Analysis of national surveillance of respiratory pathogens for community-acquired pneumonia in children and adolescents.

BACKGROUND: Respiratory infections among children, particularly community-acquired pneumonia (CAP), is a major disease with a high frequency among outpatient and inpatient visits. The causes of CAP vary depending on individual susceptibility, the epidemiological characteristics of the community, and the season. We performed this study to establish a nationwide surveillance network system and identify the causative agents for CAP and antibiotic resistance in Korean children with CAP. METHODS: The monitoring network was composed of 28 secondary and tertiary medical institutions. Upper and lower respiratory samples were assayed using a culture or polymerase chain reaction (PCR) from August 2018 to May 2020. RESULTS: A total of 1023 cases were registered in patients with CAP, and PCR of atypical pneumonia pathogens revealed 422 cases of M. pneumoniae (41.3%). Respiratory viruses showed a positivity rate of 65.7% by multiplex PCR test, and human rhinovirus was the most common virus, with 312 cases (30.5%). Two hundred sixty four cases (25.8%) were isolated by culture, including 131 cases of S. aureus (12.8%), 92 cases of S. pneumoniae (9%), and 20 cases of H. influenzae (2%). The cultured, isolated bacteria may be colonized pathogen. The proportion of co-detection was 49.2%. The rate of antibiotic resistance showed similar results as previous reports. CONCLUSIONS: This study will identify the pathogens that cause respiratory infections and analyze the current status of antibiotic resistance to provide scientific evidence for management policies of domestic respiratory infections. Additionally, in preparation for new epidemics, including COVID-19, monitoring respiratory infections in children and adolescents has become more important, and research on this topic should be continuously conducted in the future.

Biosynthesis of Nonimmunosuppressive ProlylFK506 Analogues with Neurite Outgrowth and Synaptogenic Activity.

Separating the immunosuppressive activity of FK506 (1) from its neurotrophic activity is required to develop FK506 analogues as drugs for the treatment of neuronal diseases. Two new FK506 analogues, 9-deoxo-36,37-dihydro-prolylFK506 (2) and 9-deoxo-31-O-demethyl-36,37-dihydro-prolylFK506 (3) containing a proline moiety instead of the pipecolate ring at C-1 and modifications at the C-9/C-31 and C-36-C-37 positions, respectively, were biosynthesized, and their biological activities were evaluated. The proline substitution in 9-deoxo-36,37-dihydroFK506 and 9-deoxo-31-O-demethyl-36,37-dihydroFK506 reduced immunosuppressive activity by more than 120-fold, as previously observed. Compared with FK506 (1), 2 and 3 exhibited ∼1.2 × 105- and 2.2 × 105-fold reductions in immunosuppressive activity, respectively, whereas they retained almost identical neurite outgrowth activity. Furthermore, these compounds significantly increased the strength of synaptic transmission, confirming that replacement of the pipecolate ring with a proline is critical to reduce the strong immunosuppressive activity of FK506 (1) while enhancing its neurotrophic activity.

Association between sensitization and allergic diseases in 7-years-old Korean children.

BACKGROUND: Sensitization is associated with the exacerbation, severity, and prognosis of allergic diseases in children. OBJECTIVE: We characterized the association between sensitization patterns and allergic diseases. METHODS: A cohort of 548 children was enrolled from Panel Study of Korean Children (PSKC) study. Skin prick tests (SPTs) for 18 common allergens, blood tests, and methacholine bronchial challenge tests were performed at age 7. The Korean version of International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used. RESULTS: The sensitization rate on SPTs was 46.4%. Sensitization to indoor allergens showed an association with symptoms of asthma (adjusted odds ratio [aOR], 2.39; 95% confidence intervals [95% CIs], 1.10-5.23), allergic rhinitis (AR, aOR 2.08, 95% CIs 1.42-3.06), and atopic dermatitis (AD, aOR 2.36, 95% CIs 1.24-4.50) in the preceding 12 months. In contrast, sensitization to outdoor allergens was associated with AR diagnosis only (aOR 2.40, 95% CIs 1.30-4.41). The number of sensitized allergens was associated with a lifetime diagnosis and symptoms in the preceding 12 months of AR and asthma, but not with AD or BHR. A higher degree of sensitization to indoor allergens was associated with symptoms in the preceding 12 months of asthma, AR, AD, and that for outdoor allergens was associated with symptoms in the prior 12 months of asthma and AR. CONCLUSIONS: The sensitization patterns including allergen type, number, and degree of sensitization are helpful for interpreting the association between sensitization and allergic diseases and identifying the pathophysiologies and diverse phenotypes of allergic diseases.

