Yoshihisa Ishiura

EGFR Mutation of Tumor and Serum in Gefitinib-Treated Patients with Chemotherapy-Naive Non–small Cell Lung Cancer

Background: The authors evaluate the efficacy and safety of gefitinib monotherapy in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC). A secondary endpoint is to evaluate the relationship between clinical manifestations and epidermal growth factor receptor (EGFR) mutation status. Methods: Japanese chemotherapy-naive NSCLC patients were enrolled. They had measurable lesions, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ and bone marrow function. Patients received 250 mg of oral gefitinib daily. EGFR mutations in exon 18, 19, and 21 of DNA extracted from tumor and serum were analyzed by genomic polymerase chain reaction and direct sequence. Results: All 30 patients were eligible for the assessment of efficacy and safety. An objective response and stable disease were observed in 10 patients (33.3%) and nine patients (30.0%), respectively. The median time to progression was 3.3 months and the median overall survival was 10.6 months. The 1-year survival rate was 43.3%. Grade 3 toxicities were observed in seven patients. EGFR mutation was observed in four of 13 (30.8%) tumors, and two of them achieved partial response. In serum samples, three of 10 patients with EGFR mutations in the serum before treatment had a response to gefitinib. EGFR mutation was observed in 10 of 27 and significantly more frequently observed in the posttreatment samples from patients with a partial response or stable disease than in those from patients with progressive disease (p = 0.006). Conclusions: Gefitinib monotherapy in chemotherapy-naive NSCLC patients was active, with acceptable toxicities. These results warrant further evaluation of gefitinib monotherapy as a first-line therapy. The EGFR mutation in serum DNA may be a biomarker for monitoring the response to gefitinib during treatment.

Atopy in cough sensitivity to capsaicin and bronchial responsiveness in young females

We have shown previously that female sex is a determinant of cough sensitivity to inhaled capsaicin, but the relationship between atopy and the cough sensitivity has not been examined. The capsaicin cough threshold, defined as the lowest concentration of capsaicin causing five or more coughs, nonspecific bronchial responsiveness, defined as the provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20), total immunoglobulin E (IgE) and specific IgEs to eight common aeroallergens (house dust 1, 2 and 6, Dermatophagoides pteronyssinus and D. farinae, Japanese cedar, ragweed and orchard grass) in the serum were measured in 71 nonsmoking, healthy young women aged 20.6+/-0.1 yrs (mean+/-EM). A structured interviewer-led questionnaire on allergic diseases revealed that one and six subjects had mild current and past asthma, respectively. These seven subjects were excluded from the data analysis. PC20 was significantly lower in 42 subjects showing a positive specific IgE than in 22 subjects showing a negative specific IgE to any of the eight allergens (p<0.05), while the capsaicin cough threshold was not significantly different between the subgroups. PC20 was significantly lower in subjects with positive specific IgE to Dermatophagoides and house dust, but not to the three kinds of pollen examined. It was confirmed that atopy indicated by specific immunoglobulin E to mite-related antigens, but not to pollen antigens, is associated with nonspecific bronchial responsiveness, and it is suggested that atopy is not a determinant of airway cough sensitivity in healthy, nonasthmatic subjects.

Asthma severity is associated with an increase in both blood CXCR3+ and CCR4+ T cells.

Objectives:  A predominance of type 2 helper T cells (Th2) in the bronchoalveolar space and peripheral blood is a well‐accepted feature of bronchial asthma. However, the relationship between peripheral blood Th2 cells and asthma severity has not been thoroughly investigated.

Potentiation of allergic bronchoconstriction by repeated exposure to formaldehyde in guinea‐pigs in vivo

Background Indoor formaldehyde (FA) might worsen allergies and be an underlying factor for the increasing incidence and severity of asthma; the exact mechanism, however, remains unclear.

Ambroxol for the prevention of acute upper respiratory disease.

Although acute upper respiratory diseases (AURDs) such as common cold and influenza are common, few interventions have been proven to be effective in their prevention and treatment. The aim of this study was to assess the efficacy of ambroxol for preventing AURD. Fifty-four patients were randomly divided into 3 groups: a rebamipide (non-mucoactive drug) group (300 mg/day), carbocisteine group (1500 mg/day) and ambroxol group (45 mg/day). The study was divided into 2 terms, the first half-year (summer season) and the second half-year (winter season). In the preceding winter, only 19.5% of the patients had been vaccinated against influenza viruses (flu). The primary goal of this study was to evaluate the effectiveness of mucoactive drugs in decreasing the frequency of AURD. Treatment with ambroxol, but not carbocisteine, significantly reduced the median number of AURD episodes (P=0.0049 vs. rebamipide). Thirty-three patients without vaccination against flu were assessed especially during the second half-year. Treatment with ambroxol also significantly reduced the median number of AURD episodes in this assessment (P=0.0028 vs. rebamipide in the second half-year). In conclusion, ambroxol may be useful for preventing AURD.

