Cough in lung cancer (LC) is a significant unmet need. There are no evidence-based effective antitussives for its treatment and a lack of well-designed trials incorporating validated cough assessment tools and placebo controls. There is little research on its underlying mechanisms, perhaps with the assumption that it is simply 'due to the cancer'. Therefore, we have sought to characterise cough in terms of its severity, impact on quality of life, frequency and prevalence using LC specific subjective and objective assessment tools for the first time. We have also explored its potential mechanisms and treatment. Published preclinical data show that the substance P/neurokinin-1(NK1) pathway is implicated in cough in 5 different species. This pathway is targeted by the antiemetic aprepitant in humans. Data on the use of aprepitant as a novel antitussive are presented. To characterise cough and assess cough assessment tools in a cohort of patients with LC attending outpatient clinics, subjective and objective cough assessment tools including 24-hour ambulatory cough monitoring (ACM), were used to determine the cough severity, frequency, impact and cough- associated clinical factors in a longitudinal study. To determine cough prevalence, a cross sectional study of all patients attending thoracic oncology outpatient clinics in a single centre over a defined period were approached to determine whether they had a cough, to provide demographic and cancer related data and if applicable, to complete the Manchester Cough in Lung Cancer Scale (MCLCS) cough impact questionnaire and the cough severity visual analogue scale. To explore the role of the NK1 pathway in cough in patients with LC, a single-arm randomised placebo controlled pilot trial assessing aprepitant for the treatment of cough was conducted. The presented data demonstrated that cough affects over half of patients with LC, representing a huge unmet clinical need. Over 2/3rds of patients felt that their cough was severe enough to warrant treatment and over 1/4 described it as painful. Patients with LC suffer from a very severe and frequent cough. Its impact is considerable, with effects on physical, psychological and social domains. The longitudinal study is the first to report that cough severity and impact is predicted by gastro-intestinal co-morbidities rather than cancer related factors. The presented data demonstrate that ACM is feasible and acceptable to patients with LC. This provides researchers with an objective endpoint for use in clinical trials. The MCLCS performs well and is valid. The cough intervention trial is the first to demonstrate that aprepitant is associated with lower subjective cough scores and cough frequency using validated cough assessment tools. No antitussive therapy study has ever shown a positive antitussive effect using both types of cough assessment tools in the LC population. This suggests that the substance P/NK1 pathway is implicated in cough in LC and identifies this as a potential new therapeutic target, providing exciting data and hope for future patients with LC.

Background: Peripheral neuropathy is a common treatment-related adverse effect associated with vincristine. Vincristine is a major CYP3A4 substrate and is often administered alongside the neurokinin-1 (NK-1) receptor antagonists, aprepitant or fosaprepitant, which are moderate CYP3A4 inhibitors. This inhibition may result in increased concentrations of vincristine and an increased incidence of toxicity. Objective:The primary objective of this study was to investigate if there is a clinically significant drug interaction between vincristine and aprepitant or fosaprepitant resulting in early-onset peripheral neuropathy. The secondary objective of this study was to investigate the cumulative rate of chemotherapy-induced peripheral neuropathy (CIPN). Methodology:This was a single-centered, retrospective, cohort chart review. Patients receiving vincristine-based chemotherapy between 1 July 2010 through 30 June 2018 were identified and reviewed for concomitant use of aprepitant or fosaprepitant and incidence of neuropathy. Early-onset CIPN was defined as neuropathy onset during the first cycle of chemotherapy. Results:A total of 115 subjects were retrospectively reviewed over the study period, of whom 71 were included in the aprepitant/fosaprepitant group and 44 were included in the group without a NK-1 receptor antagonist. Of the subjects who received aprepitant/fosaprepitant, 26.7% experienced early-onset peripheral neuropathy as compared to 22.7% in the group without a NK-1 receptor antagonist (P = 0.627). Overall, CIPN was higher in the group who received aprepitant/fosaprepitant compared to the group without (56% vs. 36%, P = 0.036). Conclusion:There appears to be an increased risk of CIPN with the concomitant use of vincristine and aprepitant or fosaprepitant.