Vegetable dietary pattern may protect mild and persistent allergic rhinitis phenotype depending on genetic risk in school children.

BACKGROUND: The effect of diet on allergic rhinitis (AR), its severity in children, and whether it modifies AR depending on genetic susceptibility are unknown. We investigated the association between dietary patterns and AR in school children and the influence of diet on AR according to a genetic risk score (GRS). METHODS: Totally, 435 7-year-old school children were recruited from the Panel Study on Korean Children. We used dietary patterns (vegetable, sugar, and meat) and dietary inflammatory index (DII) as dietary parameters. AR and its severity were defined by questionnaires about treatment in the previous 12 months and the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline, respectively. A GRS was calculated using 6 single nucleotide polymorphisms for allergic diseases. RESULTS: A vegetable diet containing a lot of anti-inflammatory nutrients and higher vitamin D level in blood were negatively correlated, while DII was positively correlated with triglyceride level and triglyceride/HDL cholesterol. Vegetable diet (aOR, 95% CI = 0.73, 0.58-0.94) and DII (1.13, 1.01-1.28) were associated with AR risk. In particular, a high-vegetable diet resulted in a lower risk of mild and persistent AR (aOR, 95% CI = 0.24, 0.10-0.56) while a high DII represented a higher risk (2.33, 1.06-5.10). The protective effect of vegetable diet on AR appeared only among children with a lower GRS (adjusted P = .018). CONCLUSIONS: A vegetable dietary pattern characterized by high intake of anti-inflammatory nutrients and higher vitamin D level in blood might be associated with a lower risk of mild and persistent AR. This beneficial effect is modified by a genetic factor.

Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity.

A reduction in the strong immunosuppressive activity of FK506 (1) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (7) exhibited a >900-fold reduction in the in vitro immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. 7 exhibited robust synergistic antifungal activity with fluconazole. FK506 (1) is a 23-membered macrolide produced by several Streptomyces species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca2+-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FK506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.

In Vitro and In Vivo Assessment of FK506 Analogs as Novel Antifungal Drug Candidates.

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with that of FK506. The four FK506 analogs generally possessed lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of its in vivo antifungal efficacy in a murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, when it was used in combination with fluconazole, it significantly extended the survival of C. neoformans-infected mice, confirming the synergistic in vivo antifungal efficacy between these two agents.

Phase I/II Study of Weekly Oraxol for the Second-Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer.

BACKGROUND: Oraxol consists of paclitaxel and HM30181A, a P-glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM-OXL-201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second-line chemotherapy for metastatic or recurrent gastric cancer (GC). METHODS: In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m(2) per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated. RESULTS: In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m(2). In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression-free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug-related adverse events (grade ≥3) were neutropenia and diarrhea. CONCLUSION: Oraxol exhibited modest efficacy and favorable toxicity profiles as second-line chemotherapy for GC.

Pharmacokinetic properties and bioequivalence of olmesartan medoxomil/hydrochlorothiazide in healthy Korean male subjects.

UNLABELLED: Olmesartan medoxomil inhibits the vasoconstrictor effects of angiotensin II. Hydrochlorothiazide (HCTZ) promotes sodium excretion, resulting in a reduction of plasma volume and peripheral resistance. A combination of these agents is known to have a greater effect for the treatment of hypertension than monotherapy with either one of these components. OBJECTIVE: To assess bioequivalence between fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide (HCTZ) in healthy Korean subjects. METHODS: 40 healthy Korean volunteers were randomized into two groups. After administration of a single dose of investigational products, blood samples were collected before study drug administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 36 hours after study drug administration. The plasma concentrations of olmesartan and HCTZ were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance (ANOVA) on logarithmically transformed data. RESULTS: The corresponding 90% CIs for the geometric mean ratio of the test to reference drugs were 0.93 - 1.04, 0.93 - 1.04, and 0.95 - 1.10. For HCTZ treatments, the 90% CIs for the geometric mean ratio of test to reference drugs were 0.95 - 1.03 for AUClast, 0.96 - 1.03 for AUC∞, and 0.89 - 1.04 for Cmax. CONCLUSION: This study demonstrated that the test and reference products met the regulatory criteria assuming bioequivalence. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles of the test and reference drugs.

