Harumi Nishiyama

Tachykinins via tachykinin NK2 receptor activation mediate ozone-induced increase in the permeability of the tracheal mucosa in guinea-pigs

Acute exposure to ozone is known to cause airway hyperresponsiveness, which, at least in part, seems to result from an increase in the permeability of the airway mucosa. Recently, we demonstrated that depletion of sensory neuropeptides inhibits the ozone‐induced increase in the permeability of the tracheal mucosa in guinea‐pigs. The aim of this study was to determine whether tachykinins mediate ozone‐induced increase in the permeability of the tracheal mucosa in guinea‐pigs. Anaesthetized guinea‐pigs were exposed to either 3 p.p.m. ozone or filtered air for 30 min. Immediately after exposure, a tracheal segment was isolated in vivo and administered with horseradish peroxidase (HRP). The permeability was assessed by monitoring the appearance of HRP in the blood. A low dose of NKA increased the permeability of the tracheal mucosa, whereas a low dose of SP was without effect. Low and high doses of the selective NK3 receptor agonist, senktide, were also without effect. The effect of a low dose of NKA was abolished by the NK2 receptor antagonist, SR‐48,968. A high dose of SP increased the permeability in a manner reversible by the NK1 receptor antagonist, CP‐96,345. Pretreatment with SR‐48,968 completely inhibited the ozone‐induced increase in the permeability, whereas CP‐96,345 had no effect. It is thus concluded that endogenous tachykinins mediate the ozone‐induced increase in the permeability of the tracheal mucosa in guinea‐pigs mainly via NK2 receptor activation.

Insufficient Effectiveness of 5-Hydroxytryptamine-3 Receptor Antagonists Due to Oral Morphine Administration in Patients With Cisplatin-Induced Emesis

PURPOSE To compare the effect of 5-hydroxytryptamine-3 (5HT(3)) receptor antagonists in cancer patients receiving chemotherapy including cisplatin (CDDP), with or without sustained-release oral morphine (MS Contin; Shionogi Co, Osaka, Japan). PATIENTS AND METHODS We retrospectively studied 58 lung cancer patients given chemotherapy including at least 50 mg/m(2) CDDP with 5-HT(3) receptor antagonists between January 1996 and December 1997. Number of vomiting episodes, average proportions of hospital-supplied meals consumed (0 to 100%, as an index of appetite), and nausea severity scores (0 to 2 points, subjective patient judgment) were compared between oral morphine-administered (+) and morphine-free (-) groups. RESULTS Sixteen morphine(+) and 42 morphine(-) cases were used. In cases of acute emesis (within 24 hours after CDDP injection), morphine(+) and morphine(-) groups were significantly different in number of vomiting episodes (1.25 and 0.14, respectively; P <.0001), appetite (58.13% and 90.24%; P <.0001), and nausea severity scores (1.63 and 0.62; P <.0001). In delayed-emesis cases (24 to 120 hours after CDDP), these groups differed significantly in number of vomiting episodes (1.94 and 0.43, respectively; P =.0001), appetite (23.13% and 52.08%; P <.0001), and nausea severity (1.38 and 0.91; P =.009). There were no significant differences in sex, age, anticancer drugs concurrent with CDDP, CDDP dose, corticosteroid administration, clinical stage, or type of 5-HT(3) antagonist. CONCLUSIONS These data suggest that morphine can markedly reduce the effectiveness of 5-HT(3) receptor antagonists in patients receiving chemotherapy that includes CDDP. These results require confirmation by reinvestigation of clinical data on the efficacy of 5-HT(3) receptor antagonists and by extensive prospective analyses.

Combined effects of ozone and cigarette smoke on airway responsiveness and vascular permeability in guinea pigs.

The effects of combined exposure to ozone and cigarette smoke on airway responsiveness and tracheal vascular permeability, compared with those of single exposure were examined in guinea pigs. Airway responsiveness was assessed by measuring the specific airway resistance (sRaw) as a function of increasing concentration of inhaled methacholine aerosol immediately, 5 hr, and 24 hr after exposure. In a parallel study, tracheal vascular permeability was quantified by measuring the tracheal extravasation of intravenously administered Evans blue dye. Neither exposure to 1 ppm ozone for 30 min nor 5 puffs of cigarette smoke increased airway responsiveness or vascular permeability at any time after exposure. Combined exposure to 1 ppm ozone for 30 min and 5 puffs of cigarette smoke caused airway hyperresponsiveness and increased vascular permeability immediately after exposure. Exposure to 1 ppm ozone for 90 min increased both airway responsiveness and vascular permeability immediately after exposure. Exposure to 10 puffs of cigarette smoke increased airway responsiveness but not vascular permeability immediately after exposure. Combined exposure to 1 ppm ozone for 90 min and 10 puffs of cigarette smoke increased both airway responsiveness and vascular permeability immediately after exposure. The combined exposure to ozone and cigarette smoke thus increased both airway responsiveness and tracheal vascular permeability to a greater extent than did exposure to a single agent, suggesting that a combination of air pollutants has a more deleterious effect both on airway responsiveness and on tracheal vascular permeability than does either agent alone in guinea pigs.

Neuropeptides mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea pigs

We examined the effects of acute exposure to ozone on the permeability of the tracheal mucosa and the contribution of neural pathways to the effects of ozone using horseradish peroxidase (HRP; mol wt 40,000) as a marker of lumen-to-blood transfer of a macromolecule in guinea pigs in vivo. Each guinea pig was anesthetized and exposed for 30 min to either ozone [0.5 or 3 parts/million (ppm)] or air. Immediately after exposure, a tracheal segment was isolated between two polyethylene cannulas in vivo and filled with HRP solution (50 mg/ml). Blood samples were drawn before and 10, 20, 30, and 40 min after the intratracheal instillation of HRP. The plasma levels of HRP in guinea pigs exposed for 30 min to 3 ppm of ozone, but not to 0.5 ppm of ozone, were significantly greater than those in guinea pigs exposed to air. Although the increased plasma HRP levels after exposure to 3 ppm of ozone were unaffected by propranolol or atropine, they were completely inhibited by pretreatment with capsaicin (50 mg/kg sc, injected in two doses). These results suggest that endogenous neuropeptides mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea pigs in vivo, but neither an adrenergic nor a cholinergic pathway appears to be involved.We examined the effects of acute exposure to ozone on the permeability of the tracheal mucosa and the contribution of neural pathways to the effects of ozone using horseradish peroxidase (HRP; mol wt 40,000) as a marker of lumen-to-blood transfer of a macromolecule in guinea pigs in vivo. Each guinea pig was anesthetized and exposed for 30 min to either ozone [0.5 or 3 parts/million (ppm)] or air. Immediately after exposure, a tracheal segment was isolated between two polyethylene cannulas in vivo and filled with HRP solution (50 mg/ml). Blood samples were drawn before and 10, 20, 30, and 40 min after the intratracheal instillation of HRP. The plasma levels of HRP in guinea pigs exposed for 30 min to 3 ppm of ozone, but not to 0.5 ppm of ozone, were significantly greater than those in guinea pigs exposed to air. Although the increased plasma HRP levels after exposure to 3 ppm of ozone were unaffected by propranolol or atropine, they were completely inhibited by pretreatment with capsaicin (50 mg/kg sc, injected in two doses). These results suggest that endogenous neuropeptides mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea pigs in vivo, but neither an adrenergic nor a cholinergic pathway appears to be involved.

Phase I/II trial of docetaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

AbstractBackground. This trial was conducted to determine the maximum tolerated dose (MTD) and principal toxicities of combinations of docetaxel and carboplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy, and to find suitable doses for phase II studies in Japanese subjects. Methods. Japanese patients with advanced NSCLC and performance status 0 to 2 according to the World Health Organization classification, but previously untreated with chemotherapy received docetaxel followed by carboplatin, each infused over a 1-h period. The carboplatin dose was based on the target area under the curve (AUC), using Calverts formula. Dose levels studied were: docetaxel (mg/m2)/carboplatin AUC (mg/ml·min), 50/4, 60/4, and 60/5, repeated every 3 weeks. Granulocyte-colony stimulating factor (G-CSF) support was first used when dose-limiting toxicities (DLTs) were encountered. Results. Of 14 patients entered, 12 were assessable for toxicity and response. The MTD schedule was: docetaxel, 60 mg/m2, with carboplatin, AUC 5 mg/ml·min (DLTs in 3 of 3 patients). The recommended dosage was: docetaxel, 60 mg/m2, with carboplatin, AUC 4 mg/ml·min (DLTs in 2 of 6 patients). The main toxic effect was neutropenia, and any nonhematologic toxic effects were mild. No thrombocytopenia occurred. Six of the 12 patients (50%) showed responses; 4 of the 6 at the recommended doses. Conclusion. Docetaxel 60 mg/m2, given over a 1-h period, followed by carboplatin, AUC 4 mg/ml·min, given over a 1-h period, is recommended for phase II studies in Japan. This combined chemotherapy has mild toxicity, except for neutropenia, and is useful and easy to administer. We therefore believe that phase II and phase III studies of this therapy would be well justified.