Neurokinin receptor antagonism: a patent review (2014-present).

INTRODUCTION: The tachykinin family of peptides (substance P, neurokinin A) via the neurokinin-1 (NK-1), NK-2, and NK-3 receptors is involved in many physiological/physiopathological actions. Antagonists of these receptors may be used to treat many human pathologies. AREAS COVERED: This review offers an overview (from 2014 to present) of the actions exerted by NK receptor (NK-R) antagonists on emesis, pruritus, cardiomyopathy, respiratory tract diseases, bacterial infection, cancer, ocular pain, corneal neovascularization, excess of body fat/weight, conditioned fear, social isolation stress, hot flush, melanogenesis, follicle development, fish reproduction, and sex-hormone-dependent diseases. EXPERT OPINION: From 2014, no invention has been published using NK-2R antagonists. Although the tachykinin/NK receptor system is involved in a great number of mechanisms, to date, the use of only five NK-1R antagonists have been approved in humans but no NK-2R or NK-3R antagonist. NK receptor antagonists are safe in human trials and are potential therapeutic agents, but this potential is currently minimized. In humans, more studies on molecules acting as NK receptor antagonists and exerting a potential therapeutic action must be carried out. The antipruritic or antitumor action of NK-1R antagonists must be explored in greater depth: the highest safe dose and the time of administration (for a long period of time) of these antagonists must be well established.

Eugenol and liposome-based nanocarriers loaded with eugenol protect against anxiolytic disorder via down regulation of neurokinin-1 receptors in mice.

Anxiety disorder is a psychiatric disorder characterized by extreme fear or worry. It is highly prevalent worldwide which affects daily life and is also an enormous health burden. Neurokinin 1 receptor (NK1R) is a G protein coupled receptor, expressed in both central and peripheral nervous system, involved in affective behaviors. NK1R has established role in anxiety and it is also an important target for pathogenesis of anxiety disorder. Therefore, it has been hypothesized in previous studies that the blockades of NK1R may have antidepressant and anxiolytic effects. The present study deals with the molecular mechanism of protective activity of eugenol against anxiolytic disorder. A pre-clinical animal study was performed on 42 BALB/c mice. Animals were given stress through conventional restrain model. The mRNA expression of NK1R was analyzed by real time RT-PCR. Moreover, the NK1R protein expression was also examined by immunohistochemistry in whole brain and mean density was calculated. The mRNA and protein expressions were found to be increased in animals given anxiety as compared to the normal control. Whereas, the expressions were decreased in the animals treated with eugenol and its liposome-based nanocarriers in a dose dependent manner. However, the results were better in animals treated with nanocarriers as compared to the compound alone. It is concluded that the eugenol and its liposome-based nanocarriers exert anxiolytic activity by down-regulating NK1R protein expression in mice.

Emerging targets for cough therapies; NK1 receptor antagonists.

Cough is mediated by vagal afferent fibres innervating the larynx and proximal airways. Pre-clinical studies suggest that vagal C fibres produce Substance P, one of the tachykinin family of neuropeptides, which has been shown to enhance cough via the neurokinin-1 (NK-1) receptor and studies in animal models have also shown that NK-1 antagonists are effective at blocking induced cough. In the past, tachykinin receptor antagonists have yielded disappointing results in treating asthma and cough, however most of the activity of the agents tested was restricted to the peripheral nervous system and also the outcomes measures evaluating cough not optimal. More recently a small proof of concept study has suggest that aprepitant, an NK-1 antagonist licensed for the prevention of chemotherapy induced nausea and vomiting, might have beneficial effects on cough frequency in patients with lung cancer. In this review we investigate the current evidence for the anti-tussive effect of these therapies and the clinical trials in progress.

The NK1 receptor antagonist serlopitant for treatment of chronic pruritus.

Introduction: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK1) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin. Areas covered: This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK1 receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies. Expert opinion: There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.

One shot NEPA plus dexamethasone to prevent multiple-day chemotherapy in sarcoma patients.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared and disturbing adverse events of cancer treatment associated with decreased adherence to effective chemotherapy regimens. For high-risk soft tissue sarcoma patients, receiving multiple-day chemotherapy (MD-CT), antiemetic guidelines recommend a combination of an NK1 receptor antagonist (NK1-RA), a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone on each day of the antineoplastic treatment. NEPA is the first oral fixed-dose combination of a highly selective NK1-RA, netupitant, and second-generation 5HT3-RA, palonosetron. So far, no data has been published in literature about the efficacy of a single dose of NEPA in MD-CT. METHODS: We performed a prospective, non-comparative study to assess the efficacy of one shot of NEPA plus dexamethasone in sarcoma patients receiving MD-CT. The primary efficacy endpoint was a complete response (CR: no emesis, no rescue medication) during the overall phase (0-120 h) in cycle 1. The main secondary endpoints were CR during the overall phase of cycles 2 and 3. RESULTS: The primary endpoint was reached in 88.9% of patients. Cycles 2 and 3 overall CR rates were 88.9% and 82.4%, respectively. The antiemetic regimen was well tolerated. CONCLUSIONS: This pilot study showed the benefit of one shot of NEPA to prevent CINV in sarcoma patients receiving MD-chemotherapy.

