Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (19)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ebihara, S.
Right arrow Articles by Sasaki, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ebihara, S.
Right arrow Articles by Sasaki, H.
(Chest. 2003;124:1009-1015.)
© 2003 American College of Chest Physicians

Impaired Efficacy of Cough in Patients With Parkinson Disease*

Satoru Ebihara, MD, PhD; Hiroshi Saito, MD, PhD, FCCP; Akio Kanda, MD; Mizue Nakajoh, MD, PhD; Hidenori Takahashi, MD, PhD; Hiroyuki Arai, MD, PhD and Hidetada Sasaki, MD, PhD, FCCP

* From the Department of Geriatric and Respiratory Medicine (Drs. Ebihara, Kanda, Nakajoh, Takahashi, Arai, and Sasaki), Tohoku University School of Medicine, Sendai, Japan; and the Department of Neurology (Dr. Saito), National Nishitaga Hospital, Sendai, Japan.

Correspondence to: Hidetada Sasaki, MD, PhD, FCCP, Professor and Chairman, Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Seiryo-machi 1–1, Aoba-ku, Sendai 980-8574, Japan; e-mail: dept{at}geriat.med.tohoku.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Aspiration pneumonia, a leading cause of death in patients with Parkinson disease (PD), usually occurs at the advanced stages of the disease. We investigated both motor and sensory components of cough and induced-sputum substance P (SP) concentrations in patients with early and advanced stages of PD to assess whether cough efficacy is impaired in PD.

Subjects: Fifteen female patients with early stages of PD (Hoehn and Yahr stage II-III), 10 patients with advanced stages of PD (Hoehn and Yahr stage IV), and 15 age-matched female control subjects were investigated.

Measurements: The motor component of cough efficacy was assessed by monitoring voluntary maximal cough peak flow. The sensory component of cough efficacy was assessed by measuring cough reflex sensitivity to citric acid inhalation. Sputum SP concentrations were measured in sputum induced by hypertonic saline solution inhalation.

Results: The mean (± SD) cough peak flow rates in patients with both early PD (230 ± 74 L/min; p < 0.005) and advanced PD (186 ± 60 L/min; p < 0.0001) were significantly weaker than that in control subjects (316 ± 70 L/min). Cough reflex sensitivity in patients with advanced PD (46.7 ± 49.3 g/L) was significantly lower compared to control subjects (14.5 ± 16.6 g/L; p < 0.01) and patients with early PD (11.2 ± 14.8 g/L; p < 0.005). The sputum SP concentration was significantly lower in patients with advanced PD (11.2 ± 8.4 pg/mL) compared to that in control subjects (35.6 ± 15.4 pg/mL) and patients with early PD (28.5 ± 16.4 pg/mL).

Conclusion: In the early stages of the disease, mainly the motor component of cough was impaired. In advanced stages of the disease, both the motor and sensory components of cough were impaired. Sputum SP concentration significantly declined in patients with advanced PD. The results suggest that the combination of impaired motor and sensory components of cough may play an important role in the development of aspiration pneumonia in PD.

Key Words: cough • cough peak flow • cough reflex sensitivity • Parkinson disease


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Despite the progress in therapy for Parkinson disease (PD), PD is still associated with significant morbidity and mortality.1 Aspiration pneumonia is a leading cause of death in patients with PD.1 Airway protective mechanisms such as swallowing and cough may play a role in aspiration pneumonia. Although swallowing disorders in patients with PD are well-known,2 3 4 it has not been established whether the efficacy of cough in patients with PD is impaired.

Cough is an important defense mechanism, the main function of which is to remove mucus and/or foreign bodies from the airways by generating a high expiratory flow. The impairment of cough efficacy could be due to the dysfunction of either motor components (ie, cough intensity such as cough peak flow) or sensory components (ie, cough reflex sensitivity) of cough. The risk of aspiration pneumonia is increased in stroke patients with a weak voluntary cough peak flow5 and impaired cough reflex sensitivity.6 7 In patients with motor neuron disease, declined cough peak flow was related to episodes of choking.8 Cough peak flow is also lower in patients with muscular dystrophy,9 10 11 12 amyotrophic lateral sclerosis,11 12 13 and spinal cord injury,14 who are susceptible to fatal aspiration pneumonia. Cough reflex sensitivity is diminished in patients after heart-lung transplantation,15 also making them highly susceptible to aspiration pneumonia.

