Selective Neurokinin-1 Receptor Antagonist Research Articles

Evaluation of aprepitant as an add-on therapy for prevention of chemotherapy induced nausea and vomiting in children

Background: Chemotherapy-induced nausea and vomiting (CINV), represents a common and distressing side effect associated with antineoplastic treatment in pediatric patients. Aprepitant, a selective neurokinin-1 receptor antagonist, is recommended for preventing CINV in combination with a standard antiemetic regimen in children undergoing chemotherapy. This study aimed to evaluate the effectiveness of aprepitant as an add-on therapy to the standard antiemetic regimen for the prevention of CINV in children. Methods: This randomized control study was conducted in the BSMMU, Dhaka, Bangladesh from February 2020 to October 2020. Forty-six children with malignancy undergoing chemotherapy were divided into two arms: the Aprepitant arm (23 patients receiving granisetron, dexamethasone, and aprepitant) and the control arm (23 patients receiving Granisetron and Dexamethasone). Data were analyzed using SPSS version 22.0. Results: The complete response rates for the aprepitant versus control arm during the acute and overall phase were 82% vs. 40% (p=0.003) and 65% vs. 26% (p=0.008), respectively. However, a higher percentage of patients who achieved complete response in the delayed phase was also observed, though statistically not significant (65% vs 40%, p=0.077). In the acute phase, there was a significant reduction in mild to moderate vomiting in the Aprepitant arm as compared to the control arm (p=0.01). In the overall phase, 35% of patients in the Aprepitant arm had mild to moderate vomiting as compared to 74% in the control group (p=0.027). No major adverse effects were reported by patients or caregivers. Conclusions: Adding Aprepitant to the standard antiemetic regimen was effective and safe in preventing CINV, especially in the acute phase, in pediatric patients receiving the moderately and highly emetogenic chemotherapy (HEC).

Association of Neurokinin-1 Receptor Signaling Pathways with Cancer.

Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity. This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed. NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.

Clinical Applications of Substance P (Neurokinin-1 Receptor) Antagonist in Canine Medicine.

Substance P binds to the Neurokinin-1 (NK-1) receptors found in the emetic center of the central nervous system (CNS) to induce emesis. Maropitant is a selective NK-1 receptor antagonist that inhibits the binding of substance P to NK-1 receptors and is commonly used to prevent and treat vomiting in dogs. This review study aimed to discuss and analyze the therapeutic potential of substance P (Neurokinin-1 receptor) antagonist with a particular focus on the drug maropitant in canine medicine. A systematic literature review was performed to identify the existing literature on the subject during the past 20 years (2001-2021) using such databases as ScienceDirect, PubMed, Scopus, and Google Scholar. The initial search identified 173 articles; however, 41 articles were selected for further analysis, based on the specific inclusion and exclusion criteria. Studies have already confirmed the role of substance P and NK-1 receptors in central pain processing, intestinal smooth muscle contraction, vasodilation, and neurogenic inflammation. Maropitant is one of the most effective veterinary antiemetic drugs that work well against peripheral and central stimuli that trigger the vomiting center. It has been already demonstrated that the therapeutic efficacy of maropitant for managing acute vomiting in dogs is associated with pancreatitis, gastritis, and parvoviral enteritis. It can also prevent and treat chemotherapy-induced emesis and delay the signs of nausea and adverse gastrointestinal effects. Regarding the broad-spectrum antiemetic activity of maropitant, it can be recommended for managing uremic vomiting in dogs. In addition, it has also exhibited an anesthetic sparing effect since the dogs treated with maropitant require a slightly lower percentage of isoflurane as an inhalational anesthetic. The NK-1 receptors are also identified in different areas of the pain pathways. Therefore, NK-1 receptor antagonists might be effective for managing visceral pain. However, further studies are required to establish the broad therapeutic potential of NK-1 receptor antagonist drugs, such as maropitant in canine medicine. It has been shown that the pain associated with the subcutaneous administration of maropitant is due to metacresol, a preservative used in some formulations. Therefore, the side effects can be eliminated by developing novel maropitant formulations specifically for dogs.