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.

Tropisetron attenuates lipopolysaccharide induced neuroinflammation by inhibiting NF-κB and SP/NK1R signaling pathway.

Tropisetron, an antagonist of serotonin type 3 receptors (5-HT3Rs), has been investigated in colonic inflammatory process. Since substance P/neurokinin 1 receptor (SP/NK1R) signaling pathway plays a key role in several sensory neuronal inflammatory. We evaluated the anti-inflammatory activity of tropisetron in mice cerebral cortex, and discovered that it was a potential inhibitor in LPS-mediated neuron inflammation through SP/NK1R signaling pathway. We found that tropisetron significantly reduced the increased number of iba-1 positive microglia, down-regulated the gene transcription and protein expression of IL-1ß,IL-6 and TNF-α in LPS stimulated cerebral cortex. To characterize the inhibitory mechanism of tropisetron at the SP response in inflammation, we further examined the effect of tropisetron on NF-κB and SP/NK1R signaling pathway in the process of mice cerebral cortex inflammation. We found that tropisetron inhibited the gene transcription and protein expression of NF-κB, SP, NK1R via inhibiting 5-HT3R activity. These findings might provide new insights into the anti-inflammatory activities of 5-HT3R inhibitor tropisetron, which would be the interaction of serotonin receptor signaling and SP/NK1R pathway. These might highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.

Botulinum toxin type A and gabapentin attenuate postoperative pain and NK1 receptor internalization in rats.

Treatment of postoperative pain remains a challenge in clinic. Botulinum toxin type A (BoNT/A) and gabapentin regulate the release of neurotransmitters from primary afferent neurons, but their effects of on postoperative pain are not clear. In the current study, using pain behavioral tests, Western blot analysis, and immunocytochemistry, we examined whether BoNT/A, alone or in combination with intrathecal gabapentin, inhibited pain hypersensitivity and attenuated the increase in neurokinin 1 (NK1) receptor internalization in dorsal horn neurons after plantar incision. Our data showed that pretreatment of rats with an intraplantar (2 U) 24 h before plantar incision or intrathecal (0.5 U) injection of BoNT/A 48 h before plantar incision induced a prolonged (3-5 days) decrease in pain scores and mechanical hypersensitivity, as compared to those observed with saline pretreatment. Both intraplantar and intrathecal BoNT/A pretreatment reduced synaptosomal-associated protein 25 levels in the ipsilateral lumbar dorsal root ganglia and spinal cord dorsal horn, and attenuated the increase in NK1 receptor internalization in dorsal horn neurons. Intrathecal administration of a sub-effective dose of gabapentin (50 µg) with BoNT/A (0.5 U) induced greater inhibition of pain hypersensitivity and NK1 receptor internalization than BoNT/A alone. These findings suggest that pretreatment with BoNT/A, alone or in combination with intrathecal gabapentin, may present a promising multimodal analgesia regimen for postoperative pain treatment.

Substance P and dopamine interact to modulate the distribution of delta-opioid receptors on cholinergic interneurons in the striatum.

It has been recently demonstrated that predictive learning induces a persistent accumulation of delta-opioid receptors (DOPrs) at the somatic membrane of cholinergic interneurons (CINs) in the nucleus accumbens shell (Nac-S). This accumulation is required for predictive learning to influence subsequent choice between goal-directed actions. The current experiments investigated the local neurochemical events responsible for this translocation. We found that (1) local administration of substance P into multiple striatal sub-territories induced DOPr translocation and (2) that this effect was mediated by the NK1 receptor, likely through its expression on CINs. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro-APB reduced the DOPr translocation on CINs and infusion of the D2 agonist quinpirole had no effect, co-administration of both agonists again generated DOPr translocation, suggesting the effect of the D1 agonist alone was due to receptor internalisation. In support of this, local administration of cocaine was found to increase DOPr translocation as was chloro-APB when co-administered with the DOPr antagonist naltrindole. These studies provide the first evidence of delta-opioid receptor translocation in striatal cholinergic interneurons outside of the accumbens shell and suggest that, despite differences in local striatal neurochemical microenvironments, a similar molecular mechanism - involving an interaction between dopamine and SP signalling via NK1R - regulates DOPr translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOPr distribution is regulated that may be particularly relevant to learning-induced DOPr trafficking.

