Clinical pharmacology study of the corticosteroid nasal spray dexamethasone cipecilate (NS-126): examination of the durability of efficacy in the nasal induction test.

BACKGROUND: Dexamethasone cipecilate is a corticosteroid nasal spray whose local efficacy durability has been improved by introduction of a liposoluble functional group to its chemical structure. This study was conducted to evaluate the efficacy of once-daily treatment with this drug in patients with perennial allergic rhinitis by a challenge test with house dust antigen (Phase I clinical pharmacology study). METHODS: This study was designed as a randomised placebo-controlled double-blind study in 28 patients with perennial allergic rhinitis. Either 200 µg dexamethasone cipecilate or placebo was administered once daily for 7 days, and the antigen challenge test conducted 23 h after the dose on each day. We evaluated the efficacy primarily through assessment of suppression of immediate nasal symptoms. RESULTS: When efficacy durability was evaluated by physicians based on a general assessment of the effects of suppression of nasal symptoms, the percentage of patients with efficacy lasting for 24 h differed significantly between the dexamethasone cipecilate group (69.2%, 9 out of 13) and the placebo group (15.4%, 2 out of 13) (p = 0.015). CONCLUSIONS: Dexamethasone cipecilate was shown to be a corticosteroid having sustainable local efficacy. The results suggest that once-daily administration of dexamethasone cipecilate is effective in patients with allergic rhinitis, and that its efficacy lasts for 24 h.

Olopatadine hydrochloride in children: efficacy and safety for perennial allergic rhinitis.

OBJECTIVE: The efficacy of antihistamines in perennial allergic rhinitis in children has been evaluated in studies using active comparators, whereas placebo-controlled studies are very few. A randomized, multicenter, double-blind, parallel-group clinical study was carried out to evaluate the dose-response relationship and superiority of olopatadine hydrochloride over placebo in children aged 7 to 16 years with perennial allergic rhinitis. METHODS: Subjects received twice daily treatment for two weeks with either olopatadine 2.5 mg, 5 mg or placebo after a one-week observation period. Efficacy was assessed based on the diary card score the subject (or guardian) recorded. RESULTS: Of the 302 subjects randomized, two were excluded from analysis: one did not receive treatment; the other was not monitored for efficacy parameters. The remaining 300 subjects (97 in the placebo group, 103 in the olopatadine 2.5-mg group and 100 in the olopatadine 5-mg group) constituted the full analysis set (FAS) for the efficacy analysis. As a primary endpoint, the total three nasal symptom score (for sneezing, rhinorrhea and nasal congestion) at final assessment was compared with baseline or the score obtained in the observation period. The change from baseline was then tested using analysis of covariance (ANCOVA) with the baseline score as covariate. Williams' test was applied to the least squares means estimated from this ANCOVA model for each treatment group, resulting in showing the monotonicity Williams' test assumed. The total three nasal symptom score significantly improved in the 5-mg group compared with the placebo group (p = 0.019). In contrast, the 2.5-mg group did not differ statistically from the placebo group. Adverse events occurred in 33.7% (33/98 subjects) in the placebo group, 35.9% (37/103 subjects) in the 2.5-mg group and 35.0% (35/100 subjects) in the 5-mg group. There were no serious or severe adverse events. CONCLUSIONS: Olopatadine hydrochloride 5 mg twice daily is an effective and safe treatment for perennial allergic rhinitis in children.

Comparison of fluticasone furoate and fluticasone propionate for the treatment of Japanese cedar pollinosis.

Fluticasone furoate nasal spray (FFNS) is a novel, enhanced-affinity glucocorticoid administered in a unique side-actuated device for the treatment of allergic rhinitis. No previous clinical studies have compared the efficacy of FFNS with another intranasal steroid. The purpose of this study was to compare the efficacy and safety of FFNS, 110 microg/day, once daily with fluticasone propionate nasal spray (FPNS), 200 microg/day, twice daily in patients with Japanese cedar pollinosis to support the regulatory filing in Japan. In this multicenter, randomized, placebo-controlled, double-blind, parallel-group study, patients (>or=16 years old) were randomized to receive 2 weeks of treatment with FFNS (n = 151), FFNS placebo (n = 72), FPNS (n = 148), or FPNS placebo (n = 75). FFNS once daily was noninferior to FPNS twice daily in mean change from baseline in three total nasal symptom scores (3TNSS; sneezing, rhinorrhea, and nasal congestion; -1.23 +/- 0.140 and -1.06 +/- 0.142, respectively). Compared with placebo, FFNS was superior in reducing 3TNSS (p < 0.001). Both FFNS and FPNS showed similar mean changes from baseline in 4TNSS (3TNSS and nasal itching) and individual nasal symptom scores. The onset of action for FFNS was observed from the 1st day of treatment, whereas in the FPNS group it was observed on the 2nd day. There were similar improvements in rhinoscopy findings, activity of daily life interference, and patient-rated overall evaluation to therapy in the FFNS and FPNS groups. FFNS was well tolerated. Treatment with once-daily FFNS was effective and noninferior to twice-daily FPNS in reducing nasal symptoms. Faster onset of action for FFNS was observed.