Comparison of efficacy and safety between third-dose triple and third-dose dual antihypertensive combination therapies in patients with hypertension.

We compared the efficacy and safety of third-standard-dose triple and third-standard-dose dual antihypertensive combination therapies in patients with mild to moderate hypertension. This was a phase II multicenter, randomized, double-blind, parallel-group trial. After a 4-week placebo run-in period, 245 participants were randomized to the third-dose triple combination (ALC group; amlodipine 1.67 mg + losartan potassium 16.67 mg + chlorthalidone 4.17 mg) or third-dose dual combination (AL group; amlodipine 1.67 mg + losartan potassium 16.67 mg, LC group; losartan potassium 16.67 mg + chlorthalidone 4.17 mg, AC group; amlodipine 1.67 mg + chlorthalidone 4.17 mg) therapy groups and followed up for 8 weeks. The mean systolic blood pressure (BP) reduction was -18.3 ± 13.2, -13.0 ± 13.3, -16.3 ± 12.4, and -13.8 ± 13.2 mmHg in the ALC, AL, LC, and AC groups, respectively. The ALC group showed significant systolic BP reduction compared to the AL and AC groups at weeks 4 (P = .010 and P = .018, respectively) and 8 (P = .017 and P = .036, respectively). At week 4, the proportion of systolic BP responders was significantly higher in the ALC group (42.6%) than in the AL (22.0%), LC (23.3%), and AC (27.1%) groups (P = .013, P = .021, and P = .045, respectively). At week 8, the proportion of systolic and diastolic BP responders was significantly higher in the ALC group (59.7%) than in the AL (39.3%) and AC (42.4%) groups (P = .022 and P = .049, respectively) at week 8. Third-standard-dose triple antihypertensive combination therapy demonstrated early effective BP control compared to third-standard-dose dual combination therapies, without increasing adverse drug reactions in patients with mild-to-moderate hypertension.

The pharmacokinetics of letrozole: association with key body mass metrics.

PURPOSE: To characterize the pharmacokinetics (PK) of letrozole by noncompartmental and mixed effect modeling analysis with the exploration of effect of body compositions on the PK. METHODS: The PK data of 52 normal healthy male subjects with intensive PK sampling from two separate studies were included in this analysis. Subjects were given a single oral administration of 2.5 mg letrozole (Femara®), an antiestrogenic aromatase inhibitor used to treat breast cancer. Letrozole concentrations were measured using validated high-performance liquid chromatography with tandem mass spectrometry. PK analysis was performed using NONMEM® 7.2 with first-order conditional estimation with interaction method. The association of body composition (body mass index, soft lean mass, fat free mass, body fat mass), CYP2A6 genotype (*1/*1, *1/*4), and CYP3A5 genotype (*1/*1, *1/*3, *3/*3) with the PK of letrozole were tested. RESULTS: A two-compartment model with mixed first and zero order absorption and first order elimination best described the letrozole concentration-time profile. Body weight and body fat mass were significant covariates for central volume of distribution and peripheral volume of distribution (Vp), respectively. In another model built using more readily available body composition measures, body mass index was also a significant covariate of Vp. However, no significant association was shown between CYP2A6 and CYP3A5 genetic polymorphism and the PK of letrozole in this study. CONCLUSION: Our results indicate that body weight, body fat mass, body mass index are associated with the volume of distribution of letrozole. This study provides an initial step toward the development of individualized letrozole therapy based on body composition.

Assessment of variables associated with prolonged admission duration in children with Mycoplasma pneumoniae pneumonia.

