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Background: Aprepitant, fosaprepitant, and netupitant are three common neurokinin-1 receptor antagonists (NK-1RAs) used to prevent chemotherapyinduced nausea and vomiting, following highly or moderately emetogenic chemotherapy. Understanding their different adverse event (AE) profiles may help clinicians make appropriate treatment decisions. Methods: All data collected from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the fourth quarter of 2023 underwent disproportionality analysis to detect, evaluate, and compare AE signals of the three NK-1RAs. Results: A total of 3,904, 1,123, and 243 AE reports related to aprepitant, fosaprepitant, and netupitant, respectively, were extracted from the FAERS database. Of these, more than 50% of respondents were female, and most of them were aged 45-65 years. General disorders and administration-site conditions, and gastrointestinal disorders were themost frequent signals in the system organ class of the three NK-1RA drugs. In addition, aprepitant was strongly associated with joint deposit (ROR = 26.27) and fosaprepitant was closely related to seizure-like phenomena (ROR = 26.90); two preferred terms (PTs) were not mentioned in the manual. Statistically, netupitant was likely to induce death (N = 63, ROR = 8.78, 95% CI: 6.75-11.42). Additionally, neutropenic colitis, colitis, and stomatitis were unique to netupitant. Furthermore, the AE profiles of the three NK-1RA drugs were different by gender. Conclusion: The AE profiles for aprepitant, fosaprepitant, and netupitant were different. In addition to paying attention to common AEs, clinicians need to pay attention to new emerging AEs, such as joint deposit, seizure-like phenomena, neutropenic colitis, colitis, and stomatitis, regarding the three NK-1RA drugs. Furthermore, the AE compositions of the three NK-1RA drugs were different in different genders, and clinicians should take these factors into account when selecting NK-1RAs for CINV treatment. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of a dexamethasone-sparing strategy in the treatment of breast cancer with anthracycline-cyclophosphamide therapy when combined with first-generation 5-HT3 receptor antagonists (RAs) and neurokinin-1 RAs is unclear. This is attributable to a lack of evidence fromdirect comparison of multiple doses of DEX to a single dose of DEX in combination with first-generation 5-HT3 RAs in anthracycline-cyclophosphamide therapy. Our goalwas to clarify the impact of dexamethasone-sparing strategies that involve both first-generation 5-HT3 RAs and palonosetron when combined with neurokinin-1 RAs, using a network meta-analysis. Materials and methods: A literature search was conducted on PubMed/Medline for articles published up to July 4, 2023. We included randomized controlled trials which assessed the efficacy of antiemetic regimens which combined 5-HT3 RAs and dexamethasone, with or without neurokinin-1 RAs, for the initial dose in anthracycline-cyclophosphamide therapy for patients with breast cancer. The primary outcome was the proportion of patients achieving a complete response during the delayed phase (CR-DP). Results: The difference in the proportion of patients achieving CR-DP between multiple and single doses of dexamethasone was 0.1% (95%CI: -12.4 to 12.5) with palonosetron and neurokinin-1 RAs, compared to 5.3% (95%CI: -13.4 to 23.0) with a single dose of a first-generation 5-HT3 receptor antagonist. Additionally, the difference was 12.7% (95% CI: -2.8 to 28.2) when comparing palonosetron against first-generation 5-HT3 RAs in combination with a single dose of dexamethasone and neurokinin-1 RAs. Conclusion: Palonosetron is recommended rather than a single dose of firstgeneration 5-HT3 RAs in dexamethasone-sparing strategies for anthracyclinecyclophosphamide therapy. [ABSTRACT FROM AUTHOR]

To evaluate the role of pregabalin in the protection of chemotherapy-induced nausea and vomiting, we performed a phase II randomized, double-blind, placebo-controlled trial to investigate whether pregabalin could improve the complete control of nausea and vomiting (primary end point). We enrolled 82 chemotherapy-naive patients, scheduled to receive moderately and highly emetogenic chemotherapy. All patients received IV ondansetron 8mg, dexamethasone 10mg before chemotherapy on day one and oral dexamethasone 4mg, b.d., on days two and three. Patients were randomly assigned to take pregabalin 75mg or placebo, bd, from the night before chemotherapy to day five. The overall complete response was not statistically significant between the groups (53.7 versus 48.8%, respectively, in the pregabalin group and the control group (P=0.65)). There was also no significant difference during the acute phase (first 24 hours) and delayed phase (24-120h): 80.5% versus 82.9% (P=0.77), 53.7 versus 51.2% (P=0.82), respectively. There is no role for pregabalin preventing chemotherapy-induced nausea and vomiting. Clinicaltrial.gov registration number: NCT04181346.

