aprepitant and Chronic-Disease

Chronic pruritus is a difficult condition to treat and is associated with several comorbidities, including insomnia, depression, and decreased quality of life. Treatment for chronic itch includes corticosteroids, antihistamines, and systemic therapies such as naltrexone, gabapentin, UV light therapy, and immunomodulatory treatments, including azathioprine, methotrexate, and cellcept. However, some patients still remain refractory to conventional therapy. Aprepitant is a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV, PONV). Recently, aprepitant has demonstrated effectiveness in several case series and open label trials in relieving pruritus for patients refractory to other treatments. Patients with pruritus associated with Sézary syndrome, mycosis fungoides, lung adenocarcinoma, breast carcinoma, sarcomas, metastatic solid tumors, chronic kidney disease, hyperuricemia, iron deficiency, brachioradial pruritus, and Hodgkin's lymphoma have experienced considerable symptom relief with short-term use of aprepitant (up to two weeks). Due to differences in reporting and evaluation of drug effects, the mechanism of aprepitant's role is difficult to understand based on the current literature. Herein, we evaluate aprepitant's antipruritic effects and discuss its mechanism of action and adverse effects. We propose that aprepitant is an alternative for patients suffering from pruritus who do not obtain enough symptom relief from conventional therapy.

Topics: Antiemetics; Aprepitant; Chronic Disease; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Pruritus; Quality of Life

In this work, data from two phase III studies were pooled to further evaluate the NK(1) antagonist aprepitant for prevention of cisplatin induced nausea and vomiting. One thousand and forty three patients receiving cisplatin (> or = 70 mg/m2) were randomised to receive either a control regimen (32 mg intravenous ondansetron [O] and 20 mg oral dexamethasone [D] on day 1; 8 mg D twice daily on days 2-4) or an aprepitant (A) regimen (125 mg A plus 32 mg O and 12 mg D on day 1, 80 mg A and 8 mg D once daily on days 2-3, and 8 mg D on day 4). The primary endpoint was no emesis and no rescue therapy. Potential correlations between acute and delayed emesis were assessed, as were frequency of emetic episodes by time interval and effects on nausea and quality of life as measured by the functional living index emesis (FLIE) questionnaire. In the aprepitant group, there was statistically significantly less nausea over the study period as well as higher functioning on the FLIE questionnaire in both the nausea and vomiting domains. Patients without acute emesis were more likely to have no emesis in the delayed phase. Compared with control, the aprepitant regimen improved prevention of delayed emesis by 16% points in patients without acute emesis, and by 17% points in patients with acute emesis. Among patients who did not have complete response, the frequency of emesis at various intervals over 5 days was consistently lower in patients receiving aprepitant. Analyses of this combined Phase III population further characterized the clinical profile of the aprepitant regimen, showing that delayed emesis is correlated with, but not entirely dependent on, the presence of acute emesis, and that aprepitant has a favorable effect against nausea throughout 5 days postchemotherapy. In addition, even among patients who had emesis or needed rescue therapy, aprepitant was associated with a lower frequency of these events compared with the control regimen.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Aprepitant; Chronic Disease; Cisplatin; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Morpholines; Multicenter Studies as Topic; Nausea; Randomized Controlled Trials as Topic; Treatment Outcome; Vomiting

Substance P (SP) and its receptor neurokinin 1 (NK1R) are thought to be involved in the pathogenesis of chronic prurigo. Here, we assessed SP serum levels, cutaneous NK1R expression, and the effects of topical aprepitant, an NK1R antagonist, in patients with chronic prurigo. SP and NK1R were increased, compared with controls, in the serum and in lesional vs. non-lesional skin of the patients, respectively. Aprepitant, in a randomized, placebo-controlled, split-sided, doubleblind trial, reduced the intensity of pruritus as assessed by visual analogue scale by >50% from baseline to day 28 (-35.2), but so did placebo vehicle (-38.1, p= 0.76). Overall clinical scores improved significantly by day 28 in both treatment groups, with no significant difference between the 2 groups (p=0.32). Our findings imply that both SP and NK1R are involved in the pathogenesis of chronic prurigo. Parallel groupdesigned trials are needed to assess the efficacy of topical aprepitant treatment in this condition.

Topics: Administration, Cutaneous; Aged; Aprepitant; Case-Control Studies; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Morpholines; Neurokinin-1 Receptor Antagonists; Proof of Concept Study; Prospective Studies; Prurigo; Pruritus; Receptors, Neurokinin-1; Severity of Illness Index; Substance P; Visual Analog Scale

There are few effective treatments for nausea and other symptoms in patients with gastroparesis and related syndromes. We performed a randomized trial of the ability of the neurokinin-1 receptor antagonist aprepitant to reduce symptoms in patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome.. We conducted a 4-week multicenter, double-masked trial of 126 patients with at least moderate symptoms of chronic nausea and vomiting of presumed gastric origin for a minimum of 6 months. Patients were randomly assigned to groups given oral aprepitant (125 mg/day, n = 63) or placebo (n = 63). The primary outcome from the intention-to-treat analysis was reduction in nausea, defined as a decrease of 25 mm or more, or absolute level below 25 mm, on a daily patient-reported 0-to-100 visual analog scale (VAS) of nausea severity. We calculated relative risks of nausea improvement using stratified Cochran-Mental-Haenszel analysis.. Aprepitant did not reduce symptoms of nausea, based on the primary outcome measure (46% reduction in the VAS score in the aprepitant group vs 40% reduction in the placebo group; relative risk, 1.2; 95% CI, 0.8-1.7) (P = .43). However, patients in the aprepitant group had significant changes in secondary outcomes such as reduction in symptom severity (measured by the 0-5 Gastroparesis Clinical Symptom Index) for nausea (1.8 vs 1.0; P = .005), vomiting (1.6 vs 0.5; P = .001), and overall symptoms (1.3 vs 0.7; P = .001). Adverse events, predominantly mild or moderate in severity grade, were more common in aprepitant (22 of 63 patients, 35% vs 11 of 63, 17% in the placebo group) (P = .04).. In a randomized trial of patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome, aprepitant did not reduce the severity of nausea when reduction in VAS score was used as the primary outcome. However, aprepitant had varying effects on secondary outcomes of symptom improvement. These findings support the need to identify appropriate patient outcomes for trials of therapies for gastroparesis, including potential additional trials for aprepitant. ClinicalTrials.gov no: NCT01149369.

Topics: Adult; Antiemetics; Aprepitant; Chronic Disease; Double-Blind Method; Female; Gastroparesis; Humans; Male; Middle Aged; Morpholines; Nausea; Treatment Outcome; Vomiting

Topics: Aprepitant; Chronic Disease; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Pruritus; Sezary Syndrome

Chronic pruritus is a global clinical problem with a high impact on the quality of life and lack of specific therapies. It is an excruciating and frequent symptom of e.g. uncurable renal, liver and skin diseases which often does not respond to conventional treatment with e.g. antihistamines. Therefore antipruritic therapies which target physiological mechanisms of pruritus need to be developed. Substance P (SP) is a major mediator of pruritus. As it binds to the neurokinin receptor 1 (NKR1), we evaluated if the application of a NKR1 antagonist would significantly decrease chronic pruritus.. Twenty hitherto untreatable patients with chronic pruritus (12 female, 8 male; mean age, 66.7 years) were treated with the NKR1 antagonist aprepitant 80 mg for one week. 16 of 20 patients (80%) experienced a considerable reduction of itch intensity, as assessed by the visual analog scale (VAS, range 0 to 10). Considering all patients, the mean value of pruritus intensity was significantly reduced from 8.4 VAS points (SD +/-1.7) before treatment to 4.9 VAS points (SD +/-3.2) (p<0.001, CI 1.913-5.187). Patients with dermatological diseases (e.g. atopic diathesis, prurigo nodularis) had the best profit from the treatment. Side-effects were mild (nausea, vertigo, and drowsiness) and only occurred in three patients.. The high response rate in patients with therapy refractory pruritus suggests that the NKR1 antagonist aprepitant may indeed exhibit antipruritic effects and may present a novel, effective treatment strategy based on pathophysiology of chronic pruritus. The results are promising enough to warrant confirming the efficacy of NKR1 antagonists in a randomized, controlled clinical trial.

Topics: Aged; Aged, 80 and over; Aprepitant; Chronic Disease; Female; Humans; Male; Middle Aged; Morpholines; Pruritus; Receptors, Neurokinin-1; Treatment Outcome