Use Of Neurokinin-1 Receptor Antagonists Research Articles

Triple Negative Breast Cancer: How Neurokinin-1 Receptor Antagonists Could Be Used as a New Therapeutic Approach.

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females. BC cells not showing HER-2/Neu amplification and not expressing estrogen/ progesterone receptors are named triple-negative BC (TNBC) cells. TNBC represents 10-15% of all BC and is associated with an aggressive clinical course. TNBC patient prognosis, survival and response to current therapies are poor and for this reason, it is crucial to search for new therapeutic targets in TNBC to develop new therapeutic strategies. One of these targets is the neurokinin-1 receptor (NK-1R). It is well known that the substance P (SP)/NK-1R system is involved in cancer progression. TNBC cells overexpress the NK-1R and, after binding to this receptor, SP promotes the proliferation/ migration of TNBC cells. Non-peptide NK-1R antagonists (e.g., aprepitant) are known to exert, via the NK-1R, an antitumor action; TNBC cells die by apoptosis. In this review, we update the data on a promising therapeutic innovation: the use of NK-1R antagonists for the treatment of TNBC patients.

Neurokinin-1 Receptor Antagonists against Hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant liver tumor that occurs during childhood. The prognosis of children with HB is favorable when a complete surgical resection of the tumor is possible, but for high-risk patients, the prognosis is much worse. New anti-HB strategies must be urgently developed. The undecapeptide substance P (SP) after binding to the neurokinin-1 receptor (NK-1R), regulates cancer cell proliferation, exerts an antiapoptotic effect, induces cell migration for invasion/metastasis, and triggers endothelial cell proliferation for neoangiogenesis. HB samples and cell lines overexpress NK-1R (the truncated form) and SP elicits HB cell proliferation. One of these strategies could be the use of non-peptide NK-1R antagonists. These antagonists exert, in a concentration-dependent manner, an antiproliferative action against HB cells (inhibit cell proliferation and induce the death of HB cells by apoptosis). NK-1R antagonists exerted a dual effect in HB: Decreased both tumor volume and angiogenic activity. Thus, the SP/NK-1R system is an important target in the HB treatment and NK-1R antagonists could act as specific drugs against HB cells. In this review, we update and discuss the use of NK-1R antagonists in the treatment of HB.

Substance P and neurokinin 1 receptor are new targets for the treatment of chronic pruritus.

Chronic pruritus is a distressing symptom associated with various dermatological conditions and systemic diseases. Current treatment options are often inadequate, resulting in impaired quality of life for many patients. An understanding of the underlying mechanisms of itch across pruritic conditions is important for development of effective, targeted treatments for chronic pruritus. To provide an overview of the pathogenesis of chronic pruritus, focusing on the role of substance P (SP) and neurokinin 1 receptor (NK1 R) in itch signalling, and to describe data supporting NK1 R antagonism as a potential strategy for the treatment of chronic pruritus. A PubMed search was conducted to determine what data were available that investigated the role of SP and NK1 R in itch signalling. SP is a neuropeptide that is a mediator of itch signalling. One of the target receptors for SP is NK1 R, which is expressed in the central nervous system and on multiple cell types involved in the initiation and transmission of itch. Studies demonstrating that SP and NK1 R are overexpressed across multiple chronic itch-inducing conditions and that NK1 R antagonism disrupts itch signalling and reduces itch provide a rationale for targeting this pathway as a potential treatment of chronic pruritus across multiple diseases. A large and growing body of evidence, including recent phase II clinical studies of NK1 R antagonists, demonstrate that SP and NK1 R play an important role in itch signalling. Additional studies are ongoing to further evaluate the use of NK1 R antagonists for the treatment of chronic pruritus. What's already known about this topic? Chronic pruritus has a significant impact on quality of life. Current treatment options for chronic pruritus are inadequate. Substance P (SP) and neurokinin 1 receptor (NK1 R) have been shown to play a role in itch signalling, and may be a rational target for addressing chronic pruritus. NK1 R antagonists are being evaluated as potential treatment for chronic pruritus. What does this study add? This review provides a compilation of the most up-to-date data elucidating the role of SP and NK1 R in itch signalling, which supports targeting this pathway as a potential treatment of chronic pruritus. NK1 R antagonism disrupts itch signalling and reduces itch. A summary of the latest data on NK1 R antagonists in the treatment of pruritus is provided.

Factors associated with neurokinin-1 receptor antagonist use among commercially insured cancer patients receiving highly emetogenic chemotherapy.

24 Background: Neurokinin-1 receptor antagonists (NK1RA) reduce chemotherapy-induced nausea/vomiting (CINV) among patients undergoing highly emetogenic chemotherapy (HEC). We evaluated factors associated with the use of NK1RA in patients treated with HEC. Methods: We performed a retrospective cohort study using Truven Health Marketscan to identify subjects who initiated HEC (doxorubicin or cisplatin) between 2009 and 2013, and concurrently received a NK1RA. Multivariable logistic regression was used, to determine the association of clinical and demographic factors and NK1RA use. Results: Of 32,004 subjects with cancer who were treated with either doxorubicin or cisplatin-containing regimens, 11,325 (33.3%) did not receive an NK1RA. From 2009 to 2013, NK1RA use increased from 53.2% to 73.5% (p < 0.0001). Compared to non-users, NK1RA users were more frequently treated with cisplatin-based regimens (67.9% vs. 32.1%, p < 0.0001), had in-network claims (66.7% vs. 33.3%, p < 0.0001), were younger, and without other comorbidities. Multivariate analysis demonstrated that NK1RA use was more likely with cisplatin compared to doxorubicin (OR = 1.71, 95% CI 1.62-1.81) and with female compared to male patients (OR = 1.75, 95% CI 1.65-1.84). In-network claims (OR 1.26, 95% CI 1.16-1.36) and comprehensive benefit plans (OR = 1.14, 95% CI 1.04-1.25) were associated with increased NK1RA use, compared to out-of network claims and preferred provider organizations (PPO), respectively. Age ≥ 65 years (OR = 0.64, 95% CI 0.5-0.69) and increased comorbidities (comorbidity score of 1: OR 0.88, 95% CI 0.83-0.94; score of 2- OR 0.61, 95% CI 0.56-0.67) versus a score of 0 were associated with decreased NK1RA use. Conclusions: A substantial proportion of patients receiving HEC do not receive NK1RA, and type of insurance coverage was associated with receipt.

Efficacy and Safety of Neurokinin-1 Receptor Antagonists for Prevention of Chemotherapy-Induced Nausea and Vomiting: Systematic Review and Meta-analysis of Randomized Controlled Trials

Can addition of neurokinin-1 receptor antagonists (NK1-RAs) be considered as an ideal strategy for the prevention of chemotherapy-induced nausea and vomiting (CINV)? Researchers differ on this question. Electronic databases were searched for randomized control trials (RCTs) that evaluated the effectiveness and safety of NK1-RAs in preventing CINV. The primary end point was complete response (CR) in the acute, delayed, and overall phases after chemotherapy. Subgroup analyses evaluated the types of NK1-RAs, routines of administration, types of malignancies, regimens used in combination with NK1-RAs, and age of patients included in the studies. The incidences of different types of adverse events were also extracted to estimate the safety of NK1-RAs. A total of 38 RCTs involving 13,923 patients were identified. The CR rate of patients receiving NK-RAs was significantly higher than patients in the control groups during overall phase (70.8% vs 56.0%, <0.001), acute phase (85.1% vs 79.6%, <0.001), and delayed phase (71.4% vs 58.2%, <0.001). There were three studies including patients of children or adolescents, the CR rate was also significantly higher in the treatment group (overall phase: OR=2.807, <0.001; acute phase: OR=2.863, P =0.012; delayed phase: OR=2.417, <0.001). For all the other outcomes, patients in the NK1-RAs groups showed improvements compared to the control groups (incidence of nausea: 45.2% vs 45.9%, <0.001; occurrence of vomiting: 22.6% vs 38.9%, <0.001; usage of rescue drugs: 23.5% vs 34.1%, <0.001). The pooled side effects from NK1-RAs did not significantly differ from previous reports and the toxicity rates in patients less than eighteen years old also did not diff between the two groups (P=0.497). However, we found that constipation and insomnia were more common in the patients of control groups, whereas diarrhea and hiccups were more frequently detected in patients receiving NK1-RAs. NK1-RAs improved the CR rate of CINV. They are effective for both adults and children. The use of NK1-RAs might be associated with the appearance of diarrhea and hiccups, while decreasing the possibility of constipation and insomnia.

