Emerging Therapeutic Options for Chronic Pruritus.

Chronic pruritus, defined as an unpleasant sensation resulting in a need to scratch that lasts more than 6 weeks, is a prevalent and bothersome symptom associated with both cutaneous and systemic conditions. Due to complex pathogenesis and profuse contributing factors, chronic pruritus therapy remains challenging. Regardless of the well-established antipruritic properties of classic pharmacotherapy (topical therapy, phototherapy and systemic therapy), these methods often provide insufficient relief for affected individuals. Owing to the growing interest in the field of pruritic research, further experimental and clinical data have emerged, continuously supporting the possibility of instigating novel therapeutic measures. This review covers the most relevant current modalities remaining under investigation that possess promising perspectives of approval in the near future, especially opioidergic drugs (mu-opioid antagonists and kappa-opioid agonists), neurokinin-1 receptor antagonists, biologic drugs, Janus kinase inhibitors, ileal bile acid transporter inhibitors, aryl hydrocarbon receptor agonists and histamine H4 receptor antagonists.

Emerging Treatments and Novel Pathways in Pruritus.

Itch treatment is a major challenge in the dermatologist's practice. We encounter patients suffering from pruritus on a regular basis, and often lack diverse treatment options to adequately respond to the patients' needs. In the last 20 years, novel pathways have been investigated that were beyond the scope of histamine. Although most did not result in a molecule available on the Canadian market, it is interesting and important as health care providers to stay up to date with new neuronal pathways involved in itch transmission and potential new therapeutic options. In this review, we will discuss pathways targeted in new topical treatments such as antagonist of proteinase-activated receptor-2, the endocannabinoid system, neurotrophins and tropomyosin-related kinase A receptor, the transient receptor potential-vanilloid or transient receptor potential-melastatine ion channels. New systemic therapies are now focusing on antagonizing the neurokinin receptor, modulating the opioidergic system, or targeting itch cytokines such as interleukin-31.

Evolution of antiemetic studies for radiation-induced nausea and vomiting within an outpatient palliative radiotherapy clinic.

PURPOSE: Radiation-induced nausea and vomiting (RINV) is a common side effect of radiotherapy and can affect up to 50-80% of patients, potentially causing detrimental effects to physical health, clinical efficacy, and patient quality of life. Antiemetic drugs act on receptors involved in the emesis pathway to block the uptake of neurotransmitters and inhibit stimulation of vomiting centers in the brain to prevent and treat RINV. The most commonly prescribed antiemetics for RINV are 5-hydroxytryptamine receptor antagonists (5-HT3 RA). Guidelines describing the optimal management of RINV are produced by the Multinational Association for Supportive Care in Cancer, the European Society of Medical Oncology, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network. This review will present findings from research on antiemetic management for RINV conducted at our center. METHODS: A selective review of research conducted in a palliative outpatient radiotherapy clinic relating to antiemetic management for RINV was performed. RESULTS: Several studies investigating the efficacy of different routes of administration, new antiemetic drug types, and novel combinations of antiemetics have been tested at our clinic to elucidate which approach provides the best response. These include studies on the use of ondansetron rapidly dissolving film, palonosetron, and the addition of a neurokinin-1 receptor antagonist to traditional 5-HT3 RA regimens. CONCLUSIONS: These studies provide a framework for future research and could potentially inform changes to future guidelines to include the use of these novel regimens and techniques.

Diagnosis and Management of Neuropathic Itch.

Neuropathic pruritus is a challenging condition that can be caused by injury or dysfunction in any part of the nervous system. A vast array of clinical pictures exist, including both localized and generalized pruritus, and their principal entities are described in this article. Diagnosis is often difficult and depends on patient history, imaging, and neurophysiologic studies. Other causes of chronic itch should be excluded. The management of neuropathic itch is demanding and the majority of interventions are not curative. The best treatment options include anticonvulsants, topical anesthetics, and capsaicin.

Therapy for pruritus in the elderly: a review of treatment developments.

INTRODUCTION: The prevalence of chronic pruritus (CP) in the general population is high and increases with age. Owing to high rates of comorbidities and polypharmacy in patients aged 65 or older, the clinical management of these patients is challenging. AREAS COVERED: In this review, the authors discuss the available therapy options for patients aged ≥ 65 with CP, including emollients for dry skin, topical therapies, phototherapy and systemic agents for CP of various origins. EXPERT OPINION: For multimorbid patients, topical substances and phototherapy constitute the best initial options. If systemic drugs are needed, the potential side-effects need to be closely monitored. In elderly patients, multiple possible factors for CP, including dermatological and systemic diseases, may be found, complicating the treatment of the underlying cause. In these cases, or when the origin remains unknown, a step-wise symptomatic therapy is recommended. The therapeutic choices should be made on an individual basis after carefully outweighing possible risks and benefits. Novel agents such as neurokinin-1 receptor antagonists and opioid-targeting drugs show promising antipruritic effects on refractory CP and seem to be well tolerated. They may be useful for elderly patients, who cannot tolerate conventional systemic agents.

