Toshimori Tanigaki

The importance of polymorphonuclear leukocytes in lipopolysaccharide-induced superoxide anion production and lung injury: ex vivo observation in rat lungs.

Abstract. The purpose of this study is to determine if the polymorphonuclear leukocyte (PMN) is a major causative agent for lipopolysaccharide (LPS)-induced lung injury and responsible for the excess production of superoxide anion in the lung. We measured superoxide anion production from the lung and pulmonary capillary permeability in rats with and without PMN depletion. The superoxide anion production from the lung was measured using a purpose-built ex vivo chemiluminescence apparatus. Pulmonary capillary permeability was evaluated by the Evans blue dye extravasation method. PMN sequestration was determined by counting PMNs in histologic tissue specimens using microscopy. All rats received 3 mg/kg LPS intravenously. Examinations were undertaken at 2, 6, and 12 h after the LPS injection. The PMN-depleted group received cyclophosphamide 4 days before the LPS injection, which resulted in a PMN count of less than 200 cells/μl. In rats without PMN depletion, Evans blue dye extravasation increased significantly at 12 h after the LPS injection; PMN sequestration increased at 2, 6, and 12 h after the LPS injection; and superoxide anion production increased at 6 h and remained elevated at 12 h after the LPS injection. The increased permeability, PMN sequestration, and superoxide anion production were not seen in the PMN-depleted group. The contribution of the xanthine/xanthine oxidase system and alveolar macrophages to the observed superoxide anion production was negligible. We conclude that, in rats, the PMN is a major causative agent in LPS-induced lung injury and is responsible for the excess production of superoxide anion in the lung.

Gefitinib‐induced lung injury successfully treated with high‐dose corticosteroids

Abstract:  A 55‐year‐old man was treated with gefitinib for disseminated pleural lesions, 1 year after resection of the left lower lobe for non‐small cell lung cancer. After 6 weeks of continuous daily treatment with oral gefitinib, he developed dyspnoea on exertion and a non‐productive cough. CXR and CT revealed focal areas of ground‐glass opacity (GGO) in the right upper lobe. Despite gefitinib being discontinued, high‐resolution CT revealed extension of GGO and restructuring of lung parenchyma, suggesting acute interstitial pneumonia. Transbronchial biopsy revealed acute‐phase diffuse alveolar damage. After administration of methylprednisolone pulse therapy (1 g/day intravenously) for three consecutive days, the areas of GGO shrank on high‐resolution CT and symptoms resolved. Diffuse alveolar damage caused by gefitinib can be successfully treated in the early phase with high‐dose corticosteroids. Patients receiving gefitinib should be carefully examined for symptoms and undergo CT if their condition deteriorates.

Furosemide Given by Inhalation Ameliorates Acute Exacerbation of Asthma

Previous studies have suggested that inhaled furosemide may have a protective effect against a wide variety of bronchoconstrictor agents, but a therapeutic effect has not been established in acute exacerbation of asthma. The purpose of this study was to investigate whether inhaled furosemide would exhibit any therapeutic benefit in acute asthma. We conducted a double-blind, placebo-controlled, randomized study in 40 patients with acute mild or moderate exacerbation of asthma. All patients received intravenous (i.v.) aminophylline 250 mg for 90 min and i.v. hydrocortisone 100 mg at entry. After randomization, 3 patients were excluded from the final analysis. At 30 min after starting i.v. aminophylline, 20 patients were given inhaled furosemide 20 mg and 17 patients received normal saline as placebo-control. Both inhalations were given by a jet nebulizer. The baseline forced expiratory volume at 1 sec (FEV1), peak expiratory flow rate (PEFR), and serum concentration of theophylline did not differ between the two groups. An increase in FEV1 in the furosemide group by 28.2 +/- 5.9% (mean +/- SE) was noted at 60 min, and this was significantly higher than in the control group. PEFR at 60 min was also significantly higher in the furosemide group than in control group. We conclude that inhaled furosemide has a bronchodilator effect on mild to moderate exacerbation of asthma when it is used with i.v. theophylline. Inhaled furosemide may benefit certain acute asthma patients, especially those suffering complications from the adverse effects of beta 2-agonists.

Rapid Response to Inhaled Frusemide in Severe Acute Asthma with Hypercapnia

We report 7 patients with severe acute asthma unresponsive to standard medication, including sympathomimetic agents, aminophylline and corticosteroids, who responded to inhaled frusemide. All were hypercapneic with a mean PaCO2 of 7.7 kPa (57.7 mm Hg) [range 6.2-8.8 kPa (46.2-66.3 mm Hg)]. Following nebulization of 20 mg frusemide, clinical response was rapid, and the mean PaCO2 fell significantly to 5.4 kPa (40.6 mm Hg) [range 5.0-6.2 kPa (37.5-46.5 mm Hg)] within 20-60 min. No adverse effect was recognized. Inhaled frusemide should be considered for treatment of acute asthma refractory to conventional therapy.

Magnetic resonance relaxation times in acute hydrostatic pulmonary edema induced by noradrenaline in rats.

Models of pulmonary edema have been used to study the nuclear magnetic resonance (NMR) characteristics of lung water. Several investigators have measured changes in the relaxation times in the permeability type of pulmonary edema, but relatively few have measured relaxation times in the hydrostatic type of pulmonary edema. In this study we determined the characteristics of NMR relaxation times T1, T2 (Hahn spin-echo decay) and water content in acute hydrostatic pulmonary edema induced by noradrenaline administration in rats. Changes in T1 and T2 showed a significant prolongation in hydrostatic pulmonary edema. T2 decay curves for peripheral lung tissues were muldexponential and fit two components [T2 fast (T2f) and T2 Slow (T2s) ]. With two-component T2 analysis, T2s showed greater prolongation than did T2f. The increase in T2s was significantly correlated with an increase in water content, but the increase in the T2f value was not correlated with water content or with a change in T2s. The T2s component, which likely reflected changes in interstitial water, was more closely related than the T2f component to an increase in water content in hydrostatic pulmonary edema. Results suggested that regional changes in hydrostatic pulmonary edema may be evaluated by multicomponent T2 analysis.

Decrease in glomerular filtration rate by plasma low-density lipoprotein cholesterol in subjects with normal kidney function assessed by urinalysis and plasma creatinine

OBJECTIVE It has not been well defined whether plasma low-density lipoprotein cholesterol (LDL-C) progresses arteriolosclerosis (arteriosclerosis of small arteries) or not. Estimated glomerular filtration rate (e-GFR) is an indicator of the function of renal arterioles and capillaries of glomeruli. The relationship between e-GFR and plasma LDL-C was studied to estimate the effect of plasma LDL-C on the function of renal arterioles and capillaries of glomeruli to speculate the effect of plasma LDL-C on arteriolosclerosis. METHODS AND RESULTS Major coronary risk factors; blood pressure, plasma lipids, and fasting plasma glucose were compared among 4 groups of examinees of a health evaluation and promotion center separated by e-GFR, namely, Control group, Group 1, 2, 3 from highest e-GFR to lowest e-GFR. Numbers of total male and female subjects were 4602 and 2920, respectively. Plasma LDL-C levels were significantly high in Group 2 and 3 in all male subjects and high in Group 1, 2, and 3 in male subjects with age of fifties, compared with Control group. Plasma LDL-C levels were significantly high in Group 1, 2, and 3 in all female subjects and high in Group 2 and 3 in female subjects with age of fifties, compared with Control group. Plasma levels of LDL-C were not significantly different at each years of age in subjects with age of fifties in both sex. BMI and waist circumference were higher in male subjects with low e-GFR but not in female subjects. Blood pressure and fasting plasma glucose were not high in subjects in Group 1, 2, and 3, compared with Control group in all subjects and subjects with age of fifties in both sex. CONCLUSIONS We concluded that the high plasma level of LDL-C was the major risk factor among coronary risk factors to reduce GFR probably due to impairing the function of renal arterioles and capillaries of glomeruli in subjects with normal kidney function assessed by urinalysis and plasma creatinine.

Exhalation immediately before inhalation optimizes dry powder inhaler use

Abstract Objective: Although exhalation immediately prior to inhalation (EPI) from dry powder inhalers (DPIs) is universally advised, its benefit has not been investigated. The objective of this study to assess the effects of EPI on inhaled flow from a DPI. Methods: We measured peak inhaled flow rate (PIFR) and inhaled gas volume of 25 volunteers unfamiliar with DPIs. They inhaled strongly and deeply through a flow meter either with or without EPI before and after connecting Turbuhaler® or Diskus®. Results: Median PIFR increased significantly with EPI both without connection to DPIs (178.8 versus 140.4 L min−1), and with connection to Diskus® (75.6 versus 67.8 L min−1), or to Turbuhaler® (51.0 versus 48.0 L min−1). As a result, the number of subjects whose PIFR exceeded 60 L min−1 was significantly increased with connection to either Diskus® (76 versus 64%) or to Turbuhaler® (24 versus 4%). EPI significantly increased median inhaled volume both without connection to DPIs (2.84 versus 1.84 L), and with connection to Diskus® (1.95 versus 1.66 L), or to Turbuhaler® (1.86 versus 1.28 L). EPI significantly increased F0.2 (flow at 0.2 s after onset of inhalation) and AC30 (flow acceleration at 30 L min−1), parameters representing the rate of flow increase during the early phase of inhalation, in all the three groups. Conclusions: EPI increases PIFR which may augment drug dispersion and facilitate fine particle generation from a DPI.

Impact of holding position during inhalation on drug release from a reservoir-, blister- and capsule-type dry powder inhaler

ABSTRACT Objective: To determine whether drug release may be impaired by tilting some dry powder inhalers (DPIs). Methods: Using an inhalation simulator, we measured drug release from Turbuhaler® (TBH), Diskus® (DKS) and Breezhaler® (BZH) at several peak inhaled flow rates (PIFs) while the DPIs were held at level and tilted (80°). Drug release was then measured from all three DPIs at 0, 30, 60 and 90° of tilt, and capsule rotation was also recorded. Results: Drug release from TBH was flow-dependent while that from DKS and BZH was flow-independent. With TBH, the plot of drug release vs. PIF either at level or at tilted position scattered along approximately the same regression lines. With DKS and BZH, drug release at tilted position was significantly lower than that while at level. With DKS the decrease was almost 20%, while with BZH, drug release frequently failed. With BZH, significant reductions in drug release were observed while the device was tilted by 30–90°. Conclusion: The position in which the DPI is held may affect drug delivery, especially when using BZH.