OTHR-16. CONCURRENT USE OF APREPITANT AND IFOSFAMIDE IN PEDIATRIC CANCER PATIENTS

BACKGROUNDAprepitant, a selective neurokinin-1 receptor antagonist, is commonly used for prevention of chemotherapy-induced nausea and vomiting. Its use with ifosfamide is controversial due to the putative risk of potentiating neurotoxicity via inhibition of cytochrome P450 3A4 (CYP3A4). The current literature examining this interaction is inconclusive, and little data exists in pediatrics. We seek to describe a single-institution experience with concurrent aprepitant and ifosfamide administration.METHODSA retrospective review of patients treated with ifosfamide and aprepitant from 2009–2018 was conducted. Data collected included demographics, tumor type, number of days of concurrent therapy, dosing, and documented of neurotoxicity.RESULTSTwenty patients aged 7–21 years (median 17 years) were identified. Diagnoses included thirteen sarcomas and seven CNS tumors (6 germ cell tumors; 1 intracranial sarcoma). Five patients received high dose ifosfamide (>2,000mg/m2/day). The number of concurrent ifosfamide and aprepitant doses ranged from 2–18 (median, 8.5). Only one patient (5%) developed ifosfamide-induced neurotoxicity: a 7-year-old female with a nongerminomatous germ cell tumor who presented with seizures and somnolence. She received methylene blue and returned to her neurologic baseline. She completed her ifosfamide course without incident. She was the only patient to require weight-based aprepitant dosing and to receive the liquid formulation.CONCLUSIONSAprepitant should be used with caution when administered concurrently with ifosfamide due to the risk of neurotoxicity. However, the incidence of neurotoxicity in this retrospective pediatric cohort was low. This interaction may be more significant in younger patients due to age-related differences in hepatic metabolism, but further study is required.

Simple Liquid Chromatography-Tandem Mass Spectrometry Method for Quantitation of Total and Free Aprepitant and Its Active N-Dealkylated Metabolites in Human Plasma.

Aprepitant, an antiemetic selective neurokinin-1 receptor antagonist, is primarily metabolized to the active N-dealkylated form (ND-AP) and then converted to its carbonyl form (ND-CAP) in humans. This study developed a simple liquid chromatography-tandem mass spectrometry method using electrospray ionization for the quantitation of plasma total and free aprepitant and its N-dealkylated metabolites and used them to analyze patient plasma. Free aprepitant and ND-AP in plasma were fractionated using centrifugal ultrafiltration. The analytes in plasma or their ultrafiltered specimens treated with triethylamine/acetonitrile were isocratically separated using a 3-μm octadecylsilyl column with a total run time of 10 minutes and scanned using positive ion electrospray ionization. The calibration curves of total aprepitant, ND-AP, and ND-CAP were prepared at concentration ranges of 50-2500, 20-1000, and 5-250 ng/mL, respectively, whereas that of free aprepitant and ND-AP were at a concentration range of 2-150 ng/mL. The intraassay and interassay accuracy and imprecision values were 93.5%-107.7% and 94.6%-103.3%, and 2.1%-7.5% and 1.0%-8.9%, respectively. Aprepitant and its metabolites did not exhibit any matrix effects or instabilities in the plasma specimens. In cancer patients receiving oral aprepitant, the plasma concentration ranges of total aprepitant, ND-AP, and ND-CAP, and free aprepitant and ND-AP were 137-2170, 104-928, 22.4-97.6, 8.11-60.0, and 3.53-56.0 ng/mL, respectively. The median plasma free fraction proportion of aprepitant and ND-AP was 4.14% and 4.90%, respectively. The present developed method showed an acceptable analytical performance and can be used to evaluate total and free aprepitant and its N-dealkylated metabolites in patient plasma.

Effectiveness of a novel, fixed dose combination of netupitant and palonosetron in prevention of chemotherapy induced nausea and vomiting: A real-life study from India.