[Study of recent yearly trend of increase in airborne pollen of Japanese cedar and cypress pollen].

BACKGROUND: Based on epidemiological studies of prevalence, sensitization as well as pollen survey, it is presumed that airborne Japanese cedar pollen (JCP) and cypress (JCyP) have increased progressively for past 40 years. However, because of their large yearly variations, accurate objective and scientific study is required to confirm if it is true or not. METHODS: We analyzed the time trends of JCP and JCy separately in 11 districts throughout Japan where have records of continuous past survey from 1986 to 2005, by regression analysis using net pollen count and their 3 and 5 running means. RESULTS: When significant slope of regression line (regression coefficient) is assumed as p < 0.05 and R2 (coefficient of determination) >0.4, significant increase in airborne pollen was revealed in the use of 5 point running mean (6 districts of total 11 in JCP and 5 in JCyP) but not net count or 3 point running mean because of correction of statistic error due to large yearly variations. This study suggested that our method used for analysis of a recent increase in airborne JCP and JCyP was useful and scientific.

[A long-term follow-up study after discontinuation of immunotherapy for Japanese cedar pollinosis].

BACKGROUND: To elucidate how long the effect of immunotherapy (IT) persist after discontinuation in patients with Japanese cedar pollinosis (JCP). METHODS: After discontinuation of IT 485 patients with JCP who completed one course of IT for 3.6 years in average were followed repeatedly up by means of author's original evaluation system of symptom-medication system from 1996 to 2005 using the method of questionnaire. Since the variations of terms after discontinuation and times of examination existed, the outcomes were averaged in every one year and follow-up seasons after discontinuation. Comparison of score and type in the year of discontinuation (base-line level) with those of follow-up was made for evaluation of outcomes. In addition, of these, 100 JCP patients, who had both intervals of 3 years or more from the discontinuation and examination times of 3 or more during the follow-up period, were examined as the evidence of reliability. RESULTS: Although the scores and types in each year were affected slightly by yearly changes in air borne pollen count, the effect persisted for 10 years with a slight change, keeping score 3 to 4. Forty two% of patients had no symptom and medication even in 2005, a year of large pollen count. Conclusively effect of the JCP IT persists satisfactorily for at least 10 years. This is the first study of long term follow-up in JCP against cross sectional study.

A multidisciplinary overview of cardiogenic shock.

Cardiogenic shock complicating acute myocardial infarction (AMI) is reviewed from multidisciplinary viewpoints encompassing both basic and clinical aspects. Insights into the absolute obligate aerobic nature of the heart which possesses neither facultative capability nor functional collateral channels, together with O2 diffusion gradients, mitochondrial O2 sensing and anaerobic ATP deficiencies, are described in some detail. Myocardial adaptive responses against energy crisis, termed the Pasteur Effect, and hypoxia inducible factor (HIF)-1 alpha are implicated for cardiomyocyte viability. Oncosis and/or lysosomal autophagy cause such overwhelming numbers (several billions) of cardiomyocyte death, virtually simultaneously following coronary thrombotic occlusion. Apoptosis is briefly described and cardiogenic shock is discussed in terms of the diagnostic criteria by MIRU, unique hemodynamic manifestations, infarct sizes and border zone extension, and potentially jeopardized myocardium in the remote areas. Reperfusion injury, i.e., reactive oxygen species (ROS), is noted as a double-edged sword. The importance of early revascularization by means of PCI, CABG, and IABP support is emphasized according to current guidelines. For innovative promise in the future, de novo development of collateral channels by growth factors and trials of stem cell implantation aimed at myocardial regeneration are introduced.

[Is the frequency of pre-seasonal manifestation in patients with Japanese cedar pollinosis so high?].

BACKGROUND: Based on subjective symptom, it has been documented that so high as 21 to 62% of patients with Japanese cedar pollinosis has pollinosis symptom before the start of pollen season. Since this is not objectively evidenced, we aimed to clarify whether or not it is true. METHOD: We quantified intranasal pollen by means of our nasal lavage method in patients with Japanese cedar pollinosis shortly after the onset of symptom during pre-, mid- and post-season from 1997 to 2005. RESULT: Significant differences in intranasal pollen count were revealed among mid- and pre- and post-season. Intra-nasal pollens, so few as 1 or less, were found in 67.8% of patients having pre-seasonal symptom, while in 12.5% during the mid-season. The majority of patients had not sufficient number of intra-nasal pollen to induce pollinosis. However, the intranasal pollen counts in preseason were related well with total airborne pollen amount in next spring. Pollens other than Japanese cedar pollen were also detected in lavages. CONCLUSION: Many factors such as method of pollen survey, personal nasal hyper-reactivity and irritation by cold air, or with pollens other than Japanese cedar may cause the pre-seasonal pollinosis symptom. High frequencies of pre-seasonal onset in previous reports may be over-estimated due to inaccurate diagnosis of Japanese cedar pollinosis.

