Antiplatelet Cilostazol, an Inhibitor of Type Iii Phosphodiesterase, Improves Swallowing Function in Patients With a History of Stroke

To the Editor: Stroke patients with dysphagia have a high incidence of aspiration, which may lead to pneumonia.1 Several investigators have reported that cilostazol, a potent inhibitor of type III phosphodiesterase, reduces the incidence of aspiration pneumonia in patients with a history of stroke,2, 3 but the mechanism by which it does so has not been completely elucidated. It has been proposed that swallowing disorders play a significant role in the development of pneumonia in patients with a history of stoke;4, 5 therefore, it was hypothesized that cilostazol may improve swallowing function in such patients by exerting pleiotropic effects through inhibiting type III phosphodiesterase. The effects of cilostazol administration on the serum and induced sputum levels of substance P, a transmitter in the nucleus of the solitary tract in the brainstem, were examined, because a significant association between systemic or airway depletion of substance P and silent aspiration and swallowing disorders has been reported in poststroke patients.6, 7 The study subjects included patients with a 1- to 6-month history of noncardioembolic cerebral infarction confirmed using computed tomography or magnetic resonance imaging. In 48 male patients (mean age±standard deviation 68±5), swallowing function was examined before and after the administration of cilostazol and compared with swallowing function after the administration of aspirin. This study was a double-blinded, placebo-controlled, three-period crossover study wherein cilostazol administered at a dose of 200 mg twice daily and aspirin administered at a dose of 200 mg/d were compared with placebo. Patients were evaluated at baseline and after 4 weeks of treatment with each drug; a 4-week washout period was allowed after the completion of treatment with each drug. Swallowing function was examined using a repetitive saliva swallowing test and a swallowing provocation test.4, 5 In brief, the ability to swallow voluntary was quantitatively measured for 30 seconds. The swallowing reflex was induced by injecting a bolus of 1 mL of distilled water into the suprapharynx through a 5-Fr small nasal catheter with the patient in the supine position. The swallowing reflex was evaluated as the latency of the response. The serum and induced sputum levels of substance P were measured using a radioimmunoassay.8 After administering 5% saline solution via an ultrasonic nebulizer for 15 minutes, blood and induced sputum samples were collected between 7:30 and 8:00 a.m. before and after the completion of the cilostazol and aspirin treatments. The significance of differences between the groups was assessed using analysis of variance, followed by t-tests with Bonferroni correction. The results are expressed as means±standard deviations, and values of P<.05 were considered to indicate statistical significance. Forty-eight patients completed the study. The latent time of swallowing reflex significantly improved after the administration of cilostazol but not after the administration of aspirin (Figure 1). Cilostazol increased the frequency of voluntary swallowing in 30 seconds (from 4.9±0.2 to 5.6±0.2), but aspirin did not (from 4.9±0.2 to 5.1±0.2). The induced sputum and serum substance P levels also improved after cilostazol administration sputum: from 16.6±3.4 to 30.1±6.2 pg/mL; serum: from 28.2±4.4 to 44±5.2 pg/mL) but not after aspirin administration (sputum: from 16.6±3.8 to 18.1±4.4 pg/mL; serum: from 28.2±4.4 to 30.6±4.6 pg/mL). No obvious untoward effects were observed. Effects of cilostazol and aspirin on swallowing reflex in patients with a history of stroke. The latency of swallowing reflex (seconds) was examined after 4 weeks administration of cilostazol, aspirin, and placebo. ns=nonsignificant. The present study indicated that cilostazol but not aspirin improved swallowing reflex in patients with a history of stroke. Cilostazol also increased airway and systemic substance P levels in these patients. Thus, the improvement in swallowing function may contribute to the reduction in the incidence of pneumonia in poststroke patients treated with cilostazol. Substance P is a transmitter in the nucleus of the solitary tract in the brainstem, and its level in induced sputum and blood is considerably associated with the swallowing function.6, 7 In experimental data, cilostazol has been reported to increase cyclic adenosine monophosphate (cAMP)-responsive element binding protein (CREB) phosphorylation, leading to upregulation of several apoptotic and dopaminergic genes.9 This pathway may be involved in the improvement in swallowing function through the increase in substance P level in such patients. The other mechanism underlying the improvement in swallowing function may be associated with saliva secretion, which the cAMP signaling pathway in the salivary acinar cells mediates.10 The cilostazol-activated CREB plays a critical role in protein secretion from the parotid acinar cells. Increased saliva production by cilostazol may improve the swallowing function in these patients. In conclusion, the potent inhibitor of type III phosphodiesterase—cilostazol—improves swallowing function through increased production of substance P in poststroke patients. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the author and has determined that none of the authors have any financial or any other kind of personal conflicts with this letter. Dr. Teramoto was supported by a research grant from Mitsui Life Social Welfare Foundation Japan fund and by research grant from Mitsukoshi Health and Welfare Foundation in Japan. There is no conflict of interest regarding the present study. Author Contributions: Shinji Teramoto: study concept and design. Hiroshi Yamamoto, Yasuhiro Yamaguchi, Masaki Ishii, Hibi Shinichiro, Takeo Ishii: acquisition of subjects and/or data, analysis. Haruki Kume: interpretation of data. Yasuyoshi Ouchi: preparation of letter. Sponsor's Role: No sponsor in this study.