Aprepitant for the Treatment of Chronic Refractory Pruritus.

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.

[Up-regulated expression of NK1R in eosinophil-enriched blood cells from patients with chronic spontaneous urticaria].

Objective To investigate the expressions of substance P (SP) and neurokinin-1 receptor (NK1R) in eosinophil-enriched blood cells from patients with chronic spontaneous urticaria (CSU). Methods Peripheral venous blood samples were collected from patients with CSU and healthy controls (HCs), and then stimulated with crude extracts of Artemisia pollen, dust mite, and Platanus pollen (all at concentrations of 0.1 and 1.0 µg/mL). The expressions of SP and NK1R in eosinophil-enriched blood cells were detected by flow cytometry. Results Compared with HCs, eosinophil proportion in peripheral blood of CSU patients increased 1.2-fold. Percentage of NK1R+ eosinophils in the patients with CSU was elevated up to 66% compared with HCs when cultured in the medium only. However, the level of SP decreased by 40% in the CSU patients. In eosinophil-enriched blood cells from the CSU patients, the crude extract of dust mite at 0.1 µg/mL induced approximately 1.11-fold increase of NK1R expression. Conclusion Expression of NK1R increases in the eosinophils of CSU patients. Blockers of NK1R might be used for CSU treatment.

Targeting tachykinin receptors in neuroblastoma.

Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma.

Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression.

Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.

Itch in Atopic Dermatitis Management.

Patients with atopic dermatitis (AD) suffer from chronic inflammatory dermatitis and antihistamine-resistant itch. The management of intractable pruritus in AD is important, requiring the development of new therapeutic approaches. At present, the standard treatments for AD include topical anti-inflammatory drugs such as calcineurin inhibitors and corticosteroids. Topical emollient treatment is recommended to moisten the skin and to restore and maintain barrier function. Phototherapy is also effective in reducing the number of epidermal nerve fibers, normalizing imbalances in the levels of expression of axon guidance molecules, and inhibiting pruritus. Systemic treatments such as cyclosporine A and aprepitant are used to treat severe and intractable pruritus in AD. Clinical trials of dupilumab and CIM331 have displayed a significant reduction of pruritus in patients with AD. New antipruritic approaches are targeted to the central nervous system such as spinal interneurons and glial cells. This chapter describes therapeutic approaches for attenuating intractable itch in AD.

Investigation of Neurokinin-1 Receptor Antagonism as a Novel Treatment for Chronic Bronchitis in Dogs.

BACKGROUND: Canine chronic bronchitis (CCB) results in cough lasting ≥2 months and airway inflammation. Adverse effects include risk of secondary infection associated with lifelong corticosteroid administration and prompt investigation into alternative therapies. Neurogenic pathways mediated by tachykinins that bind neurokinin (NK) 1 receptors may induce cough and airway inflammation. Maropitant, a NK-1 receptor antagonist, has been advocated for treatment of CCB based on anecdotal improvement, but without scientific evidence. HYPOTHESIS/OBJECTIVES: Maropitant will blunt clinical signs and airway inflammation associated with CCB. ANIMALS: Client-owned dogs (n = 8) with cough >2 months, thoracic radiographic evidence of airway disease and sterile airway inflammation (>7% non-degenerate neutrophils, >7% eosinophils or both) on bronchoalveolar lavage (BAL) enrolled. METHODS: Maropitant (2 mg/kg) administered q48h for 14 days. Study endpoints included client perception of clinical signs (surveys at baseline and 14 days, and visual analogue scale [VAS] at baseline, 7, and 14 days), and BAL % neutrophils and eosinophils (baseline and 14 days). One-way repeated measures ANOVA (VAS) and Wilcoxon-signed rank-sum tests (BAL cells, cough frequency) used with P < .05 considered significant. RESULTS: Maropitant significantly decreased cough frequency (P < .001) and VAS scores (P = .005). No differences in BAL % neutrophils or % eosinophils noted with treatment (P = .279 and P = .382, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Preliminary results suggest that although maropitant may have antitussive properties leading to perceived clinical improvement, its failure to diminish airway inflammation makes it unsuitable for treatment of CCB. Future studies could evaluate maropitant as a cough suppressant for other respiratory disorders in dogs.

Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities.