[Nasal symptoms in persons with normal nose].

BACKGROUND: Nasal symptoms such as sneezing, stuffy nose and runny nose occur in allergic and nonallergic rhinitis. Normal nose also sometimes has these symptoms. It is necessary to define what is the symptom of normal nose in order to make a proper diagnosis of rhinitis, grading of severity of nasal symptom in rhinitis and criteria of normalization after the treatment of rhinitis. METHODS: 235 persons who had no perceptive nasal symptom and history of nasal disease at present and past, and cold at present, were sampled from the registered list of a health care organization, and examined their nasal symptom by mailing a self-administered questionnaire of nasal symptom. In addition, 54 patients, who visited 4 otolarngology clinics due to diseases other than rhinitis and were diagnosed as normal nose, were examined, using the same questionnaire. RESULTS: Response rate from persons mailed was 49.8%. Nasal symptom was infrequent in patients at clinic more than persons sampled from the list. Nasal symptom in 117 responders with normal nose had none or occasional and momentary stuffy nose. Sneezing and/or nose blow was less than 5 times a day, and itchy nose and postnasal drip were 30% and 25% respectively. These symptoms, if appeared, were less than 4 days per week. CONCLUSION: Grading "minus", normal, is zero in sneezing and runny nose and none in stuffy nose in the grading system of nasal symptom used commonly in Japan. These should be changed to none or occasional, momentary, easily tolerable in stuffy nose, less than once a day or grading "plus one" (1-5 times per day) occasionally in sneezing and nose blow. Normalization after treatment could be defined according to this change.

[Natural airborne pollen contamination of clothes and facial skin].

OBJECTIVE: To clarify natural airborne Japanese cedar pollen contamination of clothes (cotton made T shirt and cap) and face skin for preventive strategy against pollinosis. METHODS: Ten non-pollinosis high school students, wearing T-shirt and cap, stayed after face washing in outdoor (school yard) and in-door (school room) for 2 hours alternatively. Wet clothes of each of three different qualities (cotton, cotton blended polyester and wool) were also left at ten points of the schoolyard. Contaminated pollens were collected using adhesive tape and counted under a microscope. RESULTS: Pollen contaminations were lesser in school room than school yard. Lesser contamination was revealed on the surface of cotton-polyester blended clothes without statistical difference when compared with cotton and wool made clothes. CONCLUSION: From this study, in going out wearing of cotton-polyester blended coat and cap, and after returning home, face washing and keeping coat and cap on a hanger at entry hall are recommended for pollen prevention.

[Clinical validity of our new patient satisfaction questionnaire for allergic rhinitis].

Patient satisfaction is recommended as a parameter to evaluate medical care from the aspect of patient. Currently, we developed a new patient satisfaction questionnaire in allergic rhinitis by means of internationally standardized psychometric validation and reliability studies. Using this questionnaire, we evaluated patient satisfaction with Japanese cedar pollinosis in 2004, who visited our own clinic (JAAC) or patients, who were sampled from the list of a health research company (JSR), in addition of literature data. As a result, there were marked differences between ours and others. The purpose of this study is to elucidate whether or not our questionnaire has a good and reliable clinical validity, and, if yes, why there were marked differences in various studies. The satisfaction (very good plus good) was 94.4% in the JAAC group and 41.2% in the JSR group respectively. We compared the mean scores of each item in questionnaire in both groups, and found higher scores in the majority of items in the former group than the latter group in accordance with difference in satisfaction. This suggested a good clinical validity in questionnaire. In nasal treatment modality, the JAAC group was. characterized by continuous use of combined topical steroid with per oral anti-allergic compound and immunotherapy during whole pollen season, when compared with the JSR group. A persistent contact with patients in immunotherapy plays an important role in establishing good doctor-patient relation and treatment outcome, resulting in increased patient satisfaction.

Fexofenadine improves the quality of life and work productivity in Japanese patients with seasonal allergic rhinitis during the peak cedar pollinosis season.

