower incidence and severity of nausea (2.5% versus 27.5%), vomiting (5% versus 25%), and required fewer rescue medications (7.5% versus 62.5%) compared to the ondansetron group. Additionally, the aprepitant group showed a higher complete response rate (90% versus 67.5%) in the 0-2 and 12-24 postoperative hours.
CONCLUSION
According to the findings of this study, aprepitant has demonstrated a greater efficacy in preventing PONV following orthognathic surgery, when compared to ondansetron.
TRIAL REGISTRATION
Iranian Registry of Clinical Trials (IRCT code: IRCT20211205053279N3), date of registration: 16/12/2022.
Topics: Humans; Ondansetron; Aprepitant; Postoperative Nausea and Vomiting; Antiemetics; Orthognathic Surgery; Iran; Double-Blind Method
PubMed: 38093201
DOI: 10.1186/s12871-023-02371-y -
ACS Omega Nov 2022This study focused on improving the physicochemical characteristics of aprepitant with poor water solubility by preparing solid dispersion (SD). To prepare the SD with...
This study focused on improving the physicochemical characteristics of aprepitant with poor water solubility by preparing solid dispersion (SD). To prepare the SD with HPMCAS-LF, the solvent evaporation method was applied. Based on dissolution analysis, the dissolution rate of SD increased by five times compared with aprepitant. In addition, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC) results suggested the presence of amorphous-form aprepitant inside SD. According to Fourier transform infrared (FTIR) spectroscopy, intermolecular hydrogen bonds were detected between polymer and aprepitant. The Caco-2 cell experiment proved that SD did not lower the transepithelial electrical resistance (TEER) values but improved the permeation amount of aprepitant. Additionally, the SD of aprepitant displayed excellent stability.
PubMed: 36385804
DOI: 10.1021/acsomega.2c04021 -
Cancer Medicine Aug 2023Non-inferiority of NEPA (fixed combination of NK receptor antagonist (RA), netupitant, and 5-HT RA, palonosetron) versus an aprepitant regimen was previously shown in a... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Non-inferiority of NEPA (fixed combination of NK receptor antagonist (RA), netupitant, and 5-HT RA, palonosetron) versus an aprepitant regimen was previously shown in a pragmatic study in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy (MEC). In the MEC group a numerically higher complete response (CR: no emesis, no rescue) rate was seen for NEPA during the overall 0-120 h phase (NEPA 76.1% vs. 63.1% aprepitant). As NEPA exhibits long-lasting efficacy, this study evaluated a prolonged period up to 144 h, beyond the traditional 120 h post-chemotherapy. In this post-hoc analysis we explore the comparative efficacy of NEPA versus the aprepitant regimen in the MEC group up to 144 h, while also assessing the impact of risk factors on CINV prevention.
METHODS
This was a pragmatic, multicenter, randomized, prospective study. Oral NEPA was administered as a single dose on day 1, while aprepitant was given on days 1-3 + ondansetron on day 1; all patients were to receive dexamethasone on days 1-4. Patients were chemotherapy-naïve and receiving MEC, with a subset evaluation of those with a risk factor for developing CINV (i.e., female, male <60 years, male ≥60 years who received carboplatin, or male ≥60 years with anxiety). CR rates were compared during the extended overall (0-144 h) phase.
RESULTS
The MEC group included 211 patients; of these 181 were in the risk factor subset. Significantly higher CR rates were seen for NEPA than aprepitant during the extended overall phase for the total MEC group (NEPA 77.1%, aprepitant 57.8%, p = 0.003) and also in the subset of patients with CINV risk factors (NEPA 73.9%, aprepitant 56.2%, p = 0.012).
CONCLUSION
A single dose of NEPA, administered on day 1 only, was more effective than a 3-day aprepitant regimen in preventing CINV for an extended duration in patients receiving MEC and in those with emetic risk factors.
Topics: Humans; Male; Female; Aprepitant; Antiemetics; Vomiting; Prospective Studies; Isoquinolines; Quinuclidines; Drug Combinations; Nausea; Cyclophosphamide; Anthracyclines; Antineoplastic Agents; Dexamethasone
PubMed: 37537943
DOI: 10.1002/cam4.6121