INTRODUCTION: Macrolide-resistant Mycoplasma pneumoniae (MRMP) has become prevalent in children. This study investigated the clinical and laboratory variables of MRMP and macrolide-sensitive M. pneumoniae (MSMP) and identified factors associated with prolonged hospital admission in children. METHODS: A prospective multicenter study was conducted in 1063 children <18 years old in July 2018-June 2020. The 454 had a positive M. pneumoniae polymerase chain reaction assay. RESULTS: Most subjects had MRMP (78.4%), and all mutated strains had the A2063G transition. We defined MRMP* (n = 285) as MRMP pneumonia requiring admission and MSMP* (n = 72) as MSMP pneumonia requiring admission. Patients with MRMP pneumonia were older, more likely to have segmental/lobar pneumonia, and had more febrile days than those with MSMP pneumonia. C-reactive protein (CRP), lactate dehydrogenase (LDH), and percentage neutrophils were more strongly associated with MRMP* than MSMP* groups. Percentage neutrophils, CRP, and alanine aminotransferase significantly changed between admission and follow-up measurements in patients with MRMP* (P < 0.05). The duration of admission positively correlated with the number of febrile days after initiation of antibiotic medication and laboratory variables (white blood cell count, CRP, and aspartate aminotransferase [AST]) (P < 0.05). Random forest analysis indicated that the number of febrile days after initiation of antibiotic medication, AST, and percentage neutrophils at admission was over five. CONCLUSIONS: This study indicated that children with M. pneumoniae pneumonia with a higher number of febrile days after initiation of antibiotic medication, AST, and percentage neutrophils at admission were more likely to have prolonged admission duration.

Sensitization to aeroallergens in Korean children: a population-based study in 2010.

We performed this study to assess the prevalence of sensitization to aeroallergens and to analyze the difference between prevalence rates according to children's ages and residential areas. In this nationwide cross-sectional study, first grade students of 45 elementary schools and 40 middle schools were randomly selected, and skin prick tests were performed for 18 inhalant allergens between October and November 2010. Of 7,829 analyzed subjects, 3,753 (47.9%) were sensitized to at least one aeroallergen. Sensitization to Dermatophagoides farinae was found to be the most prevalent in elementary schoolchildren (32.4%), followed by Dermatophagoides pteronyssinus, Tyrophagus putrescentiae, Japanese hop, and oak. In middle schoolchildren, D. pteronyssinus yielded the highest prevalence (42.7%), followed by D. farinae, T. putrescentiae, Japanese hop, and cat. In middle schoolchildren, the sensitization rate to aeroallergens in metropolitan, urban, and rural areas was 57.2%, 54.3%, and 49.8%, respectively (P = 0.019). In this age group, the sensitization rate in low, middle, high, and very high income groups was 53.8%, 51.8%, 59.0%, and 59.6%, respectively (P = 0.002). In conclusion, the sensitization rate is 47.9% and house dust mite is the most prevalent allergen in the pediatric population in Korea. The rate is higher in metropolitan areas and the highest income group than in rural areas and low income groups.

Safety evaluation of fermented Platycodon grandiflorus (Jacq.) A.DC. extract: Genotoxicity, acute toxicity, and 13-week subchronic toxicity study in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Platycodon grandiflorus (Jacq.) A.DC. is a well-known traditional herbal medicine administered for bronchitis and inflammatory diseases. Especially, anti-inflammatory effect of fermented P. grandiflorus (Jacq.) A.DC. extract (FPGE) was higher than that of P. grandiflorus (Jacq.) A.DC. extract. However, toxicological information for FPGE is lacking. AIM OF THE STUDY: In this study, we establish a toxicological profile for FPGE by testing genotoxicity, acute and 13-week subchronic toxicity. MATERIALS AND METHODS: FPGE was evaluated with bacterial reverse mutation, chromosome aberration, and micronucleus test. For the acute- and 13-week subchronic toxicity tests, FPGE was administered orally at doses of 0, 750, 1500, and 3000 mg/kg in SD rats. RESULTS: The results of the genotoxic assays indicated that FPGE induced neither mutagenicity nor clastogenicity. The acute toxicity test showed that FPGE did not affect animal mortality, clinical signs, body weight changes, or microscopic findings at ≤ 3000 mg/kg. The approximate lethal dose (ALD) of FPGE in SD rats was >3000 mg/kg. For the 13-week subchronic toxicity assay, no FPGE dose induced any significant change in mortality, clinical signs, body or organ weight, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination in either SD rat sex. The rat no observed adverse effects level (NOAEL) for FPGE was set to 3000 mg/kg. CONCLUSIONS: The present study empirically demonstrated that FPGE has a safe preclinical profile and indicated that it could be safely integrated into health products for atopic dermatitis treatment.

