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Nocturnal asthma (NA) is a high-prevalence disease that causes severe respiratory issues, leading to death from early midnight to early morning. In this research, nanoparticulate drug delivery system of methylprednisolone (MP) was developed using chitosan (CH) and pectin (PEC). MP is a synthetic corticosteroid medication widely used for its potent anti-inflammatory activity. Computational simulation study (AI-based blend analysis algorithm) was used to identify a better-mixing polymer with MP. MP nanoparticles were formulated by the ionic gelation method with the combination of CH and PEC. To modify the drug release properties, the formed beads were coated with chitosan succinate (CSSC). The morphological characteristics of the beads were determined by SEM analysis. The X-ray radiographic imaging study was used to observe the intactness of MP beads. Histopathological studies were also carried out to find out the toxicity of the beads in the organs of rats. