Aprepitant for cough in lung cancer: a randomised placebo-controlled trial and mechanistic insights

RATIONALE: Effective cough treatments are a significant unmet need in lung cancer patients. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of Neurokinin 1 (NK-1) receptors, a mechanism also implicated in cough. OBJECTIVE: To assess aprepitant in lung cancer patients with cough and evaluate mechanisms in vagal nerve tissue. METHODS: Randomised double-blind crossover trial of lung cancer patients with bothersome cough. They received three days of aprepitant or matched placebo; following a three day wash out, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease gap recording chambers, indicative of sensory nerve activation, was measured to evaluate mechanism. MEASUREMENTS AND MAIN RESULTS: Twenty lung cancer patients enrolled, mean age 66years (±7.7), 60% female, 80% non-small cell cancer, 50% advanced stage and 55% WHO performance status 1. Cough frequency improved with aprepitant, reducing by 22.2%(95%CI 2.8-37.7%) over placebo whilst awake (p=0.03), 30.3%(95%CI 12.7-44.3) over 24hours (p=0.002) and 59.8%(95%CI 15.1-86.0) during sleep (p=0.081). Patient-reported outcomes all significantly improved. Substance P depolarised both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P induced depolarisation by 78% in guinea pig (p=0.0145) and 94% in human vagus (p=0.0145). DISCUSSION: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as anti-tussive therapies. Clinical trial registration available at www.http://www.isrctn.com/, ID: ISRCTN16200035

Changes in intracellular ion activities induced by adrenaline in human and rat skeletal muscle

To study the stimulating effect of adrenaline (ADR) on active Na+/K+ transport we used double-barrelled ion-sensitive micro-electrodes to measure the activities of extracellular K+ (aKe) and intracellular Na+ (aNai) in isolated preparations of rat soleus muscle, normal human intercostal muscle and one case of hyperkalemic periodic paralysis (h.p.p.). In these preparations bath-application of ADR (10−6 M) resulted in a membrane hyperpolarization and transient decreasesaKe andaNai which could be blocked by ouabain (3×10−4 M). In the h.p.p. muslce a continuous rise ofaNai induced by elevation ofaKe to 5.2 mM could be stopped by ADR. In addition, the intracellular K+ activity (aKi), the free intracellular Ca2+ concentration (pCai) and intracellular pH (pHi) were monitored in rat soleus muscle. During ADRaKi increased, pHi remained constant and intracellular Ca2+ apparently decreased. In conclusion, our data show that ADR primarily stimulates the Na+/K+ pump in mammalian skeletal muscle. This stimulating action is not impaired in the h.p.p. muscle

Social and Cultural Dynamics of Non-Native Invasive Species

Invasive species and their management represent a complex issue spanning social and ecological systems. Invasive species present existing and potential threats to the nature of ecosystems and the products and services that people receive from them. Humans can both cause and address problems through their complex interactions with ecosystems. Yet, public awareness of invasive species and their impact is highly uneven, and public support for management and control of invasive species can be variable. Public perceptions often differ markedly from the perspectives of concerned scientists, and perceptions and support for management are influenced by a wide range of social and ecological values. In this chapter, we present a broad survey of social science research across a diversity of ecosystems and stakeholders in order to provide a foundation for understanding the social and cultural dimensions of invasive species and plan more effective management approaches. This chapter also addresses tribal perspectives on invasive species, including traditional ecological knowledge, unique cultural dimensions for tribes, and issues critical to engaging tribes as partners and leaders in invasive species management. Recognizing that natural resource managers often seek to change people’s perceptions and behaviors, we present and discuss some promising approaches that are being used to engage human communities in ways that empower and enlist stakeholders as partners in management

Bolivia (Part II: Management for sustainable forestry in other tropical countries)

Bolivia started to implement the Forestry Law (# 1700) in 1996. Since then the Bolivian forestry sector has changed significantly from an unplanned and exploitative logging regime to an organized system based on reduced impact logging techniques and management plans elaborated by trained forestry technicians and professionals. It has also expanded access to forest harvesting by allowing rural and indigenous communities the right to manage forest resources along with private companies. The law also provided a suite of technical tools to ensure the sustainable use of the forest resource. The 1996 forestry law and its implementation has resulted in a diversification of species being used for timber production, an increase in the amount of finished forest product exports, and improvements towards forest sustainability. This latter aspect is most evident in the approximately two million hectares of tropical forests that have been certified as sustainably managed under the Principles and Criteria defined by the Forest Stewardship Council (FSC) (Certificación Forestal Voluntaria 2008). Despite Bolivia’s status as a sustainable forestry leader, there are political, socioeconomic, and ecological challenges to sustainable forest management. Most of these challenges have their origins outside the forestry sector and are related to the development vision being used in the country. These limitations are of concern to the sustainability of Bolivia’s forestry sector and their recognition is important in order to be able to mitigate their effects in the future. The rest of this chapter will expand upon the successes and challenges to sustainable forest management in Bolivia

Chronic Cough is associated with increased reporting of Autonomic Symptoms

Background Patients with some neuronal hypersensitivity syndromes experience increased autonomic symptoms. Chronic cough is thought to be a neuronal hypersensitivity disorder and, therefore, may be associated with increased autonomic symptoms. Methods 96 chronic cough subjects were recruited from the tertiary cough clinic based at Wythenshawe Hospital, Manchester, UK; 76 healthy controls were also recruited. Subjects were aged >18 years. Those with significant respiratory disease, significant smoking history or taking medication known to affect cough or autonomic function were excluded. Subjects completed the Composite Autonomic Symptom Score (COMPASS) 31 autonomic symptom questionnaire, the Cough Quality of Life Questionnaire (CQLQ) and a cough severity visual analogue scale (VAS). Results 96 chronic cough subjects and 76 healthy volunteers were included in the final analysis. Mann–Whitney U-tests comparing COMPASS 31 scores in both groups showed that the total COMPASS 31 score was significantly higher in the patient group (median 18.4, interquartile range (IQR) 7.5–32.0) than the control group (median 3.6, IQR 1.1–9.5; p<0.001). The chronic cough subjects had significantly higher symptom scores than the healthy volunteer groups in all domains (p≤0.001) except vasomotor symptoms (p=0.770). There was a positive association between COMPASS 31 and CQLQ in the patient group (p<0.001, r=0.432) but not COMPASS 31 and VAS (p=0.227). Interpretation Chronic cough patients do indeed report more frequent and severe autonomic symptoms than healthy volunteers, indicating that this population may suffer from dysautonomia. At present, it remains unclear whether this occurs as a result of the cough or whether both the cough and dysfunction are part of some wider vagal pathology