Miyako Yamasaki

Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non–Small-Cell Lung Cancer

PURPOSE To investigate the efficacy and safety of nitroglycerin plus vinorelbine and cisplatin in patients with previously untreated stage IIIB/IV non-small-cell lung cancer (NSCLC) as the experimental arm for the next phase III trial. PATIENTS AND METHODS One hundred twenty patients with stage IIIB/IV NSCLC were randomly assigned to vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, with transdermally applied nitroglycerin (25 mg/patient daily for 5 days; arm A) or with placebo patch (arm B) every 3 weeks for a maximum of four cycles in a double-blind and controlled trial. Primary efficacy end points were the best confirmed response rate and time to disease progression (TTP). RESULTS The response rate in arm A (72%; 43 of 60 patients) was significantly higher than that for patients in arm B (42%; 25 of 60 patients; P < .001). Median TTP in arm A was longer than that in arm B (327 v 185 days). No severe adverse effect was recognized for either arm. The rate of grade 1 to 2 headache in arm A (30%; 18 of 60 patients) was significantly higher than that in arm B (2%; one of 60 patients; P < .001, chi(2) test). CONCLUSION Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.

Impaired urge-to-cough in elderly patients with aspiration pneumonia

BackgroundThe down-regulation of the cough reflex in patients with aspiration pneumonia can involve both cortical facilitatory pathways for cough and medullary reflex pathways. In order to study the possible involvement of the supramedullary system in the down-regulation of cough reflex, we evaluated the urge-to-cough in patients with aspiration pneumonia.MethodsCough reflex sensitivity and the urge-to-cough to inhaled citric acid were evaluated in patients with at least a history of aspiration pneumonia and age-matched healthy elderly people. The cough reflex sensitivities were defined as the lowest concentration of citric acid that elicited two or more coughs (C2) and five or more coughs (C5). The urge-to-cough scores at the concentration of C2 and C5, and at the concentration of two times dilution of C2 (C2/2) and C5 (C5/2) were estimated for each subject.ResultsBoth C2 and C5 in the control subjects were significantly greater than those for patients with aspiration pneumonia. There were no significant differences in the urge-to-cough at C2 and C5 between control subjects and patients with aspiration pneumonia. However, the urge-to-cough scores at both C2/2 and C5/2 in patients with aspiration pneumonia were significantly lower than those in control subjects. The number of coughs at C5/2 was significantly greater in the control subjects than those in the patients with aspiration pneumonia whereas the number of coughs at C2/2 did not show a significant difference between the control subjects and the patients with aspiration pneumonia.ConclusionThe study suggests the involvement of supramedullary dysfunction in the etiology of aspiration pneumonia in the elderly. Therefore, restoration of the cough motivation system could be a new strategy to prevent aspiration pneumonia in the elderly.

Perception of urge-to-cough and dyspnea in healthy smokers with decreased cough reflex sensitivity

BackgroundAlthough cigarette smoking has been implicated as an important risk factor for the development of respiratory symptoms, the perceptional aspects of two symptoms in smokers have not been fully elucidated. Therefore, we simultaneously evaluated the cough reflex sensitivity, the cognition of urge-to-cough and perception of dyspnea in both healthy smokers and non-smokers.MethodsFourteen male healthy never-smokers and 14 age-matched male healthy current-smokers were recruited via public postings. The cough reflex sensitivity and the urge-to-cough were evaluated by the inhalation of citric acid. The perception of dyspnea was evaluated by Borg scores during applications of external inspiratory resistive loads.ResultsThe cough reflex threshold to citric acid, as expressed by the lowest concentration of citric acid that elicited two or more coughs (C2) and the lowest concentration of citric acid that elicited five or more coughs (C5) in smokers was significantly higher than in non-smokers. The urge-to-cough log-log slope in smokers was significantly milder than that of non-smokers. There were no significant differences in the urge-to-cough threshold between non-smokers and smokers. There were no significant differences in perceptions of dyspnea between non-smokers and smokers.ConclusionsThe study showed that decreased cough reflex sensitivity in healthy smokers was accompanied by a decreased cognition of urge-to-cough whereas it was not accompanied by the alternation of perception of dyspnea. Physicians should pay attention to the perceptual alterations of cough in smokers.