Several bifunctional peptides were synthesized and characterized based on the pentapeptide-derived ligand NP30 (1: Tyr-DAla-Gly-Phe-Gly-Trp-O-[3',5'-Bzl(CF3)2]). Modification and truncation of amino acid residues were performed, and the tripeptide-derived ligand NP66 (11: Dmt-DAla-Trp-NH-[3',5'-(CF3)2-Bzl]) was obtained based on the overlapping pharmacophore concept. The Trp(3) residue of ligand 11 works as a message residue for both opioid and NK1 activities. The significance lies in the observation that the approach of appropriate truncation of peptide sequence could lead to a tripeptide-derived chimeric ligand with effective binding and functional activities for both mu and delta opioid and NK1 receptors with agonist activities at mu and delta opioid and antagonist activity at NK1 receptors, respectively.

N-acetyl-l-tryptophan, but not N-acetyl-d-tryptophan, rescues neuronal cell death in models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss. Evidence suggests that mitochondrial dysfunction, apoptosis, oxidative stress, inflammation, glutamate excitotoxicity, and proteasomal dysfunction are all responsible for ALS pathogenesis. N-acetyl-tryptophan has been identified as an inhibitor of mitochondrial cytochrome c release and therefore is a potential neuroprotective agent. By quantifying cell death, we demonstrate that N-acetyl-l-tryptophan (L-NAT) and N-acetyl-DL-tryptophan are neuroprotective in NSC-34 motor neuron-like cells and/or primary motor neurons, while their isomer N-acetyl-d-tryptophan has no protective effect. These findings are consistent with energy minimization and molecular modeling analysis, confirming that L-NAT generates the most stable complex with the neurokinin-1 receptor (NK-1R). L-NAT inhibits the secretion of Substance P and IL-1ß (Enzyme-Linked Immunosorbent Assay and/or dot blots) and mitochondrial dysfunction by effectively inhibiting the release of cytochrome c/Smac/AIF from mitochondria into the cytoplasm and activation of apoptotic pathways, including the activation of caspase-1, -9, and -3, as well as proteasomal dysfunction through restoring chymotrypsin-like, trypsin-like, and caspase-like proteasome activity. These data provide insight into the molecular mechanisms by which L-NAT offers neuroprotection in models of ALS and suggest its potential as a novel therapeutic strategy for ALS. We demonstrate that L-NAT (N-acetyl-l-tryptophan), but not D-NAT, rescues NSC-34 cells and primary motor neurons from cell death. L-NAT inhibits the secretion of Substance P and IL-1ß, and caspase-1 activation, the release of cytochrome c/Smac/AIF, and the activation of caspase -9, and -3, as well as proteasomal dysfunction. The data suggest the potential of L-NAT as a novel therapeutic strategy for amyotrophic lateral sclerosis (ALS). AIF, apoptosis-inducing factor.

Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review.

The prevention of chemotherapy-induced nausea and vomiting (CINV) has been revolutionized over the past 25 years. Guideline-based treatment means that vomiting can be prevented in the majority, but not in all patients. Therefore, antiemetic research continues with the goal of optimizing CINV control for all patients. This comprehensive review summarizes the research efforts in this field over the past few years. Emerging from this research are two new antiemetic agents, netupitant/palonosetron, the first antiemetic combination agent and rolapitant, a new NK1RA. In addition, studies have evaluated the benefits of olanzapine and ginger, explored optimal combinations of agents for delayed CINV prevention, confirmed that dexamethasone-sparing regimens are effective, and demonstrated the value of NK1RAs in high-dose chemotherapy settings as well as with certain moderately emetogenic chemotherapies such as carboplatin. Research has also validated the correlation between antiemetic guideline adherence and improved CINV control. Finally, regulatory authorities have utilized extreme caution in retiring some 5-HT3RAs or decreasing their maximum dose.

The NK1 receptor antagonist aprepitant attenuates NK1 agonist-induced scratching behaviour in the gerbil after intra-dermal, topical or oral administration.

Experiments were conducted to develop a model to study the effect of oral and topical administration of the NK1 receptor antagonist aprepitant, on scratching behaviour in gerbils. The gerbil was selected due to its relevance for human NK1 receptor pharmacology. Intradermal injection of a specific NK1 receptor agonist GR73632 (100 nmol/100 µl) at the rostral back of gerbils produced scratching of the injection site. This could be attenuated by intradermal co-administration of a selective NK1 receptor antagonist aprepitant (30-100-300 nmol), demonstrating the role of dermal NK1 receptor in elicitation of scratching behaviour. Likewise, scratching was attenuated by oral (0.3-3-30 mg/kg) or topical application (0.01-0.1-1% w/v) of aprepitant and pharmacokinetic analysis of aprepitant levels in brain, blood and skin supported that efficacy of topically applied aprepitant was due to dermal rather than central target engagement. In conclusion, we showed that NK1 agonist-induced scratching in the gerbil can be reversed by systemic and topical administration of aprepitant. This test system may provide a useful model for the in vivo assessment of putative antipruritic agents.

Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes.

Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence (AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving.

NK1 tachykinin receptor treatment is superior to capsaicin pre-treatment in improving functional outcome following acute ischemic stroke.

Previous results from our laboratory have shown that blockade of the substance P (SP) pathway with an NK1 tachykinin receptor antagonist significantly reduces blood brain barrier breakdown, cerebral edema and functional deficits following ischemic stroke. However, it is unclear whether removal of all neuropeptides is more efficacious than blocking SP alone. As such, the aim of the present study was to determine the effect of neuropeptide depletion with capsaicin pre-treatment on functional outcome following acute ischemic stroke in rats. Animals received 125 mg/kg of capsaicin or equal volume of saline vehicle, administered subcutaneously over a 3-day period. At 14 days following treatment animals were subject to 2h of middle cerebral artery occlusion followed by reperfusion. A subset of animals was treated with an NK1 tachykinin receptor antagonist (NAT) or vehicle at 4h after the onset of stroke only. The functional outcome of animals was assessed for a 7-day period following stroke using a rotarod device, the bilateral asymmetry test, modified neurological severity score, open field and angleboard. Although capsaicin pre-treatment improved outcome, treatment with an NK1 tachykinin receptor antagonist was superior in improving post-stroke functional outcome. This data suggests that some neuropeptides may play a beneficial role following stroke, whilst others such as SP are deleterious.

Discovery of a cyclopentylamine as an orally active dual NK1 receptor antagonist-serotonin reuptake transporter inhibitor.

Cyclopentylamine 4 was identified as a potent dual NK1R antagonist-SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.

Esmolol activates endogenous neurokinin activity inhibiting infarction-induced arrhythmias in rats: novel mechanisms of anti-arrhythmia.

Endogenous neurokinin and adrenergic mechanisms might co-participate in the pathology of acute myocardial infarction (MI). This study sought to investigate the role of endogenous neurokinin and its relationship with ß1-adrenergic mechanism in the infarction induced arrhythmias. In 60min of MI in rats, the contents of substance P (SP), a native agonist of neurokinin 1 receptor (NK1-R), norepinephrine (NE), NK1-R and ß1-adrenergic receptor in the myocardium at risk of ischemia were examined and the ventricular arrhythmias were analyzed. The effects of pretreatment with D-SP (152ng/kg), a specific antagonist of NK1-R, esmolol (10mg/kg), a specific blocker of ß1-adrenergic receptor, and a combination of the two blockers were studied. The results showed that the overlaps of up-regulation of NE, SP and the increase of ventricular arrhythmias were observed. D-SP exacerbated the episodes and duration of VT & VF by 54% and 104%, respectively (all P<0.05). Esmolol inhibited the morbidity rate, the episodes and the duration of VT & VF by 66%, 92% and 95%, respectively. Surprisingly, esmolol significantly attenuated the arrhythmogenic effect of D-SP throughout the MI, beyond the time span of esmolol action, during which a significant up-regulation of the NK1-R (by 19%, P<0.05) was detected. In conclusion, the findings of this study may indicate an anti-arrhythmic effect of endogenous neurokinin mechanism, through the activation of which, via up-regulation of NK1 receptor, esmolol may exert its anti-arrhythmic action at the early time of acute myocardial infarction.

Actual treatment of overactive bladder and urge urinary incontinence.

Overactive bladder (OAB) is defined by its hallmark symptom, urgency. It can be associated with urge urinary incontinence (UUI), and dramatically impact the patients' quality of life. Etiologies of OAB are numerous, and under this common wording, virtually all the population is covered (men as well as women, patients with or without neurogenic disease, and all age categories). OAB and UUI management have been historically based on non-interventional therapies, antimuscarinics, and surgery. In the last decade, innovations in the treatment of this highly prevalent condition have been multiple, and further insights came from various horizons (drug invention, innovative use of existing drugs, new medical devices, tissue engineering, gene and cell therapy). Notably, the use of BoNT and neuromodulation techniques have deeply modified the algorithm of specialized OAB management, delaying surgery indications and offering mini-invasive alternatives to patient refractory to behavioral and medical treatment. Whilst some of these techniques are about to reach maturity, numerous questions remain unsolved about their indications, long term effects, rank in the armamentarium, cost-effectiveness, hypothetical combination or sequential use. The present review depicts the actual wide range of options available for OAB management in adults, focusing on the latest evolutions. When relevant, a distinction was made between genders and OAB subtypes (idiopathic vs neurogenic) regarding treatment outcomes.