Altered circadian feeding behavior and improvement of metabolic syndrome in obese Tac1-deficient mice.

BACKGROUND: Metabolic function is regulated by the interplay of central and peripheral factors that ultimately regulate food intake (FI) and energy expenditure. The tachykinin substance P (SP) has been identified as a novel regulator of energy balance, however, the mechanisms underlying this effect are ill-defined and conflicting data regarding the role of SP on FI have been reported by different groups. OBJECTIVE: To further characterize the metabolic role of the Tac1 gene products (SP and neurokinin A) in mice through a series of genetic, metabolic and behavioral studies in Tac1-deficient mice. RESULTS: Tac1-/- mice are leaner than controls and display reduced FI and altered feeding circadian rhythm, supported by disrupted expression of the clock genes Cry1/2, Per1/2 in the suprachiasmatic nucleus, mediobasal hypothalamus (MBH) and liver, as well as increased proopiomelanocortin expression in the MBH. Tac1 ablation induced resistance to obesity, improved glucose tolerance, prevented insulin resistance under high-fat diet, increased activation of brown adipose tissue and improved hepatic steatosis. Moreover, deletion of Tac1 in ob/ob mice ameliorated body weight gain in females only but was sufficient to decrease fat and triglyceride content in the liver of males. CONCLUSIONS: These results provide further evidence that Tac1 controls circadian feeding behavior and metabolism in mice through mechanisms that involve the regulation of the melanocortin system. In addition, these studies suggest that the blockade of SP may offer a new method to treat metabolic syndrome.

Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant.

Aprepitant, an NK1 receptor antagonist, is approved for the treatment of chemotherapy-induced or postoperative emesis by blocking NK1 receptors in the brain stem vomiting center. The effects of NK1 receptors on gastric functions and postprandial symptoms in humans are unclear; a single, crossover study did not show a significant effect of aprepitant on gastrointestinal transit. Our aim was to compare, in a randomized, double-blind, placebo-controlled, parallel-group study (12 healthy volunteers per group), the effects of aprepitant vs. placebo on gastric emptying of solids (by scintigraphy) with a 320-kcal meal, gastric volumes (GVs; fasting and accommodation by single photon emission-computed tomography ), satiation [maximum tolerated volume (MTV)], and symptoms after a dyspeptogenic meal of Ensure. Aprepitant (125 mg on day 1, followed by 80 mg on days 2-5) or placebo, one tablet daily, was administered for 5 consecutive days. Statistical analysis was by unpaired rank sum test, adjusted for sex difference and body mass index. To assess treatment effects on symptoms, we incorporated MTV in the model. Aprepitant increased fasting, postprandial, and accommodation GV and tended to increase volume to fullness and MTV by ~200 kcal. However, aprepitant increased aggregate symptoms, nausea, and pain scores after ingestion the MTV of Ensure. There was no significant effect of aprepitant on gastric half-emptying time of solids. We conclude that NK1 receptors are involved in the control of GV and in determining postprandial satiation and symptoms. Further studies of the pharmacodynamics and therapeutic role of NK1 receptor antagonists in patients with gastroparesis and dyspepsia are warranted.NEW & NOTEWORTHY Aprepitant increases fasting, postprandial, and accommodation gastric volumes. Aprepitant increases volume to fullness and maximum tolerated volume during a nutrient drink test. NK1 receptors are involved in the control of gastric volume and in determining postprandial satiation and symptoms.

Analgesic Properties of Opioid/NK1 Multitarget Ligands with Distinct in Vitro Profiles in Naive and Chronic Constriction Injury Mice.

The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed. Structure-activity studies were performed on opioid agonist/NK1 receptor antagonist hybrid peptides by modification of the C-terminal amide substituents. All compounds were evaluated for their affinity and in vitro activity at the mu opioid (MOP) and delta opioid (DOP) receptors, and for their affinity and antagonist activity at the NK1 receptor. On the basis of their in vitro profiles, the analgesic properties of two new bifunctional hybrids were evaluated in naive and CCI-mice, representing models for acute and neuropathic pain, respectively. The compounds were administered to the spinal cord by lumbar puncture. In naive mice, the single pharmacophore opioid parent compounds provided better analgesic results, as compared to the hybrids (max 70% MPE), raising the acute pain threshold close to 100% MPE. On the other hand, the opioid parents gave poor analgesic effects under neuropathic pain conditions, while the best hybrid delivered robust (close to 100% MPE) and long lasting alleviation of both tactile and thermal hypersensitivity. The results presented emphasize the potential of opioid/NK1 hybrids in view of analgesia under nerve injury conditions.

Substance P promotes hepatic stellate cell proliferation and activation via the TGF-ß1/Smad-3 signaling pathway.

Prolonged activation and proliferation of hepatic stellate cells (HSCs) usually results in the initiation and progression of liver fibrosis following injury. Recent studies have shown that Substance P (SP) participates in the development of fibrosis. However, whether SP is involved in liver fibrosis, especially in the activation and proliferation of HSCs, is largely unknown. In the present study, we measured the effects of a series of concentrations of SP on the cell viability and activation of HSC-T6 cells and LX2 cells. The underlying mechanism was also investigated. We found that SP effectively increased cell viability, both in an MTT assay (p<0.05) and in a lactate dehydrogenase activity assay (LDH) (p<0.05). Moreover, SP upregulated the protein expression of α-SMA and Collagen I (both p<0.05) and decreased the release of lipid droplets (LDs) (p<0.05), all of which are associated with HSC activation. Apoptosis analysis revealed that SP can attenuate the increase of cell apoptosis induced by serum withdrawal (p<0.05). Furthermore, these effects were all blocked by an SP receptor antagonist, L732138. More importantly, L732138 decreased the activation of the TGF-ß1/Smad3 signaling pathway, which is highly associated with liver fibrosis. Taken together, our results demonstrate that SP can promote HSC proliferation and induce HSC activation via the TGF-ß1/Smad3 signaling pathway.

Antagonism of the Neurokinin-1 Receptor Improves Survival in a Mouse Model of Sepsis by Decreasing Inflammation and Increasing Early Cardiovascular Function.

OBJECTIVES: Sepsis remains a serious clinical problem despite intensive research efforts and numerous attempts to improve outcome by modifying the inflammatory response. Substance P, the principal ligand for the neurokinin-1 receptor, is a potent proinflammatory mediator that exacerbates inflammatory responses and cardiovascular variables in sepsis. DESIGN: The current study examined whether inhibition of the neurokinin-1 receptor with a specific antagonist (CJ-12,255) would improve survival in the cecal ligation and puncture model of sepsis in adult female outbred mice. SETTING: University basic science research laboratory. MEASUREMENTS AND MAIN RESULTS: Neurokinin-1 receptor treatment at the initiation of sepsis improved survival in cecal ligation and puncture sepsis (neurokinin-1 receptor antagonist survival = 79% vs vehicle = 54%). Delaying therapy for as little as 8 hours postcecal ligation and puncture failed to provide a survival benefit. Neurokinin-1 receptor antagonist treatment did not prevent the sepsis-induced decrease in circulating WBCs, augment the early (6 hr postcecal ligation and puncture) recruitment of inflammatory cells to the peritoneum, or improve phagocytic cell killing of pathogens. However, the neurokinin-1 receptor antagonist significantly reduced both circulating and peritoneal cytokine concentrations. In addition, the cardiovascular variable, pulse distension (a surrogate for stroke volume) was improved in the neurokinin-1 receptor antagonist group during the first 6 hours of sepsis, and there was a significant reduction in loss of fluid into the intestine. CONCLUSION: These data show that early activation of the neurokinin-1 receptor by substance P decreases sepsis survival through multiple mechanisms including depressing stroke volume, increasing fluid loss into the intestine, and increasing inflammatory cytokine production.

Neurokinin-1 receptor is a novel positive regulator of Wnt/ ß-catenin signaling in melanogenesis.

Wnt/ß-catenin signaling is essential for melanogenesis in melanocytes. Neurokinin-1 receptor (NK-1R) has recently been demonstrated to be involved in melanin production. However, the cross talk between NK-1R and Wnt/ß-catenin is poorly understood. Here, [Sar9, Met(O2)11] substance P (SMSP) was used to activate NK-1R, while L-733060 was used to inhibit it. The effects of NK-1R activation and inhibition on Wnt and its inhibitors were analyzed using western blot and real-time quantitative PCR. The results showed that SMSP positively regulated Wnt/ß-catenin signaling by increasing the expression of ß-catenin and p-GSK3ß protein, which resulted from the weakened expression of the Wnt inhibitor Dickkopf-1 (DKK1). On the contrary, L-733060 lowered the expression of ß-catenin and p-GSK3ß protein through the up-regulation of DKK1 expression. Furthermore, in L-733060-treated mice, it was found that the pigmentation level as well as the melanogenic proteins and ß-catenin protein expression were down-regulated, while the expression of DKK1 was up-regulated. These results showed the interaction between NK-1R and Wnt in human melanocytes in vitro and C57BL/6J mice in vivo, indicating that NK-1R may positively regulate melanogenesis through Wnt/ß-catenin signaling pathway.