Pulmonary function of healthy Korean children from three independent birth cohorts: Validation of the Global Lung Function Initiative 2012 equation.

BACKGROUND AND OBJECTIVE: Global Lung Function Initiative (GLI) 2012 equations were developed to resolve the age-related disparity in interpreting spirometry results. Local validation of the equation is needed, especially in Northeast Asian children. This study evaluated the GLI equation in Korean children. METHODS: Spirometry indices (FEV1, FVC, FEV1/FVC, and FEF25%-75%) and clinical information were gathered from three population-based birth cohorts. Predicted GLI reference values and z scores of spirometry results were calculated for 1239 healthy children. The mean, standard deviation of z scores were compared with the expected 0 and 1. Probabilities of falling below the lower limit of normal (LLN) (z score: -1.64) were compared with the expected value 5%. GLI z scores were assessed according to low (<-2), normal (≥-2 and ≤2), and high (>2) BMI z score groups. RESULTS: Mean z scores significantly differed from 0 for FEV1/FVC in males (mean [95% confidence interval]: 0.18 [0.08, 0.27]) and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in females (-0.23 [-0.31, -0.15] and -0.26 [-0.36, -0.16], respectively). The standard deviation was larger than 1 for all variables in males and FVC and FEV1/FVC in females. The probability of falling below the LLN was significantly larger than 5% for FEV1 (12.13% [9.64, 14.77]), FVC (15.86% [13.06, 18.81]), and forced expiratory flow at 25%-75% of forced vital capacity (FEF25%-75%) (7.31% [5.29, 9.49]) in males and FVC (11.91% [9.40, 14.60]) in females. FEV1 and FVC z scores increased across low to high body mass index (BMI) groups, and FEV1/FVC decreased from low to high BMI groups. CONCLUSION: GLI equations marginally differ from real-world values, which should be considered by pulmonologists in practice or research.

Development of Non-Immunosuppressive FK506 Derivatives as Antifungal and Neurotrophic Agents.

FK506, also known as tacrolimus, is a clinically important immunosuppressant drug and has promising therapeutic potentials owing to its antifungal, neuroprotective, and neuroregenerative activities. To generate various FK506 derivatives, the structure of FK506 has been modified by chemical methods or biosynthetic pathway engineering. Herein, we describe the mode of the antifungal action of FK506 and the structure-activity relationship of FK506 derivatives in the context of immunosuppressive and antifungal activities. In addition, we discuss the neurotrophic mechanism of FK506 known to date, along with the neurotrophic FK506 derivatives with significantly reduced immunosuppressive activity. This review suggests the possibility to generate novel FK506 derivatives as antifungal as well as neuroregenerative/neuroprotective agents.

Comparison of Pharmacokinetics of a Fixed-Dose Combination of Amlodipine/Losartan/Rosuvastatin with Concomitant Administration of Amlodipine/Losartan and Rosuvastatin in Healthy Volunteers.

BACKGROUND: A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet. SUBJECTS AND METHODS: A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUClast) and the maximum plasma concentration (Cmax) were calculated. Safety was monitored throughout the study. RESULTS: The GMR (90% CI) values of AUClast and Cmax were 0.9946 (0.9663-1.0238) and 0.9690 (0.9379-1.0011) for amlodipine, 0.9855 (0.9422-1.0308) and 0.9178 (0.8349-1.0089) for losartan, 0.9814 (0.9501-1.0136) and 0.9756 (0.9313-1.0219) for EXP3174, and 0.9448 (0.8995-0.9923) and 0.9609 (0.8799-1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment. CONCLUSION: We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.

Risk Factors and Comorbidities Associated With the Allergic Rhinitis Phenotype in Children According to the ARIA Classification.