Postoperative nausea and vomiting (PONV) is a major problem after surgery. Even with double prophylactic therapy including dexamethasone and a 5-hydroxytryptamine-3 receptor antagonist, the incidence is still high in many at-risk patients. Fosaprepitant, a neurokinin-1 receptor antagonist, is an effective antiemetic, but its efficacy and safety in combination antiemetic therapy for preventing PONV remain unclear. In this randomised, controlled, double-blind trial, 1154 participants at high risk of PONV and undergoing laparoscopic gastrointestinal surgery were randomly assigned to either a fosaprepitant group (n =577) receiving fosaprepitant 150 mg i.v. dissolved in 0.9% saline 150 ml, or a placebo group (n =577) receiving 0.9% saline 150 ml before anaesthesia induction. Dexamethasone 5 mg i.v. and palonosetron 0.075 i.v. mg were each administered in both groups. The primary outcome was the incidence of PONV (defined as nausea, retching, or vomiting) during the first 24 postoperative hours. The incidence of PONV during the first 24 postoperative hours was lower in the fosaprepitant group (32.4% vs 48.7%; adjusted risk difference −16.9% [95% confidence interval: −22.4 to −11.4%]; adjusted risk ratio 0.65 [95% CI: 0.57 to 0.76]; P <0.001). There were no differences in severe adverse events between groups, but the incidence of intraoperative hypotension was higher (38.0% vs 31.7%, P= 0.026) and intraoperative hypertension (40.6% vs 49.2%, P= 0.003) was lower in the fosaprepitant group. Fosaprepitant added to dexamethasone and palonosetron reduced the incidence of PONV in patients at high risk of PONV undergoing laparoscopic gastrointestinal surgery. Notably, it increased the incidence of intraoperative hypotension. NCT04853147. [ABSTRACT FROM AUTHOR]

Background. Chemotherapy (CT) is a mainstay of treatment for malignant tumors. CT-induced nausea and vomiting are observed in 3090% of patients within 0120 h after moderate and highly emetogenic CT administration. These adverse events can severely impact the quality of treatment, daily life, and adherence to treatment, thus reducing the effectiveness of therapy and survival. Materials and methods. The author provides the results of a systematic review of research papers, including clinical studies, on the efficacy of the neurokinin-1 receptor antagonist fosaprepitant to prevent CT-induced nausea and vomiting. Data from the PubMed database were reviewed. Results. The prevention and treatment of CT-associated nausea and vomiting are vital during special therapy, including symptomatic therapy. International organizations recommend using a triple combination with antagonists of neurokinin-1 and 5-hydroxytryptamine-3 receptors and dexamethasone. According to the data obtained, the efficacy of fosaprepitant has been proven in delayed and general phases in several large, well-planned studies; the drug reduces the incidence of adverse events by 2.74.4 times compared with aprepitant. Conclusion. Fosaprepitant is an antagonist of neurokinin-1 receptors; when administered intravenously, it rapidly converts into aprepitant. When used as part of a triple combination with 5-hydroxytryptamine-3 receptor antagonists and dexamethasone in patients receiving moderate and highly emetogenic CT leads to a higher rate of complete response when controlling nausea and vomiting. In general, fosaprepitant is well tolerated.

Abstract Background Highly emetogenic chemotherapy induces emesis in cancer patients without prophylaxis. The purpose of this study was to evaluate the efficacy and safety of a fosaprepitant‐based triple antiemetic regimen for the prevention of chemotherapy‐induced nausea and vomiting (CINV) in patients with solid malignant tumors, determine risk factors and externally validate different personalized risk models for CINV. Methods This phase III trial was designed to test the non‐inferiority of fosaprepitant toward aprepitant in cancer patients who were to receive the first cycle of single‐day cisplatin chemotherapy. The primary endpoint was complete response (CR) during the overall phase (OP) with a non‐inferiority margin of 10.0%. Logistic regression models were used to assess the risk factors of CR and no nausea. To validate the personalized risk models, the accuracy of the risk scoring systems was determined by measuring the specificity, sensitivity and area under the receiver operating characteristic (ROC) curve (AUC), while the predictive accuracy of the nomogram was measured using concordance index (C‐index). Results A total of 720 patients were randomly assigned. CR during the OP in the fosaprepitant group was not inferior to that in the aprepitant group (78.1% vs. 77.7%, P = 0.765) with a between‐group difference of 0.4% (95% CI, ‐5.7% to 6.6%). Female sex, higher cisplatin dose (≥ 70 mg/m2), no history of drinking and larger body surface area (BSA) were significantly associated with nausea. The AUC for the acute and delayed CINV risk indexes was 0.68 (95% CI: 0.66‐0.71) and 0.66 (95% CI: 0.61‐0.70), respectively, and the C‐index for nomogram CINV prediction was 0.59 (95% CI, 0.54‐0.64). Using appropriate cutoff points, the three models could stratify patients with high‐ or low‐risk CINV. No nausea and CR rate were significantly higher in the low‐risk group than in the high‐risk group (P < 0.001). Conclusions Fosaprepitant‐based triple prophylaxis demonstrated non‐inferior control for preventing CINV in patients treated with cisplatin‐base chemotherapy. Female cancer patients without a history of alcohol consumption, with larger BSA and received high‐dose cisplatin might be more vulnerable to CINV. Three personalized prediction models were well‐validated and could be used to optimize antiemetic therapy for individual patients.