BACKGROUNDA new, oral fixed dose combination of highly selective neurokinin-1 receptor antagonist, netupitant with 5HT3 receptor antagonist, netupitant and palonosetron (NEPA) was approved in India for prevention of chemotherapy induced nausea and vomiting (CINV).AIMTo assess effectiveness of NEPA in real-world scenario.METHODSWe retrospectively assessed the medical records and patient dairies of adult patients who received highly emetogenic or moderately emetogenic chemotherapy (HEC/MEC) and treated with NEPA (Netupitant 300 mg + Palanosetron 0.50 mg) for prevention of CINV. Complete response (CR) was defined as no emesis or no requirement of rescue medication in overall phase (0 to 5 d), acute phase (0-24 h) and delayed phase (2 to 5 d).RESULTSIn 403 patients included in the analysis, mean age was 56.24 ± 11.11 years and 55.09% were females. Breast cancer (25.06%) was most common malignancy encountered. HEC and MEC were administered in 54.6% and 45.4% patients respectively. CR in overall phase was 93.79% whereas it was 98.01% in acute CINV and 93.79% in delayed CINV. Overall CR in HEC and MEC groups was 93.63% and 93.98% respectively. CR was more than 90% in different chemotherapy cycles except in group of patients of cycle 4 where CR was 88.88%.CONCLUSIONNEPA is a novel combination that is effective in preventing CINV in up to 93% cases treated with highly emetogenic or moderately emetogenic chemotherapy. This study brings the first real-life evidence of its effectiveness in India population.

Netupitant/palonosetron (NEPA) and dexamethasone for prevention of emesis in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide: a multi-cycle, phase II study

BackgroundNEPA is an oral fixed-dose combination of netupitant, a new highly selective neurokinin-1 receptor antagonist, and palonosetron. This study was conducted to evaluate whether the efficacy of NEPA against chemotherapy-induced nausea and vomiting (CINV) in cycle 1 would be maintained over subsequent chemotherapy cycles in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide (AC). The study also describes the relationship between efficacy on day 1 through 5 (overall period) and control of CINV on day 6 through 21 (very late period) in each cycle.MethodsIn this multicentre, phase II study, patients received both NEPA and dexamethasone (12 mg intravenously) just before chemotherapy. The primary efficacy endpoint was overall complete response (CR; no emesis and no rescue medication use) in cycle 1. Sustained efficacy was evaluated during the subsequent cycles by calculating the rate of CR in cycles 2–4 and by assessing the probability of sustained CR over multiple cycles. The impact of both overall CR and risk factors for CINV on the control of very late events (vomiting and moderate-to-severe nausea) were also examined.ResultsOf the 149 patients enrolled in the study, 139 were evaluable for a total of 552 cycles; 97.8% completed all 4 cycles. The proportion of patients with an overall CR was 70.5% (90% CI, 64.1 to 76.9) in cycle 1, and this was maintained in subsequent cycles. The cumulative percentage of patients with a sustained CR over 4 cycles was 53%. NEPA was well tolerated across cycles. In each cycle, patients with CR experienced a significantly better control of very late CINV events than those who experienced no CR. Among the patients with CR, the only predictor for increased likelihood of developing very late CINV was pre-chemotherapy (anticipatory) nausea (adjusted odds ratio = 0.65–0.50 for no CINV events on cycles 3 and 4).ConclusionThe high anti-emetic efficacy seen with the NEPA regimen in the first cycle was maintained over multiple cycles of adjuvant AC for breast cancer. Preliminary evidence also suggests that patients achieving a CR during the overall period gain high protection even against very late CINV events in each chemotherapy cycle.Trial registrationThis trial was retrospectively registered at Clinicaltrials.gov identifier (NCT03862144) on 05/Mar/2019.