PURPOSE: Data are lacking on the association between the allergic rhinitis (AR) phenotype and sensitization to specific allergens or bronchial hyperresponsiveness (BHR) in children. We here investigated risk factors and comorbidities, including sensitization to specific allergens and BHR, for the AR phenotype by AR and its Impact on Asthma (ARIA) classification in a general population-based birth cohort study. METHODS: We enrolled 606 children aged 7 years from the Panel Study of Korean Children. The AR phenotype was assigned in accordance with the ARIA classification in children. Skin prick tests and Provocholine provocation test were performed. Risk factors and comorbidities for AR phenotypes were then analyzed. RESULTS: The prevalence of mild and moderate to severe AR in our study cohort was 37.2% and 8.8%, respectively. Recent use of analgesics or antipyretics and current cat ownership were associated with the risk of mild persistent AR. Sensitizations to Dermatophagoides Pteronyssinus (Der p), Japanese hop and cat were associated with moderate to severe persistent AR. Children with moderate to severe AR had a higher risk of current asthma and BHR compared to mild AR cases (adjusted odds ratio [aOR], 5.26; 95% confidence interval [CI], 1.77-15.62). Moderate to severe AR with allergic sensitization was associated with the highest risk of BHR (aOR, 11.77; 95% CI, 3.40-40.74). CONCLUSIONS: Moderate to severe-persistent AR is more closely related to respiratory comorbidities and sensitizations than mild AR. Stratifying the AR phenotype by ARIA classification may assist in disease management.

Phenotypic and genotypic correction of WASP gene mutation in Wiskott-Aldrich syndrome by unrelated cord blood stem cell transplantation.

We present two cases of Wiskott-Aldrich syndrome (WAS), in which nonsense mutations in the WASP gene were corrected phenotypically as well as genotypically by unrelated cord blood stem cell transplantation (CBSCT). Two male patients were diagnosed with WAS at the age of 5-month and 3-month and each received unrelated CBSCT at 16-month and 20-month of age, respectively. The infused cord blood (CB) units had 4/6 and 5/6 HLA matches and the infusion doses of total nucleated cells (TNC) and CD34+ cells were 6.24x10(7)/kg and 5.08x10(7)/kg for TNC and 1.33x10(5)/kg and 4.8x10(5)/kg for CD34+ cells, for UPN1 and UPN2, respectively. Complete donor cell chimerism was documented by variable number tandem repeat (VNTR) with neutrophil engraftment on days 31 and 13 and platelets on days 58 and 50, respectively. Immunologic reconstitution demonstrated that CBSCT resulted in consistent and stable T-, B-, and NK-cell development. Flow cytometric analysis for immunologic markers and sequence analysis of the WASP gene mutation revealed a normal pattern after CBSCT. These cases demonstrate that CBs can be an important source of stem cells for the phenotypical and genotypical correction of genetic diseases such as WAS.

Profiles and characteristics of bronchial responsiveness in general 7-year-old children.

BACKGROUND: Although bronchial responsiveness (BR) is usually categorized as normal or hyperresponsive to aid the diagnosis of asthma, it exists on a continuous spectrum, not in a dichotomous manner. We aimed to evaluate the distribution profile of BR in a general population of 7-year-olds. METHODS: In 2015, 7-year-old Korean children from a nationwide birth cohort study visited regional study hospitals for skin prick test, standard spirometry, and bronchial provocation to establish reference values for the general population. Their BR degrees were categorized into five ordered groups: hyperresponsive BRs were classified into group 1 (provocative concentration (PC) of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV1], PC20 of <4 mg/mL) and group 2 (PC20 of ≥4 mg/mL and <16 mg/mL), and nonresponsive BRs were categorized into group 3 (final FEV1 percentage fall after inhaling 16 mg/mL of methacholine [FEV1%fall] of >15% and ≤20%), group 4 (FEV1%fall of >10% and ≤15%), and group 5 (FEV1%fall of ≤10%). RESULTS: In total, 559 subjects finished all tests reliably. Groups 1 and 2 comprised 10.0% and 15.7% of the total population, respectively. Groups 3, 4, and 5 comprised 14.7%, 18.4%, and 41.1%, respectively. As the group number increased, the proportion of those with recent wheezing and those with indoor allergen sensitization decreased (P for trend = 0.001 and P for trend < 0.001, respectively), and the baseline FEV1/FVC increased (P for trend < 0.001) CONCLUSION: BR of the 7-year-olds in the general population, while showing a wide distribution across phenotypes, is associated with allergic symptoms, negatively correlated with baseline lung function and positively correlated with indoor allergen sensitization.