Oral NEPA is the fixed‐combination antiemetic comprising netupitant (neurokinin‐1 receptor antagonist [NK1RA]) and palonosetron (5‐hydroxytryptamine‐3 receptor antagonist [5‐HT3 RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water‐soluble N‐phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1RA water solubility, preventing the occurrence of hypersensitivity and infusion‐site reactions associated with these products. In this phase 1 study, subjects received a 30‐minute placebo or fosnetupitant (17.6–353 mg) infusion and an oral NEPA or placebo capsule, with 2‐sequence crossover treatment for fosnetupitant 118‐ to 353‐mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300‐mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler‐identified infusion‐site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment‐related AEs did not increase with ascending fosnetupitant doses. The most common treatment‐related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235‐mg dose was equivalent, in terms of netupitant exposure, to 300‐mg oral netupitant. The safety profile of a single fosnetupitant 235‐mg infusion was similar to that of single‐dose oral NEPA. [ABSTRACT FROM AUTHOR]

A systematic electronic search of MEDLINE, EMBASE, and CINAHL databases aimed at comparing neurokinin-1 receptor antagonists with other antiemetics in their prevention of postoperative nausea and vomiting in adult patients undergoing laparoscopic surgery identified seven randomized controlled trials for review and meta-analysis. Preoperative aprepitant 80 mg was found to reduce nausea (RR: 0.56, 95% CI: 0.41–0.75, I2 = 0%, P = 0.89) and vomiting (RR: 0.20, 95% CI: 0.05–0.77, I2 = 0%, P = 0.96) and resulted in complete response (RR: 1.61 (1.25-2.08), I2 = 0%, P = 0.70) within the first 2 hours following surgery as well as vomiting in 2–24 hours (RR: 0.09, 95% CI: 0.02-0.36, I2 = 0%; P = 0.81) when compared to placebo or no antiemetic therapy. Preoperative aprepitant 80 mg has a superior overall effect compared to placebo or other antiemetics in the first two hours postoperatively, and thereafter reduces the risk of vomiting alone in the first 24 hours following laparoscopic surgeries.

Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the antinociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/ kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain. [ABSTRACT FROM AUTHOR]

Background: Aprepitant, a substance P neurokinin-1 receptor antagonist, is licenced for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy. Case: A 33 year-old male with metastatic gastro-oesophageal cancer had multiple admissions for refractory nausea and vomiting following insertion of an oesophageal stent. Action: Mechanical issues with the stent, stent removal and central causes were excluded. Multiple anti-emetic agents were trialled in combination and with varying routes of administration without significant symptomatic improvement. Formulation: A trial of aprepitant was proposed as an off-licence therapy. Outcome: One hundred sixty-five milligrammes of aprepitant was given orally every 3 days and then up titrated to once daily with significant symptomatic improvement enabling the patient to tolerate an oral diet. The patient remained stable at 12 weeks and has been accepted into two clinical trials for potential further cancer treatment. Lessons: Aprepitant can be effective in refractory nausea and vomiting outside of emetogenic chemotherapy and safely used as a chronic treatment. The prevalence of refractory nausea and vomiting as a rare adverse outcome post-oesophageal stent insertion should be studied. What now?: Further research of neurokinin-1 inhibitors for indications other than chemotherapy-induced nausea and vomiting is indicated. [ABSTRACT FROM AUTHOR]

A systematic electronic search of MEDLINE, EMBASE, and CINAHL databases aimed at comparing neurokinin-1 receptor antagonists with other antiemetics in their prevention of postoperative nausea and vomiting in adult patients undergoing laparoscopic surgery identified seven randomized controlled trials for review and meta-analysis. Preoperative aprepitant 80 mg was found to reduce nausea (RR: 0.56, 95% CI: 0.41–0.75, I2 = 0%, P = 0.89) and vomiting (RR: 0.20, 95% CI: 0.05–0.77, I2 = 0%, P = 0.96) and resulted in complete response (RR: 1.61 (1.25-2.08), I2 = 0%, P = 0.70) within the first 2 hours following surgery as well as vomiting in 2–24 hours (RR: 0.09, 95% CI: 0.02-0.36, I2 = 0%; P = 0.81) when compared to placebo or no antiemetic therapy. Preoperative aprepitant 80 mg has a superior overall effect compared to placebo or other antiemetics in the first two hours postoperatively, and thereafter reduces the risk of vomiting alone in the first 24 hours following laparoscopic surgeries. [ABSTRACT FROM AUTHOR]