BACKGROUND: Although currently in its infancy, quality of life (QOL) research in Japan is rapidly expanding and is expected to become a standard outcome measure in clinical trials. In Japan, QOL has not previously been assessed in patients with allergic rhinitis (AR); we report the first clinical study applying the recently validated Japanese translations of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) Questionnaire to assess the effects of the oral antihistamine, fexofenadine, on QOL and work productivity due to cedar pollinosis. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled, single-site study was conducted during the peak cedar pollinosis season in Japan. After a 7-day run-in period, subjects were randomized to receive fexofenadine HCl 60 mg twice daily (bid) or placebo for 2 weeks. RESULTS: Overall, 206 Japanese subjects with AR were included in the intention-to- treat population (fexofenadine, n = 104, and placebo, n = 102). Fexofenadine statistically significantly improved overall QOL compared with placebo (p = 0.005) and improvements were reported in the RQLQ domains: activities (p = 0.047), practical problems (p = 0.003), nasal symptoms (p = 0.003) and eye symptoms (p

Inhibitory effects of facemasks and eyeglasses on invasion of pollen particles in the nose and eye: a clinical study.

The incidence of Japanese cedar pollinosis is estimated to be about 13% of the Japanese population. In Japan it is generic to wear a facemask and eyeglasses to prevent pollen inhalation. We examined the usefulness of a facemask and eyeglasses in cooperation with volunteers. The number of pollen particles in the nasal cavity and on the conjunctiva was unchanged by wearing a facemask and eyeglasses. However, the pollen invasion rate was lower in subjects with a facemask and eyeglasses than in subjects without a facemask and eyeglasses. The decrease in pollen invasion rate in the nasal cavity due to wearing a facemask was statistically significant. This suggested that wearing a facemask has a protective effect on pollen invasion to the nose. The pollen invasion rate in the nasal cavity and on the conjunctiva was increased with increases in the wind speed. It may be difficult to avoid pollen even when wearing a facemask and eyeglasses when the wind speed is high. Further study is required to clarify the relationship between the amount of allergens and clinical symptoms.

[Treatment of Japanese cedar pollinosis and its impact on patient satisfaction].

Japanese cedar pollinosis is a major public health problem in Japan because of its severe symptom and high prevalence. However, patient satisfaction by treatment is poor according to current reports. As the treatments, pre-seasonal medication and single peroral anti-allergic drug on demand are frequently used in Japan. Against conventional methods, we treated 301 patients with Japanese cedar pollinosis by persistent use of combined drugs (topical steroid, peroral anti-allergic drug and eye drop) without pre-seasonal medication in 2003. Immunotherapy was also used in 90 patients treated. As a result, 97% of patients was satisfied in this treatment and immunotherapy contributed to reduction in the amount of drug and high treatment outcome.

[Development of patient satisfaction questionnaire in allergic rhinitis].

Recent suggestions emphasize the importance of assessing medical care outcomes from the point of view of both professional opinion and patient's subject like patient satisfaction as well as quality of life. Self-administered questionnaires are often used as an instrument for this purpose. When compared with quality of life, there is less useful questionnaire for patient satisfaction. Accordingly, we here aimed to develop the questionnaire, which is disease-specific, comprehensive, simple, clinically available and satisfied psychometric validation study. The items were collected from patients and satisfaction-related literature's review, and the total 20 were selected finally from them after excluding inadequate or overlapped items. Then, we conducted validation study in 214 subjects sampled randomly from 603 patients with Japanese cedar pollinosis who had visited clinics in 2003 by mailing self-administered questionnaire in spring, 2004. The response rate was 65.3%. In factor analysis, items were divided into four domains such as doctor-patient relationship, treatment outcome, geniality in hospital and convenience of medical service. The former two domains were the most correlated well with patient satisfaction. The quality of this questionnaire such as responsiveness, reliability, construct validity, convergent/discriminate validity, and clinical validity satisfied international standard. Thus, it was verified that our newly developed questionnaire is a useful and scientific tool for examination of patient satisfaction with medical care in allergic rhinitis.

[Are otolaryngologists specialist for pollinosis?].

It is approved that ENT doctors are specialist for pollinosis. Is it true from the point of view of patients' medical care-seeking behavior? 214 patients with Japanese cedar pollinosis who had visited medical doctors in 2003 pollen-season were randomly sampled from 603 pollinosis patients registered at a disease survey company and we mailed self-evaluation questionnaire on patients' medical care-seeking behavior on the end of pollen season in 2004. Response rate was 65.3%. Patients visited clinics in approximately 90% more than hospitals. They selected ENT in 43.9% and general physicians in 31.1%. Their selections were based on others than their specialty such as easy access and previous experience of visit, because pollinosis is not serious disease like cancer. ENT doctors treated the patients by combination of two kinds of tablet or topical steroid with tablet, while general physicians did with single kind of tablet. The patient satisfaction, and its related questions including preference, wish to revisit in next year and recommendation to their friend were not different in treatment between ENT and general physician. Doctors' attitude, and communication with patients were the most important factor for patient satisfaction as well as treatment out-come. In conclusion, patients prefer agreeable and convenient treatment. If ENT doctors still want to be specialist for pollinosis, they should take care patients well and develop their own specific treatment methodology to cure this disease.