Olanzapine With or Without Fosaprepitant for Preventing Chemotherapy Induced Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy: A Phase III Randomized, Double-Blind, Placebo-Controlled Trial (ALLIANCE A221602).

PURPOSE: A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used. MATERIALS AND METHODS: A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 -olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%. RESULTS: A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist. CONCLUSION: This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

Medicinal herbs in treating chemotherapy-induced nausea and vomiting: A review.

Cancer development entangles with mutation and selection for cells that progressively increase capacity for proliferation and metastasis at the cellular level. Surgery, chemotherapy, and radiotherapy are the standard treatments to manage several types of cancer. Chemotherapy is toxic for both normal and cancer cells and can induce unfavorable conditions, such as chemotherapy-induced nausea and vomiting (CINV), that reduce patients' quality of life. Emesis after chemotherapy is categorized into two classes acute and delayed. Since ancient times, herbal medicines have been used in various cultures to manage stomachache, vomiting, and nausea. In this manuscript, the antiemetic mechanisms of several herbal medicines and their preparations such as Zingiber officinale (5-HT, NK-1 receptor and muscarinic antagonist activity), Mentha spicata (5-HT antagonist activity), Scutellaria baicalensis (antioxidant activity), Persumac (useful in delayed phase through antioxidant, anti-inflammatory, and anti-contractile properties) and Rikkunshito (supportive in acute and delayed phase through 5-HT receptor antagonist activity) have been reviewed to show their potential effects on decreasing CINV and attract scientists attention to formulate more herbal medicine to alleviate CINV in cancer patients. However, it is crucial to say that additional high-quality investigations are required to firmly verify the clinical effectiveness and safety of each plant/compound.

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.

Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study.

BACKGROUND: Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P / neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS. AIM: To determine whether inhibition of the neurokinin-1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not. METHODS: Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross-over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed. RESULTS: Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus). CONCLUSIONS: Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.

Antiemetic effect of Xiao-Ban-Xia-Tang, a Chinese medicinal herb recipe, on cisplatin-induced acute and delayed emesis in minks.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiao-Ban-Xia-Tang (XBXT), a traditional Chinese herbal medicine, has been used in China for more than 2000 years, and proved to be effective on various cases of vomiting in the clinic. OBJECTIVE: To investigate the antiemetic effect of XBXT on cisplatin-induced acute and delayed emesis and its effective mechanism on Neurokinin-1 receptor (NK(1)-R) in the new vomiting model of minks. MATERIALS AND METHODS: Minks were randomly divided into the normal group, cisplatin group, cisplatin + ondansetron group, cisplatin + low-dose XBXT group and cisplatin + high-dose XBXT group. The antiemetic effect of drugs was investigated in the vomiting model of minks induced by cisplatin (6mgkg(-1), i.p.) in 72h observation, and the expression of NK(1)-R in the area postrema and ileum was measured by Western blot. RESULTS: The frequency cisplatin induces retching and vomiting was significantly reduced by pretreatment with XBXT in a dose-dependent manner during the 0-24-h and 24-72-h periods (P<0.05), and XBXT exhibited effective dose-dependent (P<0.05) inhibition on the increase of expression levels of NK1 receptor in both the ileum and area postrema. CONCLUSIONS: XBXT has good activity against cisplatin-induced acute and delayed emesis in minks possibly by inhibiting central or peripheral increase of NK(1)-R.

Cytotoxic treatment-induced gastrointestinal symptoms.

PURPOSE OF REVIEW: This review highlights recent updates in cytotoxic treatment-induced gastrointestinal symptoms and complications, outlines the development of new diagnostic tools, and offers an up-to-date overview on management. RECENT FINDINGS: The neurokinin-1 receptor antagonist, aprepitant, has consolidated its attributive role in the prevention of acute phase chemotherapy-induced nausea and vomiting. Delayed gastrointestinal symptomatology related to the process of cytotoxic treatment-induced mucosal damage needs to be better understood in order to enable the clinician to assess gastrointestinal mucosal damage properly by documenting symptomatology, testing functionality and visualizing anatomical changes. By contrast to the proven beneficial effects of new drugs, such as palifermin (a trophic epidermal growth factor) or amifostine (free radical scavenger), in the management of oral mucositis, efficacy still needs to be determined regarding its gastrointestinal counterpart. SUMMARY: Gastrointestinal symptoms originating from cytotoxic treatment-induced mucosal barrier injury are the clinical features of a complex, dynamic pathobiological process that diminishes the quality of life but, more importantly, places the patient at risk for serious complications, like neutropenic enterocolitis. It is crucial, therefore, to adequately detect mucosal barrier injury using a complementary approach that will allow new therapeutic options to be tested thoroughly and improve supportive care.

Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence.