The impaired motor component of cough in patients with PD has been shown by monitoring the electromyogram of abdominal muscles and maximal expiratory pressure.16 However, cough peak flow has not been measured in patients with PD. In terms of the sensory component of cough, previous studies16 17 have failed to detect the decline of cough reflex sensitivity in patients with PD. In these studies, however, the level of clinical disability was not taken into consideration when estimating cough reflex sensitivity. Since aspiration pneumonia usually occurs in patients in the advanced stages of PD, it is possible that this finding is not prominent in the early stages of the disease. Moreover, accumulating evidence shows that the cough reflex is more sensitive in women than in men,18 19 20 indicating that gender should be matched in a comparison of cough reflex sensitivities.

In the present study, we estimate both the motor and sensory components of cough efficacy by measuring the cough peak flow and sensitivity of cough reflex to citric acid in female patients with PD at different stages. In addition, we investigated sputum substance P (SP) concentration, which may play an important role in cough reflex.21


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Because gender differences in the cough peak flow22 and cough reflex sensitivity18 19 20 are known, we focused on female subjects in this study. Twenty-five female outpatients with idiopathic PD were recruited from our neurologic clinics at Tohoku University Hospital and National Nishitaga Hospital in Sendai City. The diagnosis of idiopathic PD was based on the consensus of two neurologists. The age at onset of PD was defined as the appearance of the first symptom estimated by medical interview, and the severity of PD was classified on a scale from I to V, as stage II (8 patients), stage III (7 patients), and stage IV (10 patients), according to Hoehn and Yahr.23 Here, we defined the patients with stage II or III disease as early PD, and stage IV as advanced PD. All patients had a Mini-Mental State Examination score of > 24 and had been stable for at least 3 months before entering the trial. All patients responded to and their conditions were being maintained with a combination of levodopa and carbidopa. Sixteen healthy volunteers, who were age-matched and height-matched, were recruited from the community by advertisement. All subjects were nonsmokers and had no history of chronic respiratory disease or acute respiratory problems during the previous 6 months. Patients taking angiotensin-converting enzyme inhibitors were excluded from the study.24 25 The studies were performed on two consecutive days at the same time of the day (around 2 h after taking the dopaminergic medication). On the first day, spirometry (model OST 80A; Chest Co; Tokyo, Japan), cough intensity, and cough reflex sensitivity were measured. On the second day, the sputum for SP measurement was collected. All measurements were performed by a laboratory technician who did not know the purpose of the study. The experimental protocol adhered to the Recommendations of the Declaration of Helsinki for Human Experimentation. The protocol was approved by the Tohoku University Ethics Committee. Individual informed consent was obtained after a detailed explanation of the procedure, but not of the purposes, of the study. Studies were conducted after the patients gave informed consent, according to the Declaration of Helsinki for Human Experimentation.

Cough Reflex Sensitivity
Cough reflex sensitivity to citric acid was evaluated with tidal breathing of a nebulized solution that was delivered by ultrasonic nebulizer (model MU-32; Sharp Co Ltd; Osaka, Japan).21 The nebulizer generated particles with a mean mass median diameter of 5.4 µm at an output of 2.2 mL/min. Citric acid was dissolved in saline solution, providing a twofold incremental concentration from 0.07 to 36%. Cough was recorded on a Fleisch pneumotachograph mounted at the expiratory ports of the valve. The cough threshold was defined as the concentration at which the patients coughed at least five times during 1 min of breathing the citric acid aerosol. Each nebulizer application had a 2-min interval.

Cough Intensity
Cough intensity was estimated by measuring the cough peak flow during voluntary maximal cough. To measure the cough peak flow, the sitting subjects were instructed to take a full inspiration and to cough into the face mask connected to a peak flowmeter (mini-Wright; Clement Clarke International; Harlow, UK) as forcefully as possible. The values obtained by a peak flowmeter are known to be quite close to the value obtained by a pneumotachometer.26 The presented values are the mean of the three highest values from five attempts.

