IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist.

BACKGROUND: This is the first large pharmacogenetic investigation of the inflammatory IL-4/IL-13 pathway in patients with moderate-to-severe asthma. We analyzed genomic DNA from participants in a 12-week placebo-controlled efficacy trial of pitrakinra (1, 3, or 10 mg twice daily), a novel IL-4/IL-13 pathway antagonist (Clinicaltrials.govNCT00801853). OBJECTIVES: The primary hypothesis for this analysis is that amino acid changes in the 3' end of the IL-4 receptor α gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy. METHODS: Nineteen IL4RA single nucleotide polymorphisms (SNPs) were tested in 407 non-Hispanic white subjects for association with the primary clinical end point of asthma exacerbations and changes in secondary end points for asthma symptom scores. RESULTS: The most consistent pharmacogenetic associations were observed for the correlated tagging SNPs rs8832 and rs1029489 in the IL4RA 3' untranslated and proximal regions, respectively. Subjects homozygous for the rs8832 common G allele randomized to pitrakinra (placebo group nonsignificant) had decreased asthma exacerbations and decreased nocturnal awakenings and activities limited by asthma. There was also a significant pitrakinra dose-response relationship (placebo/1 mg/3 mg/10 mg) for exacerbations in subjects homozygous for the common allele in rs1029489 (P = .005) and rs8832 (P= .009) and the intronic SNPs rs3024585, rs3024622, and rs4787956 (P = .03). CONCLUSION: This study demonstrates a significant pharmacogenetic interaction between anti-IL-4 receptor α therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist.

Pulmonary delivery of opioids as pain therapeutics.

Pulmonary opioid delivery, on the basis of the fact that small molecular entities can be rapidly and completely absorbed from the peripheral lung, poses a unique opportunity for the treatment of severe (breakthrough) pain, which currently is treated with intravenous therapy. Early clinical studies involving inhaled opioids were focused on treatment of dyspnoea and not pain management, but they showed that inhalation of various opioid compounds is safe, even in severely ill patients. The advent of specialized and efficient pulmonary drug delivery systems has facilitated the evaluation of inhaled opioids, such as morphine and fentanyl, for management of severe pain associated with surgery or malignant disease. This review will summarize recent literature on the pharmacokinetics and pharmacodynamics of inhaled opioids and will discuss safety and efficacy in comparison to injection and other opioid dosage forms available for pain therapy. Finally, regulatory considerations will be discussed towards the approval of this new delivery paradigm for opioid drugs.

Analgesic efficacy of inhaled morphine in patients after bunionectomy surgery.

BACKGROUND: The AERx Pain Management System (Aradigm Corporation, Hayward, CA) is a novel pulmonary delivery system for the systemic administration of morphine. The authors compared the relative analgesic efficacy and safety of the AERx Pain Management System with those of placebo and intravenous morphine in an orthopedic postsurgical pain model. METHODS: Eighty-nine male and female PS-1 to PS-3 patients underwent standardized bunionectomy surgery and received multiple doses of inhaled or intravenous placebo, inhaled morphine (one inhalation [2.2 mg] or three inhalations [6.6 mg]), or intravenous morphine (4 mg) in a blinded fashion. Open-label rescue morphine (2 mg) was also available as needed. Pain intensity, pain relief, and time to pain relief were measured after the first dose. Global evaluation, morphine consumption, vital signs, and adverse events were monitored for 8 h after treatment. Blinded study personnel performed all treatment administrations and pain assessments. RESULTS: Three inhalations of morphine and 4 mg intravenous morphine provided comparable single- and multiple-dose analgesia. One inhalation of morphine was statistically indistinguishable from placebo. Three inhalations of morphine and 4 mg intravenous morphine both consistently demonstrated significantly greater analgesic efficacy than did placebo and one inhalation of morphine. CONCLUSIONS: Comparable analgesic efficacy was demonstrated between a carefully matched dose of inhaled and intravenous morphine in a postsurgical pain model.