Hironobu Fukuda

The Cannabinoid Receptor Agonist WIN 55,212-2 Inhibits Antigen-Induced Plasma Extravasation in Guinea Pig Airways

Background: Although neurogenic inflammation of the airways via activation of C-fibers is thought to be important in the pathogenesis of asthma, the mechanisms regulating C-fiber activity remain uncertain. Objective: The influence of a cannabinoid receptor agonist, WIN 55,212-2, on C-fiber activation in guinea pig airways was investigated, as was the mechanism by which cannabinoids regulate antigen-induced airway inflammation. Methods: The inhibitory effect of WIN 55,212-2 on antigen-induced plasma extravasation was assessed in guinea pig tracheal tissues by photometric measurement of extravasated Evans blue dye after extraction with formamide. Results: Pretreatment with WIN 55,212-2 (0.001, 0.01 or 0.1 mg/kg) significantly and dose-dependently reduced tracheal plasma extravasation induced by inhaling a 5% ovalbumin solution for 2 min after pretreatment with a neutral endopeptidedase inhibitor (phosphoramidon at 2.5 mg/kg i.v.). A cannabinoid CB2 receptor antagonist (SR144528) blunted the inhibitory effect of WIN 55,212-2, while a cannabinoid CB1 antagonist (SR141716A) did not. Pretreatment with a neurokinin-1 receptor antagonist (FK888) significantly reduced ovalbumin-induced extravasation of Evans blue dye. Pretreatment with the combination of WIN 55,212-2 and FK888 reduced antigen-induced plasma extravasation more markedly than FK888 alone. Conclusions: These findings suggest that WIN 55,212-2 inhibits C-fiber activation via the cannabinoid CB2 receptor and thus suppresses antigen-induced inflammation in guinea pig airways.

Inhibition of common cold-induced aggravation of childhood asthma by leukotriene receptor antagonists.

BACKGROUND Virus infection is an important risk factor for aggravation of childhood asthma. The objective of this study was to examine the effect of drugs on aggravation of asthma induced by a common cold. METHODS Asthma control was examined in a survey of 1,014 Japanese pediatric patients with bronchial asthma. The occurrence of common cold, asthma control, and drugs used for asthma control were investigated using a modified Childhood Asthma Control Test (C-ACT) for patients aged <4 years old and 4 to 11 years old, and an Asthma Control Test (ACT) for patients aged 12 to 15 years old. RESULTS The status of asthma control did not differ among the age groups. The prevalence of common cold and aggravation of asthma were significantly higher in patients aged <4 years old. Control of asthma following common cold-induced aggravation was significantly less effective in patients aged <4 years old compared to those aged ≥4 years old. In patients aged <4 years old with a common cold, asthma control was significantly more effective for those treated with leukotriene receptor antagonists (LTRAs) compared to treatment without LTRAs. Asthma control did not differ between patients who did or did not take inhaled corticosteroids or long-acting β2 stimulants. CONCLUSIONS These findings showed a high prevalence of common cold in younger patients with childhood asthma and indicated that common cold can induce aggravation of asthma. LTRAs are useful for long-term asthma control in very young patients who develop an asthma attack due to a common cold.

Usefulness of suplatast tosilate, a Th2 cytokine inhibitor based on the Thl/Th2 ratio for allergic disease in children: a retrospective study

BACKGROUND Children with an atopic predisposition are presumed to have persistent Th2 dominance and thus develop allergic diseases. METHODS A total of 45 children who fell to atopic dermatitis and/or intermittent asthma or mild persistent asthma between 2002 and 2007 were enrolled and retrospectively analyzed. Twenty-four children were administered oral treatment with the immunopharmacological drug suplatast tosilate (CAS 94055-76-2) at a dose of 3 mg/kg twice daily. Twenty-one of the control group were not administered oral suplatast tosilate but treated with other drugs. Blood was collected before and after administering suplatast tosilate or other drugs, and Th1 cells, Th2 cells, the Th1/Th2 ratio, the total IgE levels, and the eosinophil count were measured. RESULTS In the suplatast tosilate group, Th1 cells increased to 7.9 (1.2-19.8) % from 5.5 (1.1-13.5) % (Wilcoxon P < 0.05), while the Th2 cells showed a decrease from 1.3 (0.5-6.5) % to 1.6 (0.4-2.9) %, but the differences were not significant. The Th1/Th2 ratio increased significantly from 4.1 (0.9-7.4) to 5.6 (1.3-15.5) (shifting to Th1 dominance) in the suplatast tosilate group (Wilcoxon P < 0.05), while it shifted to Th2 dominance in the control group (increased from 4.5 (2.2-12.2) to 5.7 (1.6-11.8)) but did not show significant difference. CONCLUSIONS The Th1/Th2 ratio increased significantly after administration of suplatast tosilate, shifting to Th1 dominance. Therefore suplatast tosilate improves Th2 dominance and may inhibit subsequent progression of allergy over the long term.