Effects of capsiate on the triggering of the swallowing reflex in elderly patients with aspiration pneumonia

Morbidity and mortality from aspiration pneumonia continue to be major health problems in the elderly. Dysphagia, such as delayed triggering of the swallowing reflex, an important respiratory defense mechanism, predisposes subjects to aspiration pneumonia. Triggering of the swallowing reflex could be accelerated if swallowed material was warmed up, even in dysphagic patients. Moreover, it has been reported that capsaicin accelerated the swallowing reflex in patients with aspiration pneumonia. Because the hot sensation is sensitized through transient receptor potential vanilloid 1 (TRPV1), the results indicate that TRPV1 stimulation together with laryngeal food stimuli accelerate swallowing reflex in the elderly. Although capsaicin is a wellknown and efficient TRPV1 agonist, its pungency is sometimes unacceptable to elderly people. Capsiate is obtained from the non-pungent cultivar of red peppers named CH-19 Sweet. CH-19 Sweet is a fixed cultivar that was selected and cultivated from a pungent cultivar, CH-19, of pepper. Capsiate is known to activate TRPV1, and, despite non-pungency, increases adrenaline secretion and oxygen consumption like capsaicin. Hence, capsiate may have a capability to accelerate the swallowing reflex without inducing a pungent sensation in elderly people. Therefore, we examine herein the effect of capsiate in elderly patients with aspiration pneumonia. Twelve elderly patients with aspiration pneumonia were recruited from those referred and admitted to the Geriatric Unit, Tohoku University Hospital for treatment of pneumonia from May 2006 to April 2007. Pneumonia was diagnosed by the presence of pulmonary infiltration on chest radiograph and computed tomography (CT) and according to systemic inflammation as determined by white blood cell (WBC) count and C-reactive protein (CRP). The criteria for pneumonia were established according to the pneumonia guidelines of the Japanese Respiratory Society. In the current study, aspiration was defined according to the Japanese Study Group on Aspiration Pulmonary Disease as pneumonia in a patient with a predisposition to aspiration because of dysphagia or swallowing disorders. We studied the swallowing reflex in 12 patients (seven men and five women) as they recovered from treatment such as antibiotic drip infusion. Informed consent was obtained from all subjects or their families. The patients fed themselves or needed help in eating. Patients had neither feeding tube nor percutaneous endoscopic gastrostomy. The protocol was approved by the Institutional Review Board of the Tohoku University Ethics Committee and it conformed to the provisions of the Declaration of Helsinki. The swallowing reflex was induced by a bolus injection of 1 mL distilled water into the pharynx through a nasal catheter (8-Fr). The subjects were unaware of the actual injection. Swallowing was identified by sub-mental electromyographic (EMG) activity and/or visual observation of characteristic laryngeal movement. EMG activity was recorded from surface electrodes on the chin. The swallowing reflex sensitivity of elderly patients was evaluated as a latent time of swallowing reflex (LTSR), timed from the injection to the onset of swallowing. Capsiate was extracted from CH-19 Sweet (kind gift from Ajinomoto, Kawasaki, Japan). Harvested chili peppers (CH-19 Sweet) were washed and dried. Then, the crude oil was extracted from the dried chili peppers using n-hexane. The crude oil was refined by distillation and column chromatography. Finally, in order to adjust the concentration, the refined oil was diluted with medium-chain Geriatr Gerontol Int 2010; 10: 107–109

Shelter-Acquired Pneumonia After a Catastrophic Earthquake in Japan

daily. Her swallowing reflex latency time normalized after ACE inhibitor treatment. She had been hospitalized three times because of COPD exacerbations in the previous year and experienced two exacerbations during the 6.1 years of follow-up. In addition to the regular treatment of COPD, ACE inhibitor treatment improved the swallowing reflexes of these individuals and reduced the frequency of COPD exacerbations (from 3 to 0.46 per year in case 1, and from 3 to 0.33 per year in case 2). The patients had not recognized their impaired swallowing reflexes, because they were on entirely oral diets without complaints of dysphagia and had no prior history of symptomatic stroke or oropharyngeal or esophageal abnormalities. Aspiration is associated with impairment of swallowing and cough reflex, which is mediated through substance P. ACE inhibitors decrease the catabolism of substance P, resulting in prevention of aspiration and protection against pneumonia in older adults. The findings of the current study suggest that ACE inhibitors protect against aspiration tracheobronchitis and exacerbations of COPD. ACE inhibitors have also been demonstrated to have beneficial effects on the heart, although the follow-up examination of these individuals, including electrocardiogram and echocardiogram, did not indicate a significant change. The blood pressure of these individual did not decrease significantly during the follow-up period. Although symptomatic hypotension has been reported to be rare, one should be careful about adverse effects of ACE inhibitor treatment in older adults. ACE inhibitor therapy is a potential option for preventing COPD exacerbations in selected individuals with impaired swallowing reflexes. Large randomized controlled clinical trials will be useful.