Background: Aprepitant, fosaprepitant, and netupitant are three common neurokinin-1 receptor antagonists (NK-1RAs) used to prevent chemotherapy-induced nausea and vomiting, following highly or moderately emetogenic chemotherapy. Understanding their different adverse event (AE) profiles may help clinicians make appropriate treatment decisions., Methods: All data collected from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the fourth quarter of 2023 underwent disproportionality analysis to detect, evaluate, and compare AE signals of the three NK-1RAs., Results: A total of 3,904, 1,123, and 243 AE reports related to aprepitant, fosaprepitant, and netupitant, respectively, were extracted from the FAERS database. Of these, more than 50% of respondents were female, and most of them were aged 45-65 years. General disorders and administration-site conditions, and gastrointestinal disorders were the most frequent signals in the system organ class of the three NK-1RA drugs. In addition, aprepitant was strongly associated with joint deposit (ROR = 26.27) and fosaprepitant was closely related to seizure-like phenomena (ROR = 26.90); two preferred terms (PTs) were not mentioned in the manual. Statistically, netupitant was likely to induce death (N = 63, ROR = 8.78, 95% CI: 6.75-11.42). Additionally, neutropenic colitis, colitis, and stomatitis were unique to netupitant. Furthermore, the AE profiles of the three NK-1RA drugs were different by gender., Conclusion: The AE profiles for aprepitant, fosaprepitant, and netupitant were different. In addition to paying attention to common AEs, clinicians need to pay attention to new emerging AEs, such as joint deposit, seizure-like phenomena, neutropenic colitis, colitis, and stomatitis, regarding the three NK-1RA drugs. Furthermore, the AE compositions of the three NK-1RA drugs were different in different genders, and clinicians should take these factors into account when selecting NK-1RAs for CINV treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Xu, Wu, Fan, Li, Zhang, Shen and Dong.)

Background: The effectiveness of a dexamethasone-sparing strategy in the treatment of breast cancer with anthracycline-cyclophosphamide therapy when combined with first-generation 5-HT3 receptor antagonists (RAs) and neurokinin-1 RAs is unclear. This is attributable to a lack of evidence from direct comparison of multiple doses of DEX to a single dose of DEX in combination with first-generation 5-HT3 RAs in anthracycline-cyclophosphamide therapy. Our goal was to clarify the impact of dexamethasone-sparing strategies that involve both first-generation 5-HT3 RAs and palonosetron when combined with neurokinin-1 RAs, using a network meta-analysis., Materials and Methods: A literature search was conducted on PubMed/Medline for articles published up to July 4, 2023. We included randomized controlled trials which assessed the efficacy of antiemetic regimens which combined 5-HT3 RAs and dexamethasone, with or without neurokinin-1 RAs, for the initial dose in anthracycline-cyclophosphamide therapy for patients with breast cancer. The primary outcome was the proportion of patients achieving a complete response during the delayed phase (CR-DP)., Results: The difference in the proportion of patients achieving CR-DP between multiple and single doses of dexamethasone was 0.1% (95%CI: -12.4 to 12.5) with palonosetron and neurokinin-1 RAs, compared to 5.3% (95%CI: -13.4 to 23.0) with a single dose of a first-generation 5-HT3 receptor antagonist. Additionally, the difference was 12.7% (95% CI: -2.8 to 28.2) when comparing palonosetron against first-generation 5-HT3 RAs in combination with a single dose of dexamethasone and neurokinin-1 RAs., Conclusion: Palonosetron is recommended rather than a single dose of first-generation 5-HT3 RAs in dexamethasone-sparing strategies for anthracycline-cyclophosphamide therapy., Competing Interests: DW reports honoraria from Chugai. HI reports receiving consulting fees from Eisai and Taiho; honoraria from Astellas, AstraZeneca, Chugai, Daiichi Sankyo, Eli Lilly, Nippon Kayaku, Ono, Sawai, Taiho, and Yakult. RK reports honoraria from Janssen. HF reports honoraria from Chugai, Daiichi Sankyo, Kyowa Kirin, Ono, Sanofi and Taiho. KK reports grants from Kyowa Kirin; honoraria from Tsumura Pharmaceuticals. MF reports honoraria from Daiichi Sankyo, Taiho, Chugai, Eisai, Lilly, and Nihon-Kayaku. AS reports institutional grants from Nippon Kayaku, Asahi Kasei Pharma, Chugai Pharm, Taiho Pharm, Daiichi Sankyo, Japan Blood Products Organization, Mochida Pharm, Sun Pharma; honoraria from Toa Eiyo, Asahi Kasei Pharma, Daiichi Sankyo, Pfizer, Eisai, Nippon Shinyaku, Kyowa Kirin, Tsumura, Towa Pharmaceutical, Nippon Kayaku, Mochida Pharmaceutical, EA Pharma, Yakult Honsha, Chugai Pharmaceutical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Watanabe, Iihara, Kobayashi, Fujii, Mori, Kumada, Shimizu, Futamura and Suzuki.)