Development and validation of a nighttime sleep diary in asthmatic children

To cite this article: Yoshihara S, Kanno N, Fukuda H, Yamada Y, Fukuda N, Tsuchiya T, Arisaka O. Development and validation of a nighttime sleep diary in asthmatic children. Pediatric Allergy Immunology 2011; 22: 667–670.

Cardiopulmonary Arrest on Arrival in an Infant due to Ruptured Hepatoblastoma

P rimary tumors of the liver account for approximately 1% of malignancies in children, with an annual incidence of 1.6 cases per million children in the United States. Between 50% and 60% of hepatic tumors in children are malignant, and >65% of these are hepatoblastomas. Hepatoblastoma occurs predominantly in children <3 years of age. A 7-month-old male infant was transferred to our hospital with cardiopulmonary arrest on arrival caused by a ruptured hepatoblastoma. He was born at 41 weeks’ gestation at 3155 g. At 4 months of age, he had developed healthy, and no abnormality was found at a routine health examination. He had fever and diarrhea approximately 5 hours before admission to our hospital; abdominal distension was not noted at this time. Thoracoabdominal radiographs showed abdominal distension (Figure, A). Post-mortem laboratory findings showed anemia (hemogulobin level, 8.1 g/dL) and a high level of alpha-fetoprotein (994 200 ng/mL). Although an autopsy was initially refused by the parents, we obtained permission for post-mortem imaging with computed tomography (CT). Whole body CT revealed multiple tumors in the lung and huge tumors with calcification

Efficacy and Safety of Salmeterol/fluticasone Combination Therapy in Infants and Preschool Children with Asthma Insufficiently Controlled by Inhaled Corticosteroids

BACKGROUND Clinical evidences of inhaled salmeterol/fluticasone propionate combination (SFC) therapy are insufficient in early childhood asthma. OBJECTIVES To examine the effects of SFC50, a combination product of salmeterol xinafoate (50 μg/day) and fluticasone propionate (100 μg/day), in infants and preschool children with asthma. METHODS The study was conducted at 31 sites in Japan. 35 patients (6 months to 5 years old) with asthma insufficiently controlled by inhaled corticosteroids (100 μg/day) were initiated to treat with SFC50 twice a day for 12 weeks with pressurized metered dose inhalers. The efficacy of SFC50 was assessed using nighttime sleep disorder score as the primary endpoint and the other efficacy measurements. The safety measurement included the incidences of adverse event (AE). RESULTS Mean patient age was 3.1 years, and 94.2% had mild-to-moderate persistent asthma (atopic type: 65.7%). Nighttime sleep disorder scores, assessed by a nighttime sleep diary, significantly decreased after treatment with SFC50 throughout the study period (p<0.01). SFC50 also significantly improved other efficacy outcomes including asthma symptom score, frequency of short-acting beta-agonist treatment, frequency of unscheduled visits to clinic, frequency of exacerbation due to virus infection, asthma control score and patient QOL score (p<0.01). AEs of cold, upper respiratory inflammation and asthmatic attack occurred in each of the 3 patients (8.6%); however, these were not regarded as treatment-related AEs. CONCLUSIONS SFC50 improved nighttime sleep disorder score and other efficacy outcome measures with no safety concerns. The results suggest that SFC50 treatment is useful to control the mild-to-moderate asthma in infant and preschool-aged children.

Prophylactic effectiveness of suplatast tosilate in children with asthma symptoms in the autumn: a pilot study.