Aging deteriorated perception of urge-to-cough without changing cough reflex threshold to citric acid in female never-smokers

BackgroundThe effect of aging on the cognitive aspect of cough has not been studied yet. The purpose of this study is to investigate the aging effect on the perception of urge-to-cough in healthy individuals.MethodsFourteen young, female, healthy never-smokers were recruited via public postings. Twelve elderly female healthy never-smokers were recruited from a nursing home residence. The cough reflex threshold and the urge-to-cough were evaluated by inhalation of citric acid. The cough reflex sensitivities were defined as the lowest concentration of citric acid that elicited two or more coughs (C2) and five or more coughs (C5). The urge-to-cough was evaluated using a modified the Borg scale.ResultsThere was no significant difference in the cough reflex threshold to citric acid between young and elderly subjects. The urge-to-cough scores at the concentration of C2 and C5 were significantly smaller in the elderly than young subjects. The urge-to-cough log-log slope in elderly subjects (0.73 ± 0.71 point · L/g) was significantly gentler than those of young subjects (1.35 ± 0.53 point · L/g, p < 0.01). There were no significant differences in the urge-to-cough threshold estimated between young and elderly subjects.ConclusionsThe cough reflex threshold did not differ between young and elderly subjects whereas cognition of urge-to-cough was significantly decreased in elderly subjects in female never-smokers. Objective monitoring of cough might be important in the elderly people.

Multidisciplinary Team-Based Approach for Comprehensive Preoperative Pulmonary Rehabilitation Including Intensive Nutritional Support for Lung Cancer Patients

Background To decrease the risk of postoperative complication, improving general and pulmonary conditioning preoperatively should be considered essential for patients scheduled to undergo lung surgery. Objective The aim of this study is to develop a short-term beneficial program of preoperative pulmonary rehabilitation for lung cancer patients. Methods From June 2009, comprehensive preoperative pulmonary rehabilitation (CHPR) including intensive nutritional support was performed prospectively using a multidisciplinary team-based approach. Postoperative complication rate and the transitions of pulmonary function in CHPR were compared with historical data of conventional preoperative pulmonary rehabilitation (CVPR) conducted since June 2006. The study population was limited to patients who underwent standard lobectomy. Results Postoperative complication rate in the CVPR (n = 29) and CHPR (n = 21) were 48.3% and 28.6% (p = 0.2428), respectively. Those in patients with Charlson Comorbidity Index scores ≥2 were 68.8% (n = 16) and 27.3% (n = 11), respectively (p = 0.0341) and those in patients with preoperative risk score in Estimation of Physiologic Ability and Surgical Stress scores >0.3 were 57.9% (n = 19) and 21.4% (n = 14), respectively (p = 0.0362). Vital capacities of pre- and post intervention before surgery in the CHPR group were 2.63±0.65 L and 2.75±0.63 L (p = 0.0043), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6815). Forced expiratory volumes in one second of pre- and post intervention before surgery in the CHPR group were 1.73±0.46 L and 1.87±0.46 L (p = 0.0012), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6424). Conclusions CHPR appeared to be a beneficial and effective short-term preoperative rehabilitation protocol, especially in patients with poor preoperative conditions.

Gender differences in perceptions of urge to cough and dyspnea induced by citric acid in healthy never smokers.

BACKGROUND The mechanism of the gender difference in cough reflex threshold has not been clearly elucidated. In the present study, we evaluated gender differences in the cough reflex threshold along with the perceptions of respiratory sensations, urge to cough, and dyspnea. METHODS Nineteen male and 20 female healthy never smokers were recruited through public postings. The cough reflex threshold and the urge to cough were evaluated by inhalation of citric acid. The perception of dyspnea was evaluated by Borg scores during applications of external inspiratory resistive loads. RESULTS The cough reflex threshold and suprathreshold to citric acid in women, as expressed by the log transformation of the lowest concentration of citric acid that elicited two or more and five or more coughs, was significantly lower than that in men. The urge-to-cough log-log slope in women (1.47 ± 0.81 point × L/g) was significantly steeper than in men (0.96 ± 0.28 point × L/g; P < .03). There were no significant differences in the urge-to-cough threshold estimated between men and women. The slope of the dyspnea Borg score change during the external inspiratory resistive loads is steeper in women (0.17 ± 0.04 point/cm H₂O/L/s) than that in men (0.13 ± 0.05 point/cm H₂O/L/s; P < .01). The urge-to-cough slope significantly correlated with the perception of dyspnea slope (r = 0.537; P < .01). CONCLUSIONS The gender difference in cough reflex threshold accompanied the gender difference in amplification rate of respiratory sensations in the same direction. The higher central gain for common pathways for respiratory sensations may play a role in lower cough reflex threshold in women. Further studies are needed to elucidate this issue.