Effects of suplatast tosilate, a new type of anti‐allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea‐pigs

Background Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non‐productive cough. Suplatast tosilate, an anti‐allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)‐4, IL‐5, immunoglobulin (Ig)E production, and local eosinophil accumulation.

Thromboxane antagonism and cough in chronic bronchitis

BACKGROUND. The increased eicosanoid synthesis has been suggested as the underlying mechanism of chronic productive cough in patients with chronic bronchitis. METHOD: The effects of the orally active thromboxane A2 (TxA2) receptor antagonist seratrodast and the cysteinyl leukotrienes (cLTs) receptor antagonist pranlukast on cough response to inhaled capsaicin were examined in sixteen patients with stable chronic bronchitis. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough sensitivity. RESULTS: The cough threshold was significantly increased compared with placebo after four-week treatment with seratrodast, but not after treatment with pranlukast. CONCLUSIONS: TxA2, but not cLTs, may be a possible modulator augmenting airway cough sensitivity in chronic bronchitis. Thromboxane antagonism may be considered to be one of the therapeutic options for the treatment of chronic productive cough.

Additive effect of continuous low-dose ofloxacin on erythromycin therapy for sinobronchial syndrome

It has been established that long-term low-dose erythromycin therapy (EM therapy) is very effective for sinobronchial syndrome, a common condition in Japan characterized by chronic upper and lower airway inflammation. The effect does not result from its bacteriocidal activity and the detailed mechanisms are not known. It takes 3-6 months for EM therapy to improve the symptoms. This study was designed to evaluate the additive effect of continuous low dosage or intermittent usual dosage of ofloxacin (OFLX) on EM therapy in patients with sinobronchial syndrome. Patients with sinobronchial syndrome were randomly allocated to receive one of the following four regimens. Patients in Group A received both low-dose OFLX and EM therapy daily for 6 months. Patients in Group B received EM therapy and intermittent treatment of OFLX for 6 months. Patients in Group C underwent EM therapy for 6 months. Patients in Group D received neither OFLX nor EM therapy. All patients were given carbocystein for more than 2 months before starting each treatment and during the study period. In patients receiving OFLX and/or EM therapy, these antimicrobial agents were well-tolerated during the treatment period. Amount of sputum in the morning was significantly less in Group C than in Group D after 3-6 months, and decreased significantly in Group A as compared with Group B after 2 weeks, Group C after 2 weeks to 2 months, and Group D after 2 weeks to 6 months. Other symptoms such as number of expectorations, difficulty of expectoration and severity of cough also improved rapidly in Group A. These findings suggest that it is useful to add low-dose OFLX to EM therapy for sinobronchial syndrome, especially within 1-2 months from starting treatment, and it may be cost-effective as this combination therapy can shorten the treatment period of EM therapy.

Prostaglandin I2 enhances cough reflex sensitivity to capsaicin in the asthmatic airway.

Inflammatory mediators are involved in the pathogenesis of airway inflammation, but the role of prostaglandin I2 (PGI2) remains obscure. This study was designed to investigate the role of PGI2 in cough reflex sensitivity of the asthmatic airway, which is characterized by chronic eosinophilic airway inflammation. The effect of beraprost, a chemically and biologically stable analogue of PGI2, on cough response to inhaled capsaicin was examined in 21 patients with stable asthma in a randomized, placebo-controlled cross over study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough reflex sensitivity. The cough threshold was significantly (p < 0.05) decreased after two weeks of treatment with beraprost [17.8 (GSEM 1.20) μM] compared with placebo [30.3 (GSEM 1.21) μM]. PGI2 increases cough reflex sensitivity of the asthmatic airway, suggesting that inhibition of PGI2 may be a novel therapeutic option for patients with asthma, especially cough predominant asthma.

Phosphodiesterase 3 inhibition and cough in elderly asthmatics

AimsCough is a common symptom of bronchial asthma, a chronic inflammatory airway disease. Recently, the therapeutic effects of selective phosphodiesterase (PDE) inhibitors have been focused on bronchial asthma. This study was designed to investigate the clinical effect of PDE 3 inhibition on cough reflex sensitivity in elderly patients with bronchial asthma.MethodsEffects of cilostazol, a PDE 3 inhibitor, on cough response to inhaled capsaicin were examined in 11 patients over 70 years with stable asthma in a randomized, placebo-controlled cross over study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough reflex sensitivity.ResultsThe cough threshold was significantly (p < 0.05) increased after two-week treatment with cilostazol (100 mg twice a day orally) compared with placebo [48.8 (GSEM 1.4) vs. 29.2 (GSEM 1.3) μM].ConclusionThese findings indicate that PDE 3 inhibition may be a novel therapeutic option for elderly patients with asthma, especially for their cough symptoms.