Sputum SP Concentration
Induced sputum was collected the day after measurements of cough reflex sensitivity, spirometry, and cough peak flow were made. Capsaicin-containing meals were not allowed for 12 h before sputum collection. Around 2 h after the intake of their regular dopaminergic medication, the sputum collection was performed. A 3% saline solution was administered via an ultrasonic nebulizer for 15 to 30 min until the sputum volume was approximately 1 mL. Because the sample contained saliva, we eliminated this contamination by visual inspection and inverted microscopy examination.27 The SP was quantified using modification of a previously described method.28 The collected 1-mL sputum samples were immediately mixed with 0.5 U/mL aprotonin and 3 mmol/L ethylenediaminetetraacetic acid, and was stored at -70°C until assay. For radioimmunoassay, the samples were mixed with 2 vol (vol/vol) acetone using a mixer at room temperature for 5 min. The precipitate was pelleted by centrifugation at 2,500g for 5 min. After centrifugation, the supernatants were extracted twice with petroleum ether, and the supernatant then was evaporated in a water bath under N2 gas. After evaporation, the dried residue was dissolved in a 0.05 mol/L Tris-HCl buffer (pH 8.65) containing 0.1% human serum albumin, 0.01 mmol/L ethylenediaminetetraacetic acid, 0.15 mmol/L NaCl, 0.002% sodium azide, and 0.2 mL samples were incubated with 0.05 mL rabbit anti-SP serum (SRL, Inc; Tokyo, Japan) for 24 h at 4°C. 125I SP, 15,000 counts per minute (NEN Life Science Products, Inc; Boston, MA) in 0.05 mL, was added, and the mixture was incubated for an additional 24 h at 4°C. Bound and free ligands were separated by adding 0.05 mol/L Tris-HCl buffer, 1% {gamma}-globulin, and 25% polyethyleneglycol (6,000 mol/L), and were centrifuged at 1,700g for 20 min. The radioactivity in the precipitate was counted in a {gamma}-spectrometer.

Statistical Analysis
Values are expressed as the mean ± SD. The comparisons of the three groups were performed by one-way analysis of variance with post hoc application of the Fisher least-significant-difference test. A p value of < 0.05 was taken to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All 41 subjects completed the experiments without any difficulties or side effects. Table 1 shows the characteristics of the subjects. There were no significant differences in age, height, FVC, and FEV1 among control subjects, patients with early PD, and patients with advanced PD. Patients with advanced PD had a tendency to have experienced a longer duration of the disease than patients with early PD.


View this table:
[in this window]
[in a new window]

  		Table 1.. Characteristics of Control Subjects and Patients With PD*

 
The intensity of maximal voluntary cough, expressed as rates of cough peak flow, both in patients with early PD (230 ± 74 L/min; p < 0.005) and advanced PD (186 ± 60 L/min; p < 0.0001) were significantly weaker than the cough intensity of control subjects (316 ± 70 L/min) [Fig 1 ]. There was no significant difference in the value of cough peak flow between patients with early PD and those with advanced PD. As shown in Figure 2 , cough reflex sensitivity in patients with advanced PD (46.7 ± 49.3 g/L) was significantly lower than that of control subject (14.5 ± 16.6 g/L; p < 0.01) and patients with early PD (11.2 ± 14.8 g/L; p < 0.005), whereas there was no significant difference in cough reflex sensitivity between control subjects and patients with mild PD. Figure 3 shows the concentration of SP in sputum among the three groups. There was no significant difference in the mean volume of induced sputum among control subjects (1.3 ± 0.5 mL), patients with early PD (1.2 ± 0.6 mL), and patients with advanced PD (1.2 ± 0.5 mL). The percentage of squamous cells in sputum was < 10% in all individuals, indicating that almost all of the sputum samples were from the tracheobronchial tree. Sputum SP concentrations were significantly lower in patients with advanced PD (11.2 ± 8.4 pg/mL) compared to those in control subjects (35.6 ± 15.4 pg/mL) and patients with early PD (28.5 ± 16.4 pg/mL), whereas there was no significant difference between control subjects and patients with early PD.



View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Comparison of cough peak flow among control subjects and patients with early PD (ie, Hoehn-Yahr stage II-III) and advanced stages of PD (ie, Hoehn-Yahr stage IV). Each symbol represents a single subject. Mean values are indicated by a horizontal bar. N.S. = no significant difference.

 


View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2.. Comparison of cough reflex sensitivity among control subjects and patients with mild PD (ie, Hoehn-Yahr stage II-III) and severe PD (ie, Hoehn-Yahr stage IV). Each symbol represents a single subject. Mean values are indicated by a horizontal bar. See the legend of Figure 1 for abbreviation not used in the text.