Cough reflex and oral chemesthesis induced by capsaicin and capsiate in healthy never-smokers

BackgroundMany tussive agents are components of foods, but little is known about the relationship between cough reflex and oral chemesthesis sensitivities. We investigated the relationships between cough reflex and oral chemesthesis in individuals using two transient receptor potential vanilloid 1 (TRPV1) agonists with different potencies: capsaicin and capsiate.MethodsTwenty-eight healthy never-smokers were allocated to evaluate cough and oral chemesthesis of capsinoids. Cough reflex sensitivities are estimated by the lowest concentrations generating five coughs by each TRPV1 agonist inhalation. Oral chemesthesis sensitivities are estimated by the lowest concentrations which generate a hot sensation when filter paper loaded with each TRPV1 agonist is placed on the tongue.ResultsThere were strong correlations between capsaicin- and capsiate-induced cough reflex sensitivities, and between capsaicin- and capsiate-induced oral chemesthesis sensitivities. However, there were no significant correlations between cough reflex and oral chemesthesis sensitivities induced by both capsaicin and capsiate. The cough reflex sensitivities are significantly greater in females than in males whereas there were no gender differences in oral chemesthesis.ConclusionThe results showed that the sensitivities of sensory afferents were different between cough reflex and oral chemesthesis, suggesting that TRPV1 sensitivities differ between organs within healthy individuals. Capsiate could be a tussigen for the cough challenge test.

Low Serum 1,25-Dihydroxyvitamin D Level and Risk of Respiratory Infections in Institutionalized Older People

measured serum concentrations of 1,25dihydroxyvitamin D and albumin, performed a tuberculin skin test (TST), an indicator of cellular immunity [7] , and retrospectively assessed the incidence of both febrile respiratory illnesses and pneumonia [8] . Study participants more than 65 years of age were recruited from a long-term care facility in Sendai, Japan. They were resident in the facility for at least 6 months and were disabled because of cerebral infarction, but had no conditions known to interfere with VD metabolism [2] . Individuals were excluded if they had malnutrition, renal failure, hepatic failure, hyperor hypoparathyroidism, active tuberculosis, malignant diseases, or if they took corticosteroids or supplementary VD [2, 6] . A blood sample was drawn for baseline assay and a TST was performed according to the national guidelines [7, 9] , both in the elderly residents and in the nursing staff of the facility as a control. Serum levels of 1,25-dihydroxyvitamin D were determined by radioimmunoassay [10] . Since there is no consensus on the optimal serum levels of 1,25-dihydroxyvitamin D [2] , we divided the elderly residents into 2 To the Editor, Pneumonia is a common cause of death among older people despite the availability of potent new antimicrobials [1] . It might be quite important to find unknown risk factors for respiratory tract infections to prevent pneumonia in the elderly. Vitamin D (VD) is both a vitamin and a hormone and is recently reported to have diverse actions [2] . VD deficiency is especially common in institutionalized elderly people probably due to limited sun exposure, skin diseases and problems of dietary intake and is associated with hip fractures and higher mortality from life-threatening conditions such as cardiovascular diseases, cancer and diabetes mellitus [2–6] . Recently, 1,25-dihydroxyvitamin D, a biologically active form of VD, was reported to be a potent immune modulator of the adaptive immune system and to stimulate the innate immune response upon infection [2] . However, the clinical significance of endogenous 1,25-dihydroxyvitamin D has not been fully studied [2, 6] . The aim of this study was to examine whether VD deficiency correlates with depressed cellular immunity and increases susceptibility to respiratory tract infections among older residents of long-term care facilities. We Received: August 12, 2009 Accepted: December 4, 2009 Published online: January 12, 2010