Investigating racial disparities in use of NK1 receptor antagonists to prevent chemotherapy-induced nausea and vomiting among women with breast cancer.

Chemotherapy-induced nausea and vomiting (CINV) is a major concern for cancer patients and, if uncontrolled, can seriously compromise quality of life (QOL) and other treatment outcomes. Because of the expense of antiemetic medications used to prevent CINV (particularly oral medications filled through Medicare Part D), disparities in their use may exist. We used 2006-2012 SEER-Medicare data to evaluate the use of neurokinin-1 receptor antagonists (NK1s), a potent class of antiemetics, among black and white women initiating highly emetogenic chemotherapy for the treatment of early-stage breast cancer. We used modified Poisson regression to assess the relationship between race and (1) any NK1 use, (2) oral NK1 (aprepitant) use, and (3) intravenous NK1 (fosaprepitant) use. We report adjusted risk ratios (aRR) and 95% confidence intervals (CI). The study included 1130 women. We observed racial disparities in use of any NK1 (aRR: 0.68, 95% CI 0.51-0.91) and in use of oral aprepitant specifically (aRR: 0.54, 95% CI 0.35-0.83). We did not observe disparities in intravenous fosaprepitant use. After controlling for variables related to socioeconomic status, disparities in NK1 and aprepitant use were reduced but not eliminated. We found racial disparities in women's use of oral NK1s for the prevention of CINV. These disparities may be partly explained by racial differences in socioeconomic status, which may translate into differential ability to afford the medication.

Involvement of substance P and the NK-1 receptor in human pathology

The peptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems, but it is also present in cells not belonging to the nervous system (immune cells, liver, lung, placenta, etc.). SP is located in all body fluids, such as blood, cerebrospinal fluid, breast milk, etc. i.e. it is ubiquitous in human body. After binding to the neurokinin-1 (NK-1) receptor, SP regulates many pathophysiological functions in the central nervous system, such as emotional behavior, stress, depression, anxiety, emesis, vomiting, migraine, alcohol addiction, seizures and neurodegeneration. SP has been also implicated in pain, inflammation, hepatitis, hepatotoxicity, cholestasis, pruritus, myocarditis, bronchiolitis, abortus, bacteria and viral infection (e.g., HIV infection) and it plays an important role in cancer (e.g., tumor cell proliferation, antiapoptotic effects in tumor cells, angiogenesis, migration of tumor cells for invasion, infiltration and metastasis). This means that the SP/NK-1 receptor system is involved in the molecular bases of many human pathologies. Thus, knowledge of this system is the key for a better understanding and hence a better management of many human diseases. In this review, we update the involvement of the SP/NK-1 receptor system in the physiopathology of the above-mentioned pathologies and we suggest valuable future therapeutic interventions involving the use of NK-1 receptor antagonists, particularly in the treatment of emesis, depression, cancer, neural degeneration, inflammatory bowel disease, viral infection and pruritus, in which that system is upregulated.

The Role of Neurokinin-1 Receptor in the Microenvironment of Inflammation and Cancer

The recent years have witnessed an exponential increase in cancer research, leading to a considerable investment in the field. However, with few exceptions, this effort has not yet translated into a better overall prognosis for patients with cancer, and the search for new drug targets continues. After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers a wide variety of functions. Antagonists against the NK-1 receptor are safe clinical drugs that are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects. Recently, it has become apparent that SP can induce tumor cell proliferation, angiogenesis, and migration via the NK-1 receptor, and that the SP/NK-1 receptor complex is an integral part of the microenvironment of inflammation and cancer. Therefore, the use of NK-1 receptor antagonists as a novel and promising approach for treating patients with cancer is currently under intense investigation. In this paper, we evaluate the recent scientific developments regarding this receptor system, its role in the microenvironment of inflammation and cancer, and its potentials and pitfalls for the usage as part of modern anticancer strategies.