We investigated roles for substance P (SP), gastrin-releasing peptide (GRP), and glutamate in the spinal neurotransmission of histamine-dependent and -independent itch. In anesthetized mice, responses of single superficial dorsal horn neurons to intradermal (i.d.) injection of chloroquine were partially reduced by spinal application of the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionate acid (AMPA)/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Co-application of CNQX plus a neurokinin-1 (NK-1) antagonist produced stronger inhibition, while co-application of CNQX, NK-1, and GRP receptor (GRPR) antagonists completely inhibited firing. Nociceptive-specific and wide dynamic range-type neurons exhibited differential suppression by CNQX plus either the GRPR or NK-1 antagonist, respectively. Neuronal responses elicited by i.d. histamine were abolished by CNQX alone. In behavioral studies, individual intrathecal administration of a GRPR, NK-1, or AMPA antagonist each significantly attenuated chloroquine-evoked scratching behavior. Co-administration of the NK-1 and AMPA antagonists was more effective, and administration of all 3 antagonists abolished scratching. Intrathecal CNQX alone prevented histamine-evoked scratching behavior. We additionally employed a double-label strategy to investigate molecular markers of pruritogen-sensitive dorsal root ganglion (DRG) cells. DRG cells responsive to histamine and/or chloroquine, identified by calcium imaging, were then processed for co-expression of SP, GRP, or vesicular glutamate transporter type 2 (VGLUT2) immunofluorescence. Subpopulations of chloroquine- and/or histamine-sensitive DRG cells were immunopositive for SP and/or GRP, with >80% immunopositive for VGLUT2. These results indicate that SP, GRP, and glutamate each partially contribute to histamine-independent itch. Histamine-evoked itch is mediated primarily by glutamate, with GRP playing a lesser role. Co-application of NK-1, GRP, and AMPA receptor antagonists may prove beneficial in treating chronic itch.

Background: Olanzapine, neurokinin-1-receptor-antagonists (NK-1-RA), and thalidomide added to palonosetron + dexamethasone (PALO-DEX) have been evaluated in separate studies as prophylaxis for chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). We conducted a Bayesian network meta-analysis to compare the prophylactic efficacy of these agents in combination with PALO-DEX.Methods: PubMed, Medline/Ovid, Embase, and Clinicaltrials.gov were searched from inception through 22 Mar 2018. Study quality was assessed using the Cochrane methodology. A Bayesian network meta-analysis using random-effects models was used to asses complete response (CR) and rate of no nausea (RNN) in acute, delayed, and overall phases and were expressed as odds ratios (OR) and 95% credible interval (95% CrI). Ranking probabilities of treatments were calculated using the surface under the cumulative ranking curve (SUCRA) to identify the probability of a given treatment as the best option against the worst option.Results: Nine RCTs involving two thousand nine hundred fifty-nine patients were included. The olanzapine-based regimen showed greater CR in the acute, delayed, and overall-phases versus the PALO-DEX regimen (OR = 3.97, 95% CrI = 1.02-19.13; OR = 5.62, 95% CrI = 1.66-28.58; OR = 4.79, 95% CrI = 1.40-24.02, respectively). Additionally, it showed greater RNN than the NK-1-RA-based and the PALO-DEX regimens in the delayed phase only (OR = 2.90, 95% CrI = 1.34-5.15; OR = 4.53, 95% CrI = 1.89-10.55, respectively). Olanzapine-, NK-1-RA-, and thalidomide-based regimens did not differ in CR in the three phases. SUCRA probabilities ranked the olanzapine-based regimen as the best option in terms of CR and RNN, while ranking the NK-1-RA-based regimens as the second best option in terms of CR throughout the three phases.Conclusion: Based on the data included in the analyses, there is insufficient evidence to support adding thalidomide or NK-1-RA to PALO-DEX in preventing CINV induced by HEC. However, adding olanzapine to PALO-DEX achieves better CR and RNN. Olanzapine side-effects and the absence of direct comparisons explain why some guidelines are cautious in suggesting the use of olanzapine. [ABSTRACT FROM AUTHOR]

Intestinal inflammation is a painful syndrome with multiple symptoms, including chronic pain. This study examined the possible role of sensory neurons and substance P in symptoms of an animal model of acute intestinal inflammation. The model was induced by injecting ethanol and zymosan into the colon of anesthetized male rats. Three hours later, sections of the colon were stained with hematoxylin and eosin. To determine the role of substance P, 5 mg/kg of the neurokinin-1 receptor (NK-1r) antagonist, CP-96,345, or 300 microg/kg of an antisense oligonucleotide targeted at NK-1r mRNA was administered. Spinal cord sections were examined for internalization of NK-1r, as an indicator of substance P release. Sections of colon revealed infiltration of inflammatory cells following ethanol and zymosan treatment. Plasma extravasation in rats given ethanol and zymosan was significantly greater than in controls given saline only (P

Although many studies have demonstrated a role for substance P in pain, there have been conflicting reports implicating the involvement of substance P in neuropathic pain models. In this study, the non-peptide neurokinin-1 (NK-1) receptor antagonist, L-732,138 was chronically administered by intrathecal (i.t.) injection to rats with mono-neuropathy produced by sciatic nerve constriction. Rats exhibited tactile allodynia and cold hyperalgesia over a 16-day testing period. L-732,138 (5-200 nmol) administered i.t. prior to and for 3 consecutive days post-surgery attenuated the mechanical allodynia and cold hyperalgesia on days 4 and 8 post-surgery. The effects of i.t. L-732,138 were also determined in rats with established nerve injury-induced neuropathy. The NK-1 receptor antagonist was injected for 4 consecutive days starting on day 8 post-sciatic nerve injury. Administration of L-732,138 (5-200 nmol) i.t. produced both anti-allodynic and anti-hyperalgesic effects on day 12, but the effect was not permanent, as nociceptive thresholds were similar to controls by day 16. These results demonstrate that substance P is involved both in the induction and the maintenance of neuropathic pain and provides justification for the development and administration of substance P antagonists for the management of clinical neuropathic pain.