PURPOSE: Urge urinary incontinence is the involuntary leakage of urine commonly occurring in older adults, particularly women. Preclinical evidence suggests that urge urinary incontinence may occur due to up-regulation of tachykinin mediated bladder/spinal reflex signaling. This study tested the hypothesis that aprepitant, a neurokinin-1 receptor antagonist, may be efficacious in the treatment of urge urinary incontinence. MATERIALS AND METHODS: This was a double-blind, randomized, placebo controlled, parallel group pilot study in which postmenopausal women with a history of urge urinary incontinence or mixed incontinence (with predominantly urge urinary incontinence) were assigned to receive a 160 mg capsule of aprepitant (61) or placebo (64) once daily for 8 weeks. The primary end point was percent change from baseline in average daily micturitions assessed by a voiding diary. Secondary end points included average daily total urinary incontinence and urge urinary incontinence episodes, and urgency episodes. RESULTS: Aprepitant significantly decreased the average daily number of micturitions compared with placebo at 8 weeks. The between-group treatment difference expressed as percent change from baseline was -6.8%, 95% CI (-12.5, -1.1) (p = 0.019). The average daily number of urgency episodes was also significantly reduced compared to placebo (p = 0.049). The average daily number of urge urinary incontinence and total urinary incontinence episodes were also reduced, although the difference was not statistically significant. Aprepitant was generally well tolerated and adverse experiences were generally mild. CONCLUSIONS: Results of this initial study suggest that neurokinin-1 receptor antagonism may represent a novel therapeutic approach to treating overactive bladder syndrome.

Aprepitant: an oral NK1 antagonist for the prevention of nausea and vomiting induced by highly emetogenic chemotherapy.

This paper reviews the clinical profile of aprepitant, the first neurokinin-1 (NK(1)) receptor antagonist to be approved for use in the prevention of chemotherapy-induced nausea and vomiting. When given to patients receiving highly emetogenic chemotherapy, aprepitant in combination with a 5-hydroxytryptamine type-3 (5HT(3)) receptor antagonist and a corticosteroid provides significantly improved protection from chemotherapy-induced nausea and vomiting over that which has been previously achievable with current antiemetics.

Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting.

Aprepitant (Emend) is the first commercially available drug from a new class of agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults. In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2 and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63-73% versus 43-52%, p < 0.01 for all comparisons). Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy. Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis. Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used. In conclusion, when added to standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer.

Functional relevance of antiemetic control. Experience using the FLIE questionnaire in a randomised study of the NK-1 antagonist aprepitant.

Little information exists on the functional impact of effective antiemetic protection. In the present study, the Functional Living Index-Emesis (FLIE), was used to assess patient-reported impact of chemotherapy-induced nausea and vomiting (CINV) after administration of a new NK-1 receptor antagonist (aprepitant). Cisplatin-treated patients in a double-blind randomised trial received either aprepitant+dexamethasone+ondansetron on day 1 and aprepitant+dexamethasone on days 2-5 or standard antiemetic therapy (dexamethasone and ondansetron on day 1 and dexamethasone on days 2-5). Emetic events, nausea ratings and rescue medications were recorded in a 5-day diary and the FLIE was completed on day 6. Compared with standard therapy, significantly more patients treated with the high dose aprepitant regimen achieved a Complete Response (71 vs 44%, P<0.001) and also reported no impact on daily life as indicated by the FLIE total score (84 vs 66%, P<0.01). Use of the FLIE demonstrated that improved control of emesis was highly effective in reducing the impact of CINV on patients' daily lives.

Tachykinins and airway microvascular leakage induced by HCl intra-oesophageal instillation.

Gastro-oesophageal reflux is a common clinical disorder associated with a variety of respiratory symptoms, including chronic cough and exacerbation of asthma. In this study, the potential role of acid-induced tachykinin release was examined in guinea pigs and rabbits, by examining the effects of the tachykinin NK1 and NK3 receptors antagonists (SR 140333 and SR 142801, respectively) (1-10 mg x kg(-1)) on plasma protein extravasation induced in airways by hydrochloric acid (HCl) infusion in the oesophagus. Guinea pigs were anaesthetised with urethane, while rabbits were subject to neuroleptoanalgesia with hypnorm. Airway vascular leakage was evaluated by measuring extravasation of Evans blue dye. All animals were pretreated with atropine (1 mg x kg(-1) i.p.), propranolol (1 mg x kg(-1) i.p.), phosphoramidon (2.5 mg x kg(-1) i.v.) and saline or tachykinin receptor antagonists (1-10 mg x kg(-1) i.p.). Infusion of 1 N HCl into the oesophagus led to a three- and five-fold increase in plasma extravasation in the main bronchi and trachea, respectively. This increase was largely prevented by the tachykinin NK1 and NK3 receptor antagonists SR 140333 and SR 142801 (1-10 mg x kg(-1)). These results suggest that protein extravasation in the airways, as induced by intraoesophageal HCl infusion, is mainly dependent on the release of tachykinins, and that both NK1 and NK3 tachykinin receptors are involved. The results suggest that HCl-induced sensory nerve stimulation may act in the periphery on intermediate neurons and/or ganglia where NK3 receptors have been shown to play an important role.

NK1 (substance P) receptor antagonists--why are they not analgesic in humans?

Tachykinin NK1 receptor antagonists have failed to exhibit efficacy in clinical trials of a variety of clinical pain states. By contrast, in preclinical studies in animals NK1 receptor antagonists have been shown to attenuate nociceptive responses sensitized by inflammation or nerve damage, although they exhibit little effect on baseline nociception. Other agents with this profile of activity in animal tests, typically nonsteroidal anti-inflammatory drugs (NSAIDs), are analgesic in humans. Thus, NK1 receptor antagonists appear able to block behavioural responses to noxious and other stressful sensory stimuli at a level detectable in animal tests but fail to provide the level of sensory blockade required to produce clinical analgesia in humans.