Clinical Pharmacology Research for Promoting Individualized Cancer Chemotherapy

Cancer chemotherapy has progressed remarkably with conventional and molecular-targeted anticancer drugs as well as immune checkpoint inhibitors. However, adverse drug reaction (ADR) management remains a challenge in cancer chemotherapy. Therefore, improving the quality of medical care through clinical pharmacology research is warranted. Intravenous injection of bendamustine in patients with follicular or mantle cell lymphoma frequently causes venous irritation. Because the underlying mechanisms are not clear, we investigated the factors responsible for bendamustine-induced venous irritation. Based on the results of our analysis, we altered the administration regimen and observed that the incidence of venous irritation, which manifested in a concentration-dependent manner following conventional approaches, significantly decreased when following the modified regimen. Guidelines on the management of chemotherapy-induced nausea and vomiting recommend aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and dexamethasone as prophylactic antiemetics. Pretreatment with high-dose chemotherapy before hematopoietic stem cell transplantation has extremely high emetogenic potential. This can be countered by using aprepitant in combination with conventional antiemetics. However, the safety and efficacy of such combinations are unexplored. Upon evaluation, we observed improved antiemetic effects without an increase in ADRs. At this symposium, I highlight the significance of clinical pharmacology research for promoting individualized cancer chemotherapy.

Efficacy, Tolerability and Pharmacokinetic Impact of Aprepitant in Sarcoma Patients Receiving Ifosfamide and Doxorubicin Chemotherapy: A Randomized Controlled Trial.

Aprepitant, a selective neurokinin-1 receptor antagonist approved for prevention of chemotherapy-induced nausea and vomiting (CINV), is an inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme, which is involved in the clearance of several chemotherapeutic agents. Here we evaluated the efficacy and toxicity of a combination of aprepitant, palonosetron, and dexamethasone as antiemetic prophylaxis in sarcoma patients receiving ifosfamide and doxorubicin chemotherapy, and examined the potential of aprepitant to affect the pharmacokinetics of ifosfamide, which is primarily metabolized by CYP3A4. A total of 108 sarcoma patients were randomly assigned to either the aprepitant group (antiemetic regimen: aprepitant, palonosetron, and dexamethasone) or the control group (antiemetic regimen: palonosetron and dexamethasone). Data on nausea, vomiting, and use of rescue medication were collected, and the primary efficacy end point was the proportion of patients with complete response (CR), defined as no vomiting and no use of rescue therapy during 120h after initiation of chemotherapy. Tolerability was evaluated on the basis of reported adverse events and laboratory assessments. Blood samples for ifosfamide pharmacokinetic analysis were collected in ten patients. The percentage of patients achieving CR was significantly higher in the aprepitant group compared with that in the control group in the acute, delay, and overall phase (78.4% vs. 59.3%, 74.5% vs. 48.1%, and 68.6% vs. 37.0%, p < 0.05, respectively). No significant differences of adverse events or hematological toxicity were detected between the two groups. Concomitant administration of aprepitant did not cause any statistically significant changes in ifosfamide pharmacokinetics. Values for aprepitant group vs. control group were as follows: geometric mean of Cmax was 119 vs. 120ng/mL, AUC0-last was 648 vs. 635ngh/mL, AUC0-inf was 681 vs. 668ngh/mL, plasma clearance was 4.40 vs. 4.49 (L/h/m2), respectively; harmonic means of t1/2 was 2.11 vs. 2.25h. This study showed that aprepitant in combination with palonosetron and dexamethasone was safe and effectively controlled CINV in sarcoma patients receiving ifosfamide and doxorubicin chemotherapy. Aprepitant may have a low potential to affect the pharmacokinetics of chemotherapeutic agents metabolized by CYP3A4.

Neurokinin-1 receptor antagonism improves postoperative neurocognitive disorder in mice

Postoperative neurocognitive disorder (PND) is a major complication in surgical patients, especially the elderly, leading to mild memory impairment after surgery. The underlying pathophysiology remains unknown, although neuroinflammation and blood-brain barrier (BBB) disruption have been increasingly implicated in PND. Emerging evidence suggests that neurokinin-1 receptor (NK-1R), the principal target of proinflammatory neuropeptide substance P (SP), plays a pivotal role in modulating neuroinflammation and BBB integrity. In this study, we used an established mouse model for PND to investigate the effects of a selective NK-1R antagonist L-733,060 on PND-like features after peripheral surgery. Hippocampal SP started to increase at 6 h, peaked at 1 day, and returned to baseline at 3 days after surgery. At 1 day after surgery, NK-1R expression was increased in the hippocampus. At this time point, NK-1R antagonist pretreatment attenuated microgliosis and prevented neutrophil infiltration after surgery. Similarly, proinflammatory cytokines interleukin-1 beta and interleukin-6 were reduced in the hippocampus in NK-1R antagonist-treated mice at 6 h after surgery. Furthermore, surgery-induced BBB disruption, assessed by albumin deposition and expression of tight junction protein claudin-5, was attenuated by NK-1R antagonism at postoperative day 1. Finally, trace fear conditioning test revealed NK-1R antagonism reversed surgery-induced cognitive impairment at 3 days after surgery. Our findings suggest that inhibition of NK-1R signaling protects hippocampus-dependent memory from surgical insult, probably through modulations of neuroinflammation and BBB integrity.

Absorption, metabolism, and excretion of the antiemetic rolapitant, a selective neurokinin-1 receptor antagonist, in healthy male subjects

Rolapitant is a neurokinin-1 receptor antagonist that is approved in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting (CINV) associated with initial and repeat courses of emetogenic cancer chemotherapy, including but not limited to highly emetogenic chemotherapy. Here, we assessed the absorption, metabolism, and excretion of 14C-labeled rolapitant in healthy male subjects. Rolapitant was administered as a single 180-mg oral dose containing approximately 100μCi of total radioactivity, with plasma, urine, and fecal samples collected at defined intervals after dosing. Rolapitant had a large apparent volume of distribution, indicating that it is widely distributed into body tissues. Rolapitant was slowly metabolized and eliminated with a mean half-life of 186h. Exposure to the major metabolite of rolapitant, C4-pyrrolidinyl hydroxylated rolapitant or M19, was approximately 50% of rolapitant exposure in plasma. Renal clearance was not a significant elimination route for rolapitant-related entities. Total radioactivity recovered in urine accounted for 14.2% of the dose, compared to 72.7% recovery in feces. Adverse events (AEs) were generally mild; there were no serious AEs, and no clinically significant changes in laboratory or electrocardiogram parameters were observed. The combination of rolapitant safety, its long half-life, extensive tissue distribution, and slow elimination via the hepatobiliary route (rather than renal excretion) suggest suitability that a single dose of rolapitant may provide protection against CINV beyond the first 24h after chemotherapy administration.

Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant.

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.

Rolapitant: An NK-1 Receptor Antagonist for the Prevention of Chemotherapy- Induced Nausea and Vomiting

Nausea and vomiting are among the most feared side effects of chemotherapy and can prevent cancer patients from completing their treatment regimens. Rolapitant is a highly selective neurokinin-1 (NK-1) receptor antagonist with very good oral activity, central nervous system penetration and a long (180-hour) plasma half-life. Unlike other available NK-1 receptor antagonists, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4. Findings from recent phase II and III clinical trials of rolapitant in patients receiving highly or moderately emetogenic chemotherapy are reviewed and discussed. The addition of a single-dose of rolapitant to combination 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone regimens provided increased protection against chemotherapyinduced nausea and vomiting, a benefit that encompassed the entire at-risk period investigated (0-120 hours after initiation of chemotherapy) in patients receiving highly or moderately emetogenic chemotherapy. Rolapitant was well tolerated by patients in these trials, with the overall frequency of treatment- related adverse events similar in patients receiving rolapitant (7.0%) and active placebo (6.3%). Rolapitant's favorable toxicity profile and lack of CYP3A4-related drug-drug interactions indicate that it would be a suitable treatment for older patients or those with multiple comorbidities, who are likely to be receiving a number of concomitant medications. Future studies should focus on the role of rolapitant in the control of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy, specific chemotherapy agents or high-dose chemotherapy and stem cell support.

Bioequivalence of Intravenous and Oral Rolapitant: Results From a Randomized, Open-Label Pivotal Study.

Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The objective of this pivotal study was to assess the bioequivalence of a single intravenous infusion of rolapitant versus a single oral dose of rolapitant. In this randomized, open-label phase 1 study, healthy volunteers were administered rolapitant as a 180-mg oral dose or a 30-minute 166.5-mg intravenous infusion. Blood samples for pharmacokinetic analysis were collected predose and at points up to 912 hours postdose. Criteria for bioequivalence of the intravenous dose versus the oral dose were met if the 90% confidence intervals (CIs) for the ratios of the geometric least-squares means (GLSMs) for the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ) and AUC from time 0 extrapolated to infinity (AUC0-∞ ) for rolapitant were within 0.80-1.25. Mean rolapitant systemic exposure and half-lives were similar in the oral (n = 62) and intravenous (n = 61) rolapitant groups. The 90%CIs of the ratio of GLSMs were within the 0.80-1.25 range for AUC0-t (0.94-1.09) and AUC0-∞ (0.93-1.10). The incidence of treatment-emergent adverse events, all mild or moderate in severity, was similar in the intravenous and oral groups. A 166.5-mg intravenous infusion of rolapitant met the bioequivalence criteria based on AUC to a 180-mg oral dose and was well tolerated.

Hyperalgesia and sensitization of dorsal horn neurons following activation of NK-1 receptors in the rostral ventromedial medulla.

Neurons in the rostral ventromedial medulla (RVM) project to the spinal cord and are involved in descending modulation of pain. Several studies have shown that activation of neurokinin-1 (NK-1) receptors in the RVM produces hyperalgesia, although the underlying mechanisms are not clear. In parallel studies, we compared behavioral measures of hyperalgesia to electrophysiological responses of nociceptive dorsal horn neurons produced by activation of NK-1 receptors in the RVM. Injection of the selective NK-1 receptor agonist Sar9,Met(O2)11-substance P (SSP) into the RVM produced dose-dependent mechanical and heat hyperalgesia that was blocked by coadministration of the selective NK-1 receptor antagonist L-733,060. In electrophysiological studies, responses evoked by mechanical and heat stimuli were obtained from identified high-threshold (HT) and wide dynamic range (WDR) neurons. Injection of SSP into the RVM enhanced responses of WDR neurons, including identified neurons that project to the parabrachial area, to mechanical and heat stimuli. Since intraplantar injection of capsaicin produces robust hyperalgesia and sensitization of nociceptive spinal neurons, we examined whether this sensitization was dependent on NK-1 receptors in the RVM. Pretreatment with L-733,060 into the RVM blocked the sensitization of dorsal horn neurons produced by capsaicin. c-Fos labeling was used to determine the spatial distribution of dorsal horn neurons that were sensitized by NK-1 receptor activation in the RVM. Consistent with our electrophysiological results, administration of SSP into the RVM increased pinch-evoked c-Fos expression in the dorsal horn. It is suggested that targeting this descending pathway may be effective in reducing persistent pain.NEW & NOTEWORTHY It is known that activation of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM), a main output area for descending modulation of pain, produces hyperalgesia. Here we show that activation of NK-1 receptors produces hyperalgesia by sensitizing nociceptive dorsal horn neurons. Targeting this pathway at its origin or in the spinal cord may be an effective approach for pain management.

Differential clinical pharmacology of rolapitant in delayed chemotherapy-induced nausea and vomiting (CINV).

Rolapitant is a highly selective neurokinin-1 receptor antagonist, orally administered for a single dose of 180 mg before chemotherapy with granisetron D1, dexamethasone 8 mg BID on day 2–4. It has a unique pharmacological characteristic of a long plasma half-life (between 163 and 183 hours); this long half-life makes a single use sufficient to cover the delayed emesis risk period. No major drug–drug interactions between rolapitant and dexamethasone or other cytochrome P450 inducers or inhibitors were observed. The clinical efficacy of rolapitant was studied in two phase III trials in highly emetogenic chemotherapy and in one clinical trial in moderately emetogenic chemotherapy. The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24–120 hours after chemotherapy). In comparison to granisetron (10 μg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2–4 and placebo, rolapitant showed superior efficacy in the control of delayed and overall emesis. This review aims at revising the pharmacological characteristics of rolapitant, offering an updated review of the available clinical efficacy and safety data of rolapitant in different clinical settings, highlighting the place of rolapitant in the management of chemotherapy-induced nausea and vomiting (CINV) among currently available guidelines, and exploring the future directions of CINV management.