<p>In the past few decades, invasive mycosis has become a growing threat to global health, afflicting millions of people and claiming the lives of more than 1.5 million patients every year. Moreover, the economic burden of mycotic infections has become increasingly exhausting especially with the recent increases in the number of the high-risk population, the immunocompromised individuals. In the USA, the cost incurred by mycotic infections was estimated to be of more than $7.2 billion only in 2017. Of particular concern, <i>Candida</i> species are the most common fungal pathogens that infect humans, resulting in considerable morbidities and mortality rates that often exceed 50%. Unfortunately, the antifungal drug discovery is currently unable to keep pace with the urgent demand for more effective therapeutic options. Further complicating the situation is the recent emergence of multidrug-resistant species such as <i>Candida</i> <i>auris</i>, triggering outbreaks of deadly Candidemia across the globe. Given the risks inherent to the traditional de-novo drug discovery, combinatorial therapeutics stands out as a promising tool to hamper drug resistance and extend the clinical utility of the existing drugs. In this study, we assembled and screened ~3147 FDA-approved drugs and clinical molecules against fluconazole-resistant <i>C. albicans</i> and <i>C. auris</i> isolates, for the aim of restoring the antifungal activity of azole antifungals against drug-resistant <i>Candida </i>species. The screen revealed five promising hits: pitavastatin (antihyperlipidemic), ospemifene (estrogen receptor modulator), sulfa antibacterial drugs, lopinavir (antiviral), and aprepitant (antiemetic).</p> <p>All identified hits demonstrated variable azole chemosensitizing activities depending on the tested <i>Candida</i> species and the azole drug. Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against isolates of <i>C. albicans</i>, <i>C. glabrata</i>, and <i>C. auris</i>. Ospemifene was able to interact synergistically with itraconazole against multiple fungal isolates including <i>Candida</i>, <i>Cryptococcus</i>, and <i>Aspergillus</i> species. Sulfa drugs displayed potent synergistic activities with different azoles against <i>C. albicans</i>, however, a limited efficacy was observed against efflux-hyperactive isolates such as <i>C. auris</i>. On the other hand, both lopinavir and aprepitant exerted potent and broad-spectrum synergistic activities with itraconazole and were effective against multiple <i>Candida</i> species including <i>C. albicans</i>, <i>C. auris</i>, <i>C. glabrata</i>, <i>C. krusie</i>, <i>C. tropicalis</i>, and <i>C. parapsilosis</i>. Furthermore, using <i>Caenorhabditis elegans</i> as an infection model, all drug combinations significantly reduced the fungal burden in the infected nematodes and significantly prolonged their survival as compared to single-drug treatments. Multiple phenotypic and molecular assays indicted that the identified hit compounds use distinct mechanisms to enhance the antifungal activity of azole drugs. These mechanisms include efflux pump inhibition, interference with the folate biosynthesis and disturbance of iron homeostasis. Taken together, this study reveals novel and potent azole chemosensitizing agents effective against multiple azole-resistant isolates and opens the door for more investigations to assess their clinical potential in human medicine as promising antifungal adjuvants.</p>

Malgré le nombre important de spécialités pharmaceutiques mises sur le marché, certains patients hospitalisés ne peuvent bénéficier d’un traitement pour lequel aucun dosage et/ou forme pharmaceutique n’est disponible. Dans ce cas, la pharmacotechnie hospitalière peut être autorisée à formuler et contrôler des préparations.L’objectif de ces travaux a été de développer une forme transdermique semi-solide, à partir de véhicules prêts à l’emploi et contenant trois antiémétiques, pour traiter les nausées et vomissements chimio-induits. Pour ce faire, l’ondansétron, la dexaméthasone et l’aprépitant ont été formulés dans cinq véhicules commerciaux de composition liposomale (PLO®, Lipovan®, Pentravan® et Pentravan Plus®) ou phytosomale (Phytobase®). Après avoir protocolisé la formulation, un contrôle qualité a été réalisé sur chaque préparation finie. Il a essentiellement porté sur l’évaluation de la teneur en principes actifs dans les formulations et sur leur homogénéité. Dans ce but une méthode séparative utilisant la CLHP-UV et une méthode basée sur la PLS-UV ont été développées et validées selon les recommandations de la Société Française des Sciences Techniques et Pharmaceutiques pour doser simultanément les trois antiémétiques.Deux études in vitro ont ensuite été mises en œuvre sur des cellules de Franz. La première, menée à l’aide de membranes d’acétate de cellulose, a montré que le PLO® et le Pentravan Plus® sont les véhicules les plus performants pour libérer les trois principes actifs (PA) formulés séparément. La seconde visait à évaluer la perméation des mêmes PA à travers des épidermes de peau d’oreilles de cochon. Elle a mis en évidence les performances du Pentravan Plus® comme véhicule pour l’administration simultanée de l’ondansétron et de la dexaméthasone par voie transdermique. La perméation de l’aprépitant étant trop faible pour envisager son administration par voie transdermique, il n’a pas été intégré à la formulation finale. Différents promoteurs d’absorption ont été évalués afin d’améliorer le passage transcutanée : le tween 20 s’est révélé tout aussi performant que l’éthanol classiquement utilisé pour l’incorporation des PA dans ces véhicules. / Despite the high number of formulations available for a drug on the pharmaceutical market, it can arise that a patient needs a treatment for which none pharmaceutical form or dosage is available. In this case, pharmacy department of the hospital may have to prepare this form, in accordance with health agency.The goal of this work was to develop a semi-solid transdermic formulation from ready for use vehicle and containing three antiemetic drugs for the treatment of chemotherapy induced nausea and vomiting. Hence, ondansetron, dexamethasone and aprepitant have been formulated in five commercial vehicles of liposomal (PLO®, Lipovan®, Pentravan® and Pentravan Plus®) or phytosomal (Phytobase®) composition. After development of a formulation protocol, quality control was carried out on every finished preparation It focused on the evaluation of the content of active ingredients in formulations and their homogeneity. For this purpose a separation method using HPLC-UV and a method based on PLS-UV have been developed and validated according to the recommendations of the French Society of Pharmaceutical Science and Technology to assay the three antiemetics simultaneously.Two in vitro studies were then implemented on a Franz cell. The first, using cellulose acetate membranes, has shown that the PLO® and the Pentravan Plus® are the most efficient vehicles for releasing the three drugs formulated separately. The second one was performed to assess the permeation of the same drug through pig ears skin epidermis. It highlighted the performances of Pentravan Plus® as a vehicle for the simultaneous transdermal administration of ondansetron and dexamethasone. Nevertheless, as permeation of aprepitant is too poor to consider its transdermal administration, it has not been included in the final formulation. Different chemical enhancers were evaluated to improve the transcutaneous passage: tween 20 appeared to be as powerful as ethanol conventionally used for the incorporation of drugs in these vehicles.