The effects of a competitive neutrophil elastase (NE) inhibitor, ONO-5046, and a recombinant human superoxide dismutase on leukotriene B4 (LTB4)-induced polymorphonuclear leukocyte (PMN)-mediated increase in microvascular permeability in isolated non-blood-perfused rabbit lungs were studied. Pulmonary microvascular permeability and lung edema were evaluated by use of the fluid filtration coefficient (Kf) and the wet-to-dry lung weight ratio (W/D), respectively. Pulmonary capillary pressure was estimated by the double occlusion technique. NE activity in the perfusate was determined using a spectrophotometric method. The PMNs (2-3 x 10(8) cells) were added into the perfusate in all groups of lungs. Injection of LTB4 (5 micrograms) increased Kf and W/D without affecting pulmonary arterial or capillary pressure. The LTB4-induced lung injury was closely associated with the increase in NE activity in the perfusate. Infusion of ONO-5046 (1 or 10 mg.kg-1 x h-1) inhibited the LTB4-induced increases in Kf, W/D, and perfusate NE activity in a dose-dependent fashion. Infusion of recombinant human superoxide dismutase (80,000 U.kg-1 x h-1) attenuated the LTB4-induced increases in Kf and W/D, although it did not influence the elevation of perfusate NE activity induced by LTB4. These results suggest that both NE and superoxide anion play important roles in the LTB4-induced PMN-mediated increase in pulmonary microvascular permeability.

To estimate the contribution of paracellular shunt pathway to the cation-selective permeability in the upper portion of the descending limb of long-looped nephron (LDLu) of hamsters, we observed the effect of protamine on salt-diffusion voltage (delta VT) and transmural resistance (RT). delta VT generated on reduction of lumen NaCl concentration was decreased from 12.0 +/- 1.4 to 7.3 +/- 1.2 mV when 100 micrograms/ml protamine were added to the lumen. Although the effect of protamine persisted after removal of the agent from the lumen, addition of 30 U/ml heparin reversed the delta VT toward the control level. The effect of protamine was dose dependent in the range from 3 to 1,000 micrograms/ml. Protamine was without effect from the bath. Studies on single salt dilution voltage revealed that 100 and 300 micrograms/ml protamine inhibited relative Na+ to Cl- permeability from 4.03 +/- 0.38 to 2.14 +/- 0.21 and from 3.75 +/- 0.37 to 1.36 +/- 0.09, respectively. Protamine markedly decreased the apparent transference number for Na+ but slightly increased the value for Cl-. Protamine also inhibited permeabilities for K+, Rb+, and Li+ relative to Cl-, indicating that the inhibitory effect of protamine was not confined to Na+ but was generalized to cations. Transmural cable analysis showed that 100 micrograms/ml protamine increased RT from 14.0 +/- 1.1 to 19.3 +/- 1.2 omega.cm2, with the effect being reversed by 30 U/ml heparin. Because the effect of protamine on RT was unaffected by ouabain in the bath, changes in RT may mainly represent those of the paracellular shunt resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

ABSTRACT[214 words (do not exceed 250)]Purpose: The clinical efficacy and outcomes of gefitinib therapy as a first-line treatment for elderly patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations were analyzed retrospectively. Patients and methods:We analyzed chemotherapy-naïve NSCLC patients aged 75 years or older who had EGFR mutations (exon 19 deletion mutation or L858R), who were initially treated with gefitinib (250 mg) once daily in Nagano Prefecture.Results: A total of 55 patients (16 men, 39 women) with a median age of 81.1 years (range: 75 -94 years) treated between April 2007 and July 2012, were analyzed. The overall response rate and disease control rate were 72.7% (95% confidence interval (CI); 59.5% -82.9%) and 92.7% (95% CI: 82.0% -97.6%), respectively. Median progression-free survival and overall survival from the start of gefitinib treatment were 13.8 months (CI: 9.9 -18.8 months) and 29.1 months (95% CI: 22.4 -not reached), respectively. Two-year survival rate was 59.5% (95% CI; 41.0% -78.8%). Major grade 3 toxicities were skin rash (1.8%) and increased levels of aspartate aminotransferase or alanine aminotransferase (7.3%). Conclusion:First-line treatment with gefitinib for elderly EGFR-mutated NSCLC patients was effective and well tolerated. The results suggest that first-line gefitinib should be considered as a preferable standard treatment in elderly patients with advanced NSCLC harboring EGFR mutations.

To evaluate the contribution of paracellular shunt pathway in ascending thin limb (ATL) of hamsters, we examined the effect of protamine, a selective blocker of paracellular conductance, on salt-diffusion voltage (dVT) and transmural resistance (RT) during in vitro microperfusion. Lumen-negative dVT generated on reduction of lumen NaCl concentration was increased further from -7.3 +/- 0.5 to -10.3 +/- 0.7 mV when 300 micrograms/ml protamine was added to the lumen, and calculated Na+/Cl- permeability ratio was decreased from 0.46 +/- 0.03 to 0.31 +/- 0.03. Although the effect of protamine persisted after removal of the agent from the lumen, addition of 30 U/ml heparin returned the dVT toward the control level. The effect of protamine was dose dependent from 30 to 300 micrograms/ml. Protamine also exerted its effect from the bath, and the effect was inhibited by heparin either from the lumen or from the bath. The inhibitory effect was almost the same when the orientation of imposed NaCl gradient was reversed. Inhibition of transcellular Cl- transport with 0.1 mM 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) in the bath caused lumen-positive dVT. This voltage was decreased significantly by protamine. Protamine markedly decreased the apparent transference number for Na+ but slightly increased the value for Cl-. Transmural cable analysis showed that 300 micrograms/ml protamine added to the lumen increased RT from 0.59 +/- 0.10 to 1.20 +/- 0.20 omega.cm2, with the effect being reversed by 30 U/ml heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Erlotinib might be an alternative option for patients resistant to cytotoxic chemotherapy even in those with EGFR wild-type NSCLC.