BACKGROUND Exacerbations of bronchial asthma usually occur in the autumn. To our knowledge, however, the effectiveness of drugs for preventing exacerbations of asthma in the autumn has not been studied previously, except for leukotriene receptor antagonists and Omalizmab. METHODS This study compared the prophylactic effectiveness of suplatast tosilate with that of mequitazine in children with asthma symptoms, which is usually exacerbated in the autumn. The study group comprised 27 children aged 2 to 15 years who required treatment for asthmatic attacks during the past year and tested positive at least for mite allergen in the preceding autumn. The subjects were randomly assigned to receive either suplatast or mequitazine. The primary endpoint of this study was the number of days without symptoms during the 8 weeks of treatment. In addition, the Japanese Pediatric Asthma Control Program (JPAC) scores were also recorded every 2 weeks in each group. RESULTS Overall, 14 patients received suplatast, and 13 received mequitazine for 8 weeks from September through early October. During follow-up, the number of days without symptoms and the total JPAC scores did not differ significantly between the groups. However, as compared with weeks 1 to 2 of treatment, the mean number of days without symptoms during weeks 7 to 8 increased significantly in only the suplatast group (8.6 vs. 11.5 days; p = 0.004). CONCLUSIONS Our results suggest that short-term additional treatment with suplatast is useful for preventing asthma symptoms in children with asthma, which is usually exacerbated in the autumn.

Congenital left brachiocephalic vein and superior vena cava aneurysms in an infant: final update with autopsy findings.

o the Editor: We previously have described the case of an infant with ongenital left brachiocephalic vein and superior vena cava SVC) aneurysms in The Journal. Unfortunately, the patient ied of chronic respiratory failure at 22 months of age because tracheostomy could not be performed, and an autopsy was erformed. Results of a gross inspection revealed numerous collatral veins of various sizes, which branched from the aneuysms and connected to the esophageal varices. The dilated lood vessel that we initially described as an SVC aneurysm as actually found to be a right brachiocephalic vein underoing fusiform dilatation, and the SVC was not dilated. The eft brachiocephalic vein aneurysm was saccular and composed f numerous interconnected cystic lesions containing thrombi Figure 1). Examination of histologic sections revealed systemic roliferation of multilocular hemangiomatous tissue that pentrated into the submucosa and muscular layer of the esophgus and rectum (Figures 2). Immunohistochemical investiation results demonstrated that the endothelial cells of the emangioma were CD34-negative (Figure 3). The overall linicopathologic findings led to a diagnosis of angiomatosis f the venous type. Angiomatosis is a diffuse form of hemangioma that ffects a large segment of the body in a contiguous fashion, P ither by vertical extension to involve multiple tissue planes or y crossing muscle compartments to involve tissues of similar ypes. Vascular malformation, arteriovenous malformation, nd venous malformation have been used as synonyms for ngiomatosis. Our experience suggests that venous-type angiomatosis hould be included in the differential diagnosis when huge ediastinal masses are present at birth.

Efficacy and safety of cardioversion with continuous landiolol infusion for atrial tachyarrhythmia in an inflammatory state caused by volvulus in a child with TARP syndrome and postoperative tetralogy of Fallot

A 2‐year‐old boy was diagnosed with TARP syndrome and underwent surgery for tetralogy of Fallot. He developed fever and had an acute abdomen. After 12 hours, atrial tachyarrhythmia (300 beats/min [bpm]) occurred. After nine administration of adenosine and two cardioversions, it relapsed promptly. Landiolol (10 μg/kg/min) was administered until the heart rate decreased to 270 bpm, and cardioversion was performed until sinus rhythm was normal. Exploratory laparotomy revealed small bowel volvulus. Systemic inflammation causing an acute abdomen may be associated with atrial tachyarrhythmia in postoperative tetralogy of Fallot. We speculated that landiolol lowered the defibrillation threshold of the atrium.

3‑Dimensional computed tomography imaging of the ring‑sling complex with non‑operative survival case in a 10‑year‑old female

We report a case of a 10-year-old female patient who survived ring-sling complex without surgery. The patient had congenital wheezing from the neonatal period and was treated after a tentative diagnosis of infantile asthma. The patient suffered from allergy and was hospitalized several times due to severe wheezing, and when she was 22 months old, she was diagnosed with ring-sling complex. We used a segmental 4 mm internal diameter of the trachea for 3-dimensional computed tomography (3D-CT). Bronchial asthma is considered an exacerbating factor in infantile period and frequently required treatment with bronchodilator. After the age of 10, the patient had recurrent breathing difficulties during physical activity and during night time, and this condition was assessed to be related to the pressure from the blood vessel on the ring. We repeated the 3D-CT evaluation later and discovered that the internal diameter of the trachea had grown to 5 mm. Eventually, patients breathing difficulties disappeared after the treatment of bronchial asthma and restriction of physical activities. Our patient remained in stable condition without undergoing any surgical procedures even after she passed the age of 10.