Aprepitant limits in vivo neuroinflammatory responses in a rhesus model of Lyme neuroborreliosis

BackgroundSubstance P (SP) is produced at high levels in the central nervous system (CNS), and its target receptor, neurokinin 1 receptor (NK-1R), is expressed by glia and leukocytes. This tachykinin functions to exacerbate inflammatory responses at peripheral sites. Moreover, SP/NK-1R interactions have recently been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis. Furthermore, we have since shown that these agents can attenuate Borrelia burgdorferi-induced neuronal and glial inflammatory mediator production in non-human primate brain explants and isolated neuronal cells.MethodsIn the present study, we have assessed the role played by endogenous SP/NK-1R interactions in damaging CNS inflammation in an established rhesus macaque model that faithfully reproduces the key clinical features of Lyme neuroborreliosis, using the specific NK-1R antagonist, aprepitant. We have utilized multiplex ELISA to quantify immune mediator levels in cerebrospinal fluid, and RT-PCR and immunoblot analyses to quantify cytokine and NK-1R expression, respectively, in brain cortex, dorsal root ganglia, and spinal cord tissues. In addition, we have assessed astrocyte number/activation status in brain cortical tissue by immunofluorescence staining and confocal microscopy.ResultsWe demonstrate that aprepitant treatment attenuates B. burgdorferi-induced elevations in CCL2, CXCL13, IL-17A, and IL-6 gene expression in dorsal root ganglia, spinal cord, and/or cerebrospinal fluid of rhesus macaques at 2 to 4 weeks following intrathecal infection. In addition, we demonstrate that this selective NK-1R antagonist also prevents increases in total cortical brain NK-1R expression and decreases in the expression of the astrocyte marker, glial fibrillary acidic protein, associated with B. burgdorferi infection.ConclusionsThe ability of a centrally acting NK-1R inhibitor to attenuate B. burgdorferi-associated neuroinflammatory responses and sequelae raises the intriguing possibility that such FDA-approved agents could be repurposed for use as an adjunctive therapy for the treatment of bacterial CNS infections.

Differential pharmacology and clinical utility of rolapitant in chemotherapy-induced nausea and vomiting.

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.

Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder

Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40mg), the NK1R antagonist GR205171 (n=6; 5mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

The spinal generator of ejaculation: Functional consequences of chronic spinalization and effect of substance P in anesthetized rats

The inability to ejaculate, i.e. anejaculation, affects the vast majority of men after spinal cord injury (SCI). Ejaculation can however be obtained in approximately half of SCI men by applying extraphysiological vibratory stimulation to the penis suggesting that a spinal neural organization commanding ejaculation exists than can be activated despite disruption of cerebral connections. In the rat, a spinal generator of ejaculation (SGE) has been identified which is notably characterized by the presence of substance P (SP) receptor (neurokinin-1 receptor) onto the constituting neurons. The aim of this study was to evaluate the consequence of chronic spinal cord section and the effect of SP on the function of the rat SGE. Electrical stimulations of varying intensity were applied to SGE in anesthetized rats 4weeks after complete transection of the thoracic spinal cord (T9) and ejaculation occurrence as well as peripheral responses, i.e. bulbospongiosus electromyogram and pressure within the seminal vesicle, were monitored. Then the effect of SP locally delivered was assessed in this experimental setting. Occurrence of ejaculation elicited by SGE stimulation, SGE excitatory threshold, and amplitude of peripheral responses were unchanged in spinalized as compared to spinally intact rats. In spinalized rats, SP triggered ejaculation upon intraspinal delivery into the SGE area and decreased the SGE stimulation intensity provoking ejaculation after intrathecal administration indicating a decrease in SGE excitatory threshold. The pro-ejaculatory inducing and facilitating effects of SP were reversed by the selective neurokinin-1 receptor antagonist RP67580. It was concluded that chronic spinalization has no significant impact on SGE functioning and SP exerts a pro-ejaculatory role at the SGE level, opening new avenues for the treatment of anejaculation in SCI men.