The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge.

BACKGROUND: Interleukin 13 (IL13) is a T-helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with lebrikizumab, an anti-IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV(1)) in a subset of subjects with uncontrolled asthma. OBJECTIVE: To evaluate efficacy and safety of lebrikizumab in subjects with mild asthma who underwent bronchial allergen challenge. METHODS: Twenty-nine subjects were randomized 1 : 1-5 mg/kg lebrikizumab (n = 13) or placebo (n = 16) administered subcutaneously every 4 weeks over 12 weeks, a total of four doses. Primary efficacy outcome was late asthmatic response (LAR) at Week 13, defined as area under the curve of FEV1 measured 2-8 h following inhaled allergen challenge. Serum biomarkers were measured to verify IL13 pathway inhibition and identify patients with an increased response to lebrikizumab. RESULTS: At Week 13, the LAR in lebrikizumab subjects was reduced by 48% compared with placebo subjects, although this was not statistically significant (95% confidence interval, -19%, 90%). Exploratory analysis indicated that lebrikizumab-treated subjects with elevated baseline levels of peripheral blood eosinophils, serum IgE, or periostin exhibited a greater reduction in LAR compared with subjects with lower baseline levels of these biomarkers. Lebrikizumab exerted systemic effects on markers of Th2 inflammation, reducing serum immunoglobulin E (IgE), chemokine ligands 13 and 17 by approximately 25% (P < 0.01). Lebrikizumab was well tolerated. CONCLUSION AND CLINICAL RELEVANCE: Lebrikizumab reduced the LAR in subjects with mild asthma. Clinical trial number NCT00781443.

Selective potentiation of insulin-mediated glucose disposal in normal dogs by the sulfonylurea glipizide.

Investigative data have suggested that the extrapancreatic actions of the sulfonylureas may be paramount in their chronic antidiabetic action. The present study examines the effects of chronic sulfonylurea treatment on in vivo insulin action. Peripheral insulin levels, hepatic glucose production (Ra), and overall glucose disposal (Rd) were studied in six awake, normal dogs given both 0.5 and 1.0 mU/kg per min pork insulin for 2.5 h. This produces stable hyperinsulinemia from 15 to 150 min. Fasting euglycemia was held constant by the glucose clamp technique and averaged 99% basal glucose in all studies. Ra and Rd were determined from infusion of [3-(3)H]glucose, begun 90 min prior to insulin infusion. 10 mg of the sulfonylurea glipizide, was given daily to the test animals for the 10 to 20 d following appropriate control studies, then was withheld for 24 h, and the dogs were restudied. Glipizide treatment did not significantly alter basal glucose turnover, Ra, mean glucose values, or mean insulin levels as determined by radioimmunoassay. Increase in Rd above basal glucose turnover in response to insulin (delta Rd) was significantly (P less than 0.05) increased by glipizide treatment at both insulin dosage levels (paired analysis). At 1.0 mU/kg per min insulin, delta Rd rose from 2.6 mg/kg per min before glipizide to 6.5 mg/kg per min after glipizide treatment. At 0.5 mU/kg per min insulin, delta Rd went from 1.1 mg/kg per min before glipizide to 2.2 mg/kg per min after glipizide treatment. Glipizide treatment doubled the effects of insulin on Rd, while showing no significant effect upon insulin suppression of Ra. We conclude that a significant extrapancreatic chronic action of glipizide lies in its ability to selectively potentiate Rd.

The hepatic extraction of gastric inhibitory polypeptide and insulin.

The hepatic extractions of gastric inhibitory polypeptide (GIP) and insulin were determined using in vitro and in vivo methods to assess the role of the liver in GIP metabolism and the possible effect of GIP on the hepatic extraction of insulin. During in vitro studies using the isolated perfused rat liver, infusion of GIP (2000 pg/ml) alone and in combination with porcine insulin (200 microU/ml) resulted in negligible hepatic extraction of immunoreactive GIP (IR-GIP) in both fed and fasted animals during either physiologically euglycemic or hyperglycemic perfusions. Hepatic extraction of insulin, however, ranged from 26-36% in fasted animals and from 7-25% in fed animals. Hepatic extraction of insulin and net hepatic glucose appearance were minimally affected by GIP. In vivo studies in awake dogs were then performed, in which simultaneous portal and peripheral venous levels of IR-GIP, immunoreactive insulin (IRI), and glucose were assessed after intraduodenal glucose administration. The portal to peripheral (PORT/PERI) venous ratio of endogenous IRI and IR-GIP reflected the findings of the in vitro studies; the PORT/PERI ratio of IRI levels rose from a basal value of 1.9 +/- 0.3 to a peak of 3.7 +/- 0.9, while the PORT/PERI ratio of IR-GIP levels rose from a basal value of 1.0 +/- 0.1 to a peak of 1.4 +/- 0.2, then rapidly returned to 1.0. The in vivo data are consistent with a continuous hepatic extraction of 40-50% of the insulin entering the liver and a negligible hepatic extraction of IR-GIP. We conclude that hepatic extraction of GIP in vitro or in vivo is minimal. In addition, while the fed state of the animal before infusion can result in changes in the in vitro hepatic extraction of insulin, GIP does not mediate these changes.

Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide.

Peptide YY (PYY) and pancreatic polypeptide (PP) have been shown to inhibit exocrine pancreatic secretion in vivo in a variety of species. This study evaluates the type of stimulation inhibited by PYY and PP by examining, in urethan-anesthetized rats, the inhibition of pancreatic secretion when stimulated to a comparable extent by cholecystokinin (CCK), 2-deoxy-D-glucose (2DG), bethanecol, and electrical vagal nerve stimulation. PYY at maximal infusion rates inhibited stimulation by CCK by 83%, bethanecol by 55%, and electrical nerve stimulation by 40%. The inhibition of CCK stimulation was half maximal at 250 pmol.kg-1.h-1. By contrast, PYY totally inhibited 2DG-stimulated secretion with half-maximal inhibition at 10 pmol. kg-1.h-1. PP acted similarly to PYY in inhibiting CCK and 2DG-stimulated pancreatic protein secretion but was fivefold weaker in each case. These findings indicate that PYY and PP have multiple actions but preferentially inhibit neurally mediated pancreatic secretion at a preacinar cell locus, possibly at a central site of action.

Endoscopic laser lithotripsy of large bile duct stones.

Experimental work has established that the Candela (Candela Laser Corporation, Wayland, MA) flashlamp excited dye laser (wavelength, 504 nm) is a highly effective method for fragmenting biliary stones and has minimal potential for injuring the bile duct wall. This technique was evaluated in 25 complex patients whose stones, usually because of large size, did not respond to standard nonoperative treatment. The laser imaging was applied through a quartz fiber and aimed either under direct vision with choledochoscopes passed percutaneously or through a special "mother" duodenoscope or under fluoroscopic guidance at standard duodenoscopy. Laser treatment resulted in some fragmentation of stones in 23 cases. Subsequently, it proved that it was possible to clear the bile duct of stones in 20 patients, 12 of them receiving successful treatment during the same endoscopic procedure. There were no significant complications. This endoscopic technique seems to be a useful new alternative to surgery in patients with large and difficult bile duct stones.