Bernardo Leon Rapoport The Medical Oncology Centre of Rosebank, Johannesburg, South Africa Abstract: Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of many cytotoxic chemotherapy regimens. CINV typically manifests during two well-defined time periods (acute and delayed phases). The acute phase is the first 24 hours after chemotherapy and is largely managed with 5-hydroxytryptamine 3 receptor antagonists. The delayed phase, a 5-day at-risk period during which patients are not often in direct contact with their health care provider, remains a significant unmet medical need. Neurokinin-1 (NK-1) receptor antagonists have demonstrated protection against acute and delayed CINV in patients treated with highly emetogenic chemotherapy and moderately emetogenic chemotherapy when used in combination with a 5-hydroxytryptamine 3 receptor antagonist and dexamethasone. Furthermore, recent data indicate that this protection is maintained over multiple treatment cycles. Rolapitant, a selective and long-acting NK-1 receptor antagonist, is approved as oral formulation for the prevention of delayed CINV in adults. This review discusses the differential pharmacology and clinical utility of rolapitant in preventing CINV compared with other NK-1 receptor antagonists. Keywords: antiemetics, highly emetogenic chemotherapy, moderately emetogenic chemotherapy, delayed chemotherapy-induced nausea and vomiting, emesis, neurokinin-1 receptor antagonists

1. Nicotine can activate primary afferent nociceptors, one result of which is to increase neurogenic plasma extravasation. In this study we have demonstrated a novel proinflammatory effect of sub-nanomolar nicotine, mediated by peripheral action at sensory neurons. This action is normally masked by adrenal medulla-derived delta-opioid receptor agonists. 2. While neurogenic plasma extravasation in the knee joint of the rat was not increased by intra-articular perfusion of nicotine (10(-8) M), perfusion of nicotine, at concentrations as low as 10(-10) M, combined with naloxone to block opioid receptors (or naltrindole to block delta-opioid receptors) was able to enhance bradykinin-induced plasma extravasation. This pro-inflammatory effect of intra-articular nicotine was mimicked by subcutaneous nicotine which was abolished by intra-articularly-administered hexamethonium, a nicotinic receptor antagonist. 3. Following denervation of the adrenal medulla, intra-articular nicotine, alone at 10(-8) M, enhanced plasma extravasation, which was no longer enhanced by naloxone. 4. Destruction of primary afferents by neonatal treatment with capsaicin or blockade of sensory neurotransmitter by neurokinin-1 receptor antagonist RP-87,580 abolished the pro-inflammatory effect of nicotine. 5. The effect of nicotine we describe in promoting inflammation is exerted at extremely low concentrations and therefore could have relevance to smokers, patients receiving medicinal nicotine as therapy and even second-hand smokers. Since receptor mechanisms on peripheral terminals of nociceptors may also be present on central terminals, actions of the endogenous nicotinic agonist acetylcholine, at central terminals of primary afferents or at other sites in the central nervous system, may be similarly modulated by opioids.