Use of Neurokinin-1 Receptor Antagonists in Patients Receiving Moderately or Highly Emetogenic Chemotherapy

Chemotherapy-induced nausea and vomiting (CINV) is a serious adverse effect of chemotherapy that limits patients' physical, mental, and functional capabilities and may cause a delay or cessation of treatment. Antiemetic therapy can reduce the incidence of CINV. Research, using data from visits by patients receiving moderately (MEC) or highly emetogenic chemotherapy (HEC), identified that antiemetics were prescribed for 86% (in 2007) and 82% (in 2008) of patients receiving MEC or HEC. For these visits, 5-hydroxytryptamine-3 receptor antagonists were prescribed in at least 97% of visits for both years, whereas neurokinin-1 (NK-1) receptor antagonists were prescribed at a rate of 10% and 11%, respectively. Studies show that nurses and physicians underestimate the incidence of CINV after HEC and MEC. Oncology nurses often critically influence patients' selection of CINV therapy and can play a significant role in increasing awareness about the benefits of adding an NK-1 receptor antagonist to standard prophylactic regimens for acute and delayed CINV.

Neurokinin-1 receptor antagonist (aprepitant) suppresses HIV-1 infection of microglia/macrophages.

Neurokinin-1 receptor (NK-1R) antagonists suppress HIV-1 infection of macrophages in vitro. We have further investigated the anti-HIV-1 activity of aprepitant, a Food and Drug Administration-approved NK-1R antagonist, and its cytotoxic effect in the macrophage/microglia system. Aprepitant inhibited infection of macrophages with primary HIV-1 R5 strains (subtypes A, D, and H; UG275, BZ163, and BCF-KITA), while it had little effect on primary HIV-1 X4 strains (subtypes B and D, BZ167 and SE365). Aprepitant, when added to microglia cultures infected with CSF-derived HIV-1 strains (JAGO or JRFL), significantly inhibited viral replication. Aprepitant also enhanced the anti-HIV-1 activity of enfuvirtide (an HIV-1 fusion inhibitor) in HIV-1-infected macrophages. Over a concentration range of 10(-9) to 10(-5) M, aprepitant had little cytotoxic effect (less than 10%) on macrophages during the in vitro cultures. Autologous human serum (< or =20%) had little effect on the anti-HIV-1 activity of aprepitant in macrophages. These observations provide additional evidence to support the potential use of NK-1R antagonists as therapeutic and immunomodulatory agents for the treatment of HIV-1 infection.

A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage

In the present review we discuss a central role for substance P (SP) in carcinogenesis. We suggest that one mechanism to induce mitogenesis of tumor cells is the activation of neurokinin-1 receptor (NK1R) through SP, linking cancer promotion and progression to a neurokinin-mediated environment. After reviewing the role of both SP and its receptor NK1R in normal and neoplastic cells we propose the use of neurokinin-1 receptor antagonists as a novel and promising approach for treating patients with cancer.

Potential therapeutic targets for neurokinin-1 receptor antagonists

The peptide substance P and its tachykinin receptor, neurokinin-1 (NK1), have been the focus of considerable research for their role in a variety of both central and peripheral diseases. Recent preclinical data, as well as relevant clinical findings, support the potential therapeutic value of NK1 receptor antagonists in centrally mediated disease states, including anxiety and depression. In addition, a separate body of literature supports the use of NK1 receptor antagonists as inhibitors of centrally mediated emetic and cough responses. The role of NK1 receptor antagonists as analgesic agents with potential to treat migraine headache has also been investigated. NK1 receptors are also found in a number of peripheral regions, including the bladder, gastrointestinal tract and bone marrow. Preclinical models have been employed to address the potential therapeutic uses for NK1 receptor antagonists in diseases associated with inflammatory responses, including asthma, irritable bowel syndrome and cystitis of the bladder. Finally, other more recent publications suggest a role for NK1 receptor antagonists as tumour suppressants and haematopoietic agents. These applications for NK1 receptor antagonists are discussed in this review.