 


View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3.. Comparison of sputum SP concentration among control subjects and patients with mild PD (ie, Hoehn-Yahr stage II-III) and severe PD (ie, Hoehn-Yahr stage IV). Each symbol represents a single subject. Mean values are indicated by a horizontal bar. See the legend of Figure 1 for abbreviation not used in the text.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Cough is an important defense mechanism functioning to remove mucus and foreign bodies from the respiratory tract by generating a high expiratory flow. In our study, we showed impaired efficacy of cough in patients with PD, with more pronounced impairment in patients with advanced PD compared to those with early PD. In the early stages of the disease, the motor component of cough was impaired. In advanced stages of the disease, both motor and sensory components of cough were impaired. Since dysphagia and the risk of aspiration worsen with the progression of PD,2 3 4 it is of importance to elucidate the factors involved in the impaired efficacy of cough in the advanced stage of PD.

Several measurements have been reported to be useful in the assessment of the motor component of the cough (ie, cough intensity), as follows: cough noise; electromyogram of abdominal muscles; and peak expiratory pressure. These measurements of the intensity of cough require special equipment and skills to measure, whereas it is quite simple to measure the cough peak flow by flowmeter. Using electromyogram and peak expiratory pressure, Fontana and colleagues16 showed that the reduced motor component of cough efficacy started in the early stages of PD. This result is consistent with our observation that was assessed by cough peak flow. The abnormal flow-volume curve in patients with PD is well-established.29 30 31 The decreased or less coordinated respiratory muscle force and/or upper airway obstruction are thought to be causes for the change in flow-volume curves in patients with PD. Reduced expiratory muscle strength is thought to be an important factor in decreased cough peak flow.16 Since the effective cough could require more delicate coordination of pharyngeal, laryngeal, and respiratory muscles than forced expiratory flow,32 the cough might be more susceptible to the disease than the maximal expiratory flow-volume curve. FVC values tended to decrease in the advanced stages of PD (Table 1) . Therefore, a failure to inspire to total lung capacity levels also may have contributed to a lowered cough peak flow. However, judging from the relatively large decrease in cough peak flow with increasing severity of disease, compared with the smaller decrease in FVC, we speculate that a significant influence of this mechanism is unlikely.

Our finding about the sensory component of cough in patients with PD differs from those of previous reports. Fontana and colleagues16 showed that cough reflex sensitivity was not significantly different between healthy control subjects and patients with PD. Smith and Wiles17 reported that patients with neurogenic dysphagia, including patients with PD, did not have a reduced cough reflex sensitivity. The apparent contradiction between their studies and ours seems to be based on differences in the severity of the disease rather than on differences in methodology. Since patients with early PD are less likely to have aspiration pneumonia, it is important to classify the stages of the disease to correlate the clinical significance of mortality from PD with impaired cough efficacy. Moreover, gender differences in cough reflex sensitivity have been reported using various stimuli.18 19 20 Women have a more sensitive cough reflex than men, whether in premenopausal or postmenopausal states.18 In the present study, we focused on the cough reflex sensitivity of female patients with different stages of PD and found that cough reflex sensitivity was significantly impaired in female patients with advanced stages of PD.

It is well-known that cough reflex sensitivity is seriously impaired in elderly patients with aspiration pneumonia.33 SP, which may play an important role in the cough reflex,21 was found to be decreased in the sputum of elderly patients with aspiration pneumonia.34 Since the major cause of death in patients with PD is aspiration pneumonia, we hypothesized that sputum SP concentrations in patients with PD also were lower. Indeed, SP concentrations in the saliva of patients with PD were found to be lower than those of age-matched control subjects.35 Moreover, the loss of SP-containing neurons in the brainstem36 and striatum37 from autopsy samples of PD patients have been reported, suggesting the systemic depletion of SP in patients with advanced stages of PD. Therefore, we measured the sputum SP concentration in patients in various stages of PD and showed a significantly decreased concentration of sputum SP only in patients with advanced PD. The result suggests that the sputum SP concentration may be related to the sensory component of cough rather than to the motor component in patients with PD. In guinea pigs, SP released from the sensory nerves in the airway has been shown as a possible endogenous substance causing cough.38 39

Since aspiration pneumonia usually occurs in the advanced stages of PD, the combined impairment of cough intensity and reflex sensitivity may play important roles in the development of aspiration pneumonia in PD patients. A strong relationship between impaired cough reflex sensitivity and the risk of aspiration pneumonia has been shown in stroke patients.6 Smith Hammond and colleagues5 have shown that an impaired cough intensity, as assessed by the flow of voluntary cough, was a risk factor for aspiration in stroke patients. Thus, the combined impairment of both the motor and sensory components of cough might be a common mechanism of aspiration pneumonia for patients with both stroke and PD.