The tachykinin receptors neurokinin 1 (NK1R) and neurokinin 2 (NK2R) are G protein-coupled receptors that bind preferentially to the natural peptide ligands substance P and neurokinin A, respectively, and have been targets for drug development. Despite sharing a common C-terminal sequence of Phe-X-Gly-Leu-Met-NH2 that helps direct biological function, the peptide ligands exhibit some degree of cross-reactivity toward each other's non-natural receptor. Here, we investigate the detailed structure-activity relationships of the ligand-bound receptor complexes that underlie both potent activation by the natural ligand and cross-reactivity. We find that the specificity and cross-reactivity of the peptide ligands can be explained by the interactions between the amino acids preceding the FxGLM consensus motif of the bound peptide ligand and two regions of the receptor: the β-hairpin of the extracellular loop 2 (ECL2) and a N-terminal segment leading into transmembrane helix 1. Positively charged sidechains of the ECL2 (R177 of NK1R and K180 of NK2R) are seen to play a vital role in the interaction. The N-terminal positions 1 to 3 of the peptide ligand are entirely dispensable. Mutated and chimeric receptor and ligand constructs neatly swap around ligand specificity as expected, validating the structure-activity hypotheses presented. These findings will help in developing improved agonists or antagonists for NK1R and NK2R., Competing Interests: Conflict of interest D. P. C. and J. B. H. are employees of Embark Biotech ApS. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Rolapitant is a selective, long‐acting neurokinin‐1 receptor antagonist, approved in the United States and Europe for prevention of delayed chemotherapy‐induced nausea and vomiting in adults. This open‐label study evaluated the effects of a new intravenous formulation of rolapitant on cytochrome P450 (CYP) enzyme (CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6) activity. On days 1 and 14, 36 healthy volunteers received a modified Cooperstown cocktail (midazolam 3 mg [CYP3A substrate], caffeine 200 mg [CYP1A2 substrate], S‐warfarin 10 mg [CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19 substrate], and dextromethorphan 30 mg [CYP2D6 substrate]). On day 7, subjects received the modified Cooperstown cocktail after 166.5‐mg rolapitant infusion. On days 21, 28, and 35, subjects received oral dextromethorphan. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC0‐last) of probe drugs post‐ vs pre–rolapitant administration were assessed using geometric least‐squares mean ratios (GMRs) with 90%CIs. The 90%CIs of the GMRs were within the 0.80–1.25 no‐effect limits for caffeine and S‐warfarin Cmax and AUC0‐last. For midazolam Cmax and AUC0‐last and omeprazole Cmax, the 90%CIs of the GMRs were marginally outside these limits. Intravenous rolapitant coadministration increased dextromethorphan exposure, peaking 14 days post–rolapitant administration (GMRs: Cmax, 2.74, 90%CI 2.21–3.40; AUC0‐last, 3.36, 90%CI 2.74–4.13). Intravenous rolapitant 166.5 mg and probe drugs were well tolerated when coadministered. These data suggest that intravenous rolapitant is not an inhibitor of CYP3A, CYP2C9, CYP2C19, or CYP1A2 but is a moderate inhibitor of CYP2D6. [ABSTRACT FROM AUTHOR]

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Chemotherapy-induced nausea and vomiting (CINV) remains a challenge in cancer care. Improved understanding of CINV pathophysiology has triggered the development of new antiemetic therapeutic options, such as selective neurokinin-1 (NK1) receptor antagonists (RAs), which effectively prevent CINV when added to a standard antiemetic regimen (serotonin-3 RA and dexamethasone). Aprepitant and its water-soluble prodrug, fosaprepitant dimeglumine, are the most widely used NK1 RAs, with extensive clinical use worldwide. Recently, a Phase III trial prospectively evaluated fosaprepitant-based antiemetic therapy for CINV prevention in a large, well-defined nonanthracycline- and cyclophosphamide-based moderately emetogenic chemotherapy population. Fosaprepitant demonstrated significantly improved efficacy outcomes compared with a control regimen and was generally well tolerated, indicating that NK1 RAs are a valuable therapeutic option in this setting. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the efficacy and safety of a 3-day aprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) during the first cycle of non-anthracycline plus cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) based on government guidelines in Korean patients.Methods: This multicenter, randomized, double-blind, phase IV trial (NCT01636947) enrolled adult South Korean patients with a broad range of tumor types who were scheduled to receive a single dose of ≥1 MEC agent. Patients were randomized to a 3-day regimen of aprepitant (aprepitant regimen) or placebo (control regimen) on top of ondansetron plus dexamethasone. The primary and key secondary efficacy endpoints were the proportions of subjects who achieved no vomiting and complete response (CR) during the overall phase.Results: Of the 494 randomized subjects, 480 were included in the modified intent-to-treat population. Response rates for no vomiting and CR in the overall phase were numerically higher for the aprepitant regimen compared with the control regimen groups, but failed to reach statistical significance (no vomiting 77.2 vs 72.0%; p = 0.191; CR 73.4 vs 70.4%; p = 0.458). Both the aprepitant and control regimens were generally well tolerated.Conclusion: A 3-day aprepitant regimen was numerically better but not statistically superior to a control regimen with respect to the achievement of no vomiting or CR during the overall phase in a non-AC MEC Korean population based on government reimbursement guidelines.Trial Registration: ClinicalTrials.gov NCT01636947 ( https://clinicaltrials.Gov/ct2/show/NCT01636947 ). [ABSTRACT FROM AUTHOR]

Even when chemotherapy-induced nausea and vomiting (CINV) can be effectively controlled in the acute phase, it may still occur in the delayed phase. Identifying atrisk patients is complex and requires consideration of clinical, personal, demographic, and behavioral factors. Delayed CINV has a significant detrimental effect on patients' daily life and is responsible for significant healthcare resource utilization. Patients who do not experience acute CINV are not necessarily exempt from delayed CINV, and healthcare professionals have been shown to underestimate the incidence of delayed CINV. Failure to protect against CINV during the first cycle of chemotherapy is the most significant independent risk factor for delayed CINV during subsequent cycles. Addition of a neurokinin-1 receptor antagonist to antiemetic prophylactic regimens involving a 5-hydroxytryptamine type 3 receptor antagonist and a corticosteroid helps to ameliorate delayed CINV, particularly vomiting. Netupitant and rolapitant are secondgeneration neurokinin-1 receptor antagonists that provide effective prophylaxis against delayed chemotherapy-induced vomiting and also have an antinausea benefit. All of the neurokinin-1 receptor antagonists with the exception of rolapitant inhibit or induce cytochrome P450 3A4 (CYP3A4), and a reduced dose of dexamethasone (a CYP3A4 substrate) should be administered with aprepitant or netupitant; by contrast, this is not necessary with rolapitant. Here we review specific challenges associated with delayed CINV, its pathophysiology, epidemiology, treatment, and outcomes relative to acute CINV, and its management within the larger context of overall CINV. [ABSTRACT FROM AUTHOR]

