Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.

RATIONALE: Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR. OBJECTIVES: An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect. METHODS: Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis. MEASUREMENTS AND MAIN RESULTS: This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC20 FEV1 from baseline averaged over the 7-day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022. CONCLUSIONS: In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted.

Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR.

BACKGROUND: Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators. METHODS: A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects. RESULTS: Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28. CONCLUSIONS: The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

Breakthrough pain in community-dwelling patients with cancer pain and noncancer pain, part 2: impact on function, mood, and quality of life.

BACKGROUND: Prior studies of breakthrough pain (BTP) largely focus on patients with advanced cancer or those receiving inpatient care. Very few studies have evaluated BTP in populations with chronic noncancer pain. Data that illuminate the impact of BTP may not generalize to other, less selected patient populations. AIM: The aim of this study was to evaluate the impact of BTP in opioid-treated ambulatory patients with chronic cancer pain or noncancer pain treated in community practices. METHODS: Eligible patients--those with any diagnosis who reported chronic pain for at least 3 months, who were receiving long-term opioid therapy, and who met criteria for controlled baseline pain--were recruited for a cross-sectional observational study by primary care physicians or community-based oncologists at 17 sites in the United States. The patients responded to a structured interview for breakthrough pain and also completed the Brief Pain Inventory-Modified Short Form (BPI-SF) and the Brief Battery for Health Improvement 2 (BBHI 2). RESULTS: Of 355 patients screened, 191 were eligible and 177 (93 percent) provided data for analysis. Twenty-six of the 78 with cancer pain (33 percent) and 48 of the 99 with noncancer pain (48 percent) had BTP. Compared with those without BTP, both patients with cancer (p = 0.004) and patients without cancer (p = 0.019) with BTP had increased pain interference in function, as measured by the BPI-SF, and patients without cancer were more impaired than patients with cancer. On the BBHI 2, BTP was associated with increased somatic complaints (p = 0.036 cancer and p = 0.024 noncancer) and pain complaints (p = 0.037 cancer and p = 0.037 noncancer); among patients without cancer, BTP was also associated with increased difficulties with functioning (p = 0.023), depression (p = 0.039), and decreased quality of life (p = 0.003). CONCLUSIONS: These data extend published observations about the association between BTP and adverse effects on mood and function to populations undergoing routine treatment in the community setting and provide evidence that these associations are greater in those with noncancer pain. They suggest the need for additional studies to clarify causality and determine whether undertreatment of BTP is a factor contributing to adverse pain-related outcomes.

Breakthrough pain in community-dwelling patients with cancer pain and noncancer pain, part 1: prevalence and characteristics.

BACKGROUND: Most breakthrough pain (BTP) studies assess patients with advanced cancer or those receiving inpatient care. Studies in noncancer populations are limited to surveys of pain clinics and patients with other advanced diseases. To better understand BTP, data are needed from less selected populations. AIM: The aim of this study was to evaluate BTP in opioid-treated ambulatory patients with chronic cancer or noncancer pain treated in community practices. METHODS: Primary care physicians or community-based oncologists recruited a convenience sample for a cross-sectional study of BTP at 17 sites in the United States. Physicians could not be pain specialists. Patients were eligible if they had any type of pain for > or = 3 months and were receiving an opioid drug on a regular basis that controlled the pain. The patients responded to a structured interview comprising items that assessed the baseline pain and items that assessed BTP, if present. RESULTS: In total, 355 patients were screened, 191 were eligible and 177 (93 percent) provided data for analysis. Seventy-eight patients had cancer pain and 99 had noncancer pain. Patients with cancer were older (mean +/- SD age 61.3 +/- 11.2 years vs 51.4 +/- 13.6 years, p < 0.001), and patients without cancer had more neuropathic pain (21 vs 12 percent, p < 0.05) and a longer pain duration (median 3.5 vs 1 years, p < 0.001). BTP occurred in 33 percent with cancer and 48 percent with noncancer pain (p = 0.042). BTP did not vary by diagnosis, but neuropathic pain was more common in those with BTP (27 vs 10 percent, p < 0.001). In patients with and without cancer, the median daily number of episodes was 1, the median time to maximum pain was 1-2 minutes, and the median duration was 45-60 minutes. There were fewer BTP precipitants in the patients with cancer (46 vs 80 percent of pains, p < 0.05), and they had less predictable pain (p < 0.05). CONCLUSIONS: The prevalence of BTP among community-dwelling patients is lower than that found in prior studies of more selected populations. BTP is more prevalent among patients with noncancer pain than patients with cancer pain, and although there are many similarities, some differences may be relevant to treatment strategies.

Prevalence and characteristics of breakthrough pain in patients receiving opioids for chronic back pain in pain specialty clinics.

OBJECTIVE: We sought to assess the prevalence and characteristics of breakthrough pain (BTP) in patients with chronic back pain. DESIGN: Researchers utilized a telephone survey using a pain assessment algorithm. This report represents a subset of patients from a larger survey of 228 patients with chronic pain unrelated to cancer. PARTICIPANTS: This study employed 117 subjects taking opioids for a primary diagnosis of back pain and receiving care at geographically dispersed pain treatment centers. Subjects had pain lasting at least six months and had "controlled" baseline pain. RESULTS: Eighty-seven subjects (74 percent) experienced 93 types of BTP. The median number of BTP episodes per day was two; median time to maximum intensity was 10 minutes, and median duration was 55 minutes. Onset could not be predicted for 46 percent of pains. Eighty-three percent of subjects used shorter-acting opioids for BTP. Other medications used for pain included NSAIDs, antidepressants, anticonvulsants, skeletal muscle relaxants, intrathecal local anesthetics, and transdermal local anesthetics. CONCLUSIONS: These patients with opioid-treated chronic back pain commonly experienced BTP, which often had a rapid onset and a relatively short duration and was difficult to predict. Opioids were the mainstay of pharmacologic therapy, but nonopioid analgesics and adjuvant analgesics were commonly used.