Because aspiration pneumonia is the most common cause of death in PD patients,1 the related conditions should be treated more extensively in order to improve their survival. This study and observations of the elderly with cerebral vascular diseases34 suggest that reduced SP concentration is related to aspiration pneumonia in patients with advanced PD. The effort to increase the concentration of SP by angiotensin-converting enzyme inhibitors25 could be useful to reduce the risk of pneumonia in patients with PD, just as it is useful in older patients with cerebral vascular diseases.24 Further studies are needed to clarify whether interventions that are useful for treating aspiration pneumonia in the elderly40 are also beneficial for patients with PD.


   Acknowledgements
 
The authors thank Mr. Grant for reading the manuscript.


   Footnotes
 
Abbreviations: PD = Parkinson disease; SP = substance P

This study was supported by Grants-in-Aid for Encouragement of Young Scientists (No. 13770292) to Dr. Ebihara from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Received for publication May 20, 2003. Accepted for publication February 5, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Nakashima, K, Maeda, M, Tabata, M, et al (1997) Prognosis of Parkinson’s disease in Japan. Eur Neurol 38(suppl),60-63
  2. Robbins, JA, Logemann, JA, Kirshner, HS Swallowing and speech production in Parkinson’s disease. Ann Neurol 1986;19,283-287[CrossRef][ISI][Medline]
  3. Nilsson, H, Ekberg, O, Olsson, R, et al Quantitative assessment of oral and pharyngeal function in Parkinson’s disease. Dysphagia 1996;11,144-150[CrossRef][ISI][Medline]
  4. Leopold, NA, Kagel, MC Laryngeal deglutition movement in Parkinson’s disease. Neurology 1997;48,373-375[Abstract/Free Full Text]
  5. Smith Hammond, CA, Goldstein, LB, Zajac, DJ, et al Assessment of aspiration risk in stroke patients with quantification of voluntary cough. Neurology 2001;56,502-506[Abstract/Free Full Text]
  6. Addington, RW, Stephens, RE, Gilliland, KA Assessing the laryngeal cough reflex and risk of developing pneumonia after stroke. Stroke 1999;30,1203-1207[Abstract/Free Full Text]
  7. Kobayashi, H, Hoshino, M, Okayama, K, et al Swallowing and cough reflexes after onset of stroke [letter]. Chest 1994;105,1623[CrossRef][Medline]
  8. Hadjikoutis, S, Eccles, R, Wiles, M Coughing and choking in motor neuron disease. J Neurol Neurosurg Psychiatry 2000;68,601-604[Abstract/Free Full Text]
  9. Szeinberg, A, Tabachnik, E, Rashed, N, et al Cough capacity in patients with muscular dystrophy. Chest 1988;94,1232-1235[Medline]
  10. Bach, JR, Ishikawa, Y, Kim, H Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 1997;112,1024-1028[ISI][Medline]
  11. Tzeng, AC, Bach, JR Prevention of pulmonary morbidity for patients with neuromuscular disease. Chest 2000;118,1390-1396[CrossRef][Medline]
  12. Suarez, AA, Pessolano, FA, Monteiro, SG, et al Peak flow and peak cough flow in the evaluation of expiratory muscle weakness and bulbar impairment in patients with neuromuscular disease. Am J Phys Med Rehabil 2002;81,506-511[CrossRef][ISI][Medline]
  13. Bach, JR Amyotrophic lateral sclerosis: prolongation of life by noninvasive respiratory aids. Chest 2002;122,92-98[CrossRef][Medline]
  14. Mansel, JK, Norman, JR Respiratory complications and management of spinal cord injuries. Chest 1990;97,1446-1452[Medline]
  15. Higenbottam, T, Jackson, M, Woolman, P, et al The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989;140,58-61[ISI][Medline]
  16. Fontana, GA, Pantaleo, T, Lavorini, F, et al Defective motor control of coughing in Parkinson’s disease. Am J Respir Crit Care Med 1998;158,458-464[Abstract/Free Full Text]
  17. Smith, PEM, Wiles, CM Cough responsiveness in neurogenic dysphagia. J Neurol Neurosurg Psychiatry 1998;64,385-388[Abstract/Free Full Text]
  18. Fujimura, M, Kasahara, K, Kamio, Y, et al Female gender as a determinant of cough threshold to inhaled capsaicin. Eur Respir J 1996;9,1624-1626[Abstract]