Introduction: Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of many cytotoxic chemotherapy regimens. Although sustained antiemetic control across repeated chemotherapy cycles is important for cancer treatment continuation, few studies have investigated the efficacy of antiemetic prophylaxis over multiple chemotherapy cycles. Areas covered: Here we discuss the use of antiemetic hydroxytryptamine type 3 (5-HT3) receptor and neurokinin (NK)-1 receptor antagonists for prevention of CINV, limiting our review to clinical trials in the context of multiple-cycle chemotherapy, with a focus on the NK-1 receptor antagonist rolapitant. 5-HT3receptor antagonists may be effective in controlling CINV over repeated chemotherapy cycles, but evidence comes primarily from noncomparative studies. NK-1 receptor antagonists provide increased protection against CINV but differences in endpoint selection and methods of analysis preclude meaningful comparisons between agents. Rolapitant shows sustained control of emesis and nausea over multiple cycles of chemotherapy, and compared to other NK-1 receptor antagonists, has a longer half-life and reduced potential for cytochrome P450 3A4-mediated drug-drug interactions. Expert commentary: Trial design should be a key consideration in future studies of CINV therapies, including analytical methods utilized, choice of endpoints, and methods for accounting for nonresponders and patient attrition over multiple cycles of chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Aprepitant, as a neurokinin-1 receptor (NK-1R) antagonist, originally applied for curing chemotherapy-induced nausea and vomiting, has been reported to have significant antitumor effect on several malignant tumors. However, the effect of aprepitant on gallbladder cancer (GBC) is not clear yet. This study aimed to investigate the anti-tumor activity of aprepitant on GBC and the potential mechanisms., Methods: The NK-1R expression of gallbladder cancer cells were examined by immunofluorescence. MTT assay, wound healing and transwell migration assay were applied to detect the effect of aprepitant on cell proliferation, migration and invasion. Flow cytometry was used to detect the apoptosis rate. The effects of aprepitant on the expressions of cytokine were examined by real-time quantitative PCR and MAPK activation were detected via immunofluorescence and western blotting. Besides, xenograft model was established to investigate the effect of aprepitant in vivo., Results: Our results indicated that NK-1R was markedly expressed in gallbladder cancer cells and aprepitant effectively inhibited the proliferation, migration and invasion. Furthermore, the apoptosis, ROS and inflammation response were significantly boosted by aprepitant in GBC. Aprepitant induced NF-κB p65 nuclear translocationin and increased the expressions of p-P65, p-Akt, p-JNK, p-ERK and p-P38, as well as the mRNA levels of inflammatory cytokines IL-1β, IL-6 and TNF-α. Consistently, aprepitant suppressed the growth of GBC in xenograft mice model., Conclusion: Our study demonstrated that aprepitant could inhibit the development of gallbladder cancer via inducing ROS and MAPK activation, which suggested that aprepitant may become a promising therapeutic drug against GBC., (© 2023. The Author(s).)

Purpose: Racial minority cancer patients may experience underuse of antiemetic medications to prevent chemotherapy-induced nausea and vomiting (CINV). In addition to its adverse implications for quality of life, antiemetic underuse may contribute to observed disparities in acute illness during chemotherapy. To understand the potential contribution of CINV prophylaxis to breast cancer disparities, we assessed racial variation in potent antiemetic use and post-chemotherapy utilization related to CINV and the relationship between the two.Methods: We used SEER-Medicare data to evaluate the health care utilization in the 14 days following chemotherapy initiation among black and white women receiving highly emetogenic chemotherapy for breast cancer. We used modified Poisson regression to assess the relationship between (1) race and CINV-related utilization and (2) NK1 use and CINV-related utilization, overall and stratified by race. We report adjusted risk ratios (aRR) and 95 % confidence intervals (CI).Results: The study included 1130 women. Black women were 11 % less likely than white women to use neurokinin-1 receptor antagonists (NK1s) for CINV prophylaxis (p = 0.02); however, they experienced fewer CINV-related encounters following chemotherapy (unadjusted RR = 0.63, 95 %CI = 0.40-0.99; p = 0.05). After adjustment for clinical covariates, estimates were similar but no longer statistically significant (p = 0.07). Among white women, NK1 use was associated with increased CINV-related utilization (aRR NK1 users vs. non-users: 1.35, 95 % CI = 1.07-1.69, p = 0.01), likely resulting from unmeasured confounders.Conclusion: Black women were less likely to use NK1s- and CINV-related services. Racial variation in CINV-related services use may be partly explained by differential symptom reporting or access to care. [ABSTRACT FROM AUTHOR]