Acute neurokinin-1 receptor antagonism fails to dampen airflow limitation or airway eosinophilia in an experimental model of feline asthma.

OBJECTIVES: Feline allergic asthma is a chronic inflammatory disorder of the lower airways that may manifest with acute, life-threatening clinical signs. Tachykinins released from sensory nerves and immune cells binding neurokinin (NK)-1, NK-2 and NK-3 receptors have been implicated in asthma pathogenesis. Maropitant, an NK-1 receptor antagonist, blocks neuroimmune pathways and may be a viable treatment option for cats in asthmatic crisis. Using an experimental chronic allergic feline asthma model, we hypothesized that a single dose of maropitant given immediately after allergen challenge would blunt clinical signs, airway hyperresponsiveness (AHR) and airway eosinophilia. METHODS: Cats (n = 7) induced to have an asthmatic phenotype using Bermuda grass allergen (BGA) were enrolled in a prospective, placebo-controlled crossover design study. Cats randomly received maropitant (2 mg/kg SC) or placebo (saline SC) immediately post-BGA challenge, followed 12 h later by pulmonary mechanics testing and measurement of airway eosinophils. After a 2 week washout, cats were crossed-over to the alternate treatment. Study endpoints included subjective clinical scoring systems post-BGA challenge, ventilator-acquired pulmonary mechanics to assess AHR after bronchoprovocation with methacholine and collection of bronchoalveolar lavage fluid to quantify airway eosinophilia. Data were analyzed using a Mann-Whitney rank sum test with P <0.05 considered significant. RESULTS: A single injection of maropitant failed to diminish clinical composite score (P = 0.902), visual analogue scale scoring (P = 0.710), AHR (P = 0.456) or airway eosinophilia (P = 0.165) compared with placebo. CONCLUSIONS AND RELEVANCE: A single injection of maropitant given immediately post-allergen challenge was ineffective at blunting clinical signs, AHR and airway eosinophilia, and cannot be recommended as treatment for feline status asthmaticus.

Pharmacogenetics of chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is associated with distressing adverse effects observed in patients during cytotoxic chemotherapy. One of the potential factors explaining suboptimal response to currently used antiemetics is variability in genes encoding enzymes and proteins that play a role in the action of antiemetic drugs. Pharmacogenomics studies of CINV are sparse and focus mainly on polymorphisms associated with serotonin receptor, drug metabolism and drug transport. Currently, the role of pharmacogenetics in mechanisms of CINV has not been fully unraveled, and it is premature to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice. More uniform studies, with genetic profiles and biomarkers relevant for the proposed target and transporter mechanisms, are needed.

Meta-analysis of adjunctive non-NK1 receptor antagonist medications for the control of acute and delayed chemotherapy-induced nausea and vomiting.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a distressing chemotherapy-induced symptom that may adversely impact the quality of life of cancer patients. METHODS: We conducted a systematic search of the Pubmed, Bireme, and Cochrane databases for randomized clinical trials that were published in English and that evaluated the combination of adjunctive non-neurokinin 1 (NK1) antagonist drugs (i.e., neuroleptics, anticonvulsants, benzodiazepines, and cannabinoids) with 5-hydroxytryptamine 3 (5-HT3) antagonists for adult cancer patients who were scheduled to receive moderate or highly emetogenic chemotherapy. We employed the Review Manager (RevMan) Computer program Version 5.2 for statistical calculations. RESULTS: We included 13 studies with a total of 1,669 patients. We observed a higher complete protection for acute CINV with adjunctive medications (risk ratio (RR) = 0.55; 95% confidence interval (CI) 0.30-1.01; p = 0.05; I2 = 47%), which was not the case for the delayed period (RR = 0.89; 95% CI 0.73-1.10, p = 0.29, I2 = 15%). We also observed that these adjunctive medications significantly increased the complete control of nausea (RR = 0.72; 95% CI 0.55-0.95; p = 0.02, I2 = 83%) and vomiting (RR = 0.61; 95% CI 0.50-0.75; p < 0.00001; I2 = 60%). There was no subgroup analysis evidence of the superiority of any single group of adjunctive medications. CONCLUSIONS: We conclude that adjunctive non-NK1 antagonist medications may be useful for CINV control. Prospective randomized studies incorporating these low-cost medications into new regimens combining 5-HT3 and NK1 antagonists may be warranted.