  19. Dicpinigaitis, PV, Rauf, K The influence of gender on cough reflex sensitivity. Chest 1998;113,1319-1321[ISI][Medline]
  20. Rostami-Hodjegan, A, Abdul-Manap, R, Wright, CE, et al The placebo response to citric acid-induced cough: pharmacodynamics and gender differences. Pulm Pharmacol Ther 2001;14,315-319[CrossRef][ISI][Medline]
  21. Sekizawa, K, Jia, YX, Ebihara, T, et al Role of substance P in cough. Pulm Pharmacol 1996;9,323-328[CrossRef][ISI][Medline]
  22. Singh, P, Mahajan, PR, Murty, GE, et al Relationship of peak flow rate and peak velocity time during voluntary coughing. Br J Anaesth 1995;74,714-716[Abstract/Free Full Text]
  23. Hoehn, MM, Yahr, M Parkinsonism: onset, progression, and mortality. Neurology 1967;17,427-442[Free Full Text]
  24. Sekizawa, K, Matsui, T, Nakagawa, T, et al ACE inhibitors and pneumonia [letter]. Lancet 1998;352,1069[ISI][Medline]
  25. Tomaki, M, Ichinose, M, Miura, M, et al Angiotensin conversing enzyme (ACE) inhibitor-induced cough and substance P. Thorax 1996;51,199-201[Abstract]
  26. Pedersen, OF, Pedersen, TF, Miller, MR Gas compression in lung decreases peak expiratory flow depending on resistance of peak flowmeter. J Appl Physiol 1997;83,1517-1521[Abstract/Free Full Text]
  27. Tomaki, M, Ichinose, M, Miura, M, et al Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis. Am J Respir Crit Care Med 1995;151,613-617[Abstract]
  28. Joyce, TJ, Yood, RA, Carraway, RE Quantification of substance-P and its metabolites in plasma and synovial fluid from patients with arthritis. J Clin Endocrinol Metab 1993;77,632-637[Abstract]
  29. Bogaard, JM, Hovestadt, A, Meerwaldt, J, et al Maximal expiratory and inspiratory flow-volume curves in Parkinson’s disease. Am Rev Respir Dis 1989;139,610-614[ISI][Medline]
  30. De Bruin, PFC, De Bruin, VMS, Lees, AJ, et al Effects of treatment on airway dynamics and respiratory muscle strength in Parkinson’s disease. Am Rev Respir Dis 1993;148,1576-1580[ISI][Medline]
  31. Herer, B, Arnuff, I, Housset, B Effects of levodopa on pulmonary function in Parkinson’s disease. Chest 2001;119,387-393[Medline]
  32. Irwin, RS, Boulet, L, Cloutier, MM, et al Managing cough as a defense mechanism and as a symptom. Chest 1998;114(suppl),133S-181S
  33. Sekizawa, K, Ujiie, Y, Itabashi, S, et al Lack of cough reflex in aspiration pneumonia. Lancet 1990;335,1228-1229[ISI][Medline]
  34. Nakagawa, T, Ohrui, T, Sekizawa, K, et al Sputum substance P in aspiration pneumonia [letter]. Lancet 1995;345,1447[ISI][Medline]
  35. Iwasaki, K, Wang, Q, Seki, H, et al The effects of the traditional Chinese medicine, "Banxia Houpo Tang (Hange-Koboku To)" on the swallowing reflex in Parkinson’s disease. Phytomedicine 2000;7,259-263[ISI][Medline]
  36. Halliday, GM, Li, YW, Blumbergs, PC, et al Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease. Ann Neurol 1990;27,373-385[CrossRef][ISI][Medline]
  37. Sakamoto, S, Goto, S, Ito, H, et al Striosomal organization of substance P-like immunoreactivity in parkinsonian patients. Neurology 1992;42,1071-1075[Abstract/Free Full Text]
  38. Ujiie, Y, Sekizawa, K, Aikawa, T, et al Evidence for substance P as an endogenous substance causing cough in guinea pigs. Am Rev Respir Dis 1993;148,1628-1632[ISI][Medline]
  39. Sekizawa, K, Ebihara, T, Sasaki, H Role of substance P in cough during bronchoconstriction in awake guinea pigs. Am J Respir Crit Care Med 1995;151,815-821[Abstract]
  40. Yamaya, M, Yanai, M, Ohrui, T, et al Interventions to prevent pneumonia among older adults. J Am Geriatr Soc 2001;49,85-90[CrossRef][ISI][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (19)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ebihara, S.
Right arrow Articles by Sasaki, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ebihara, S.
Right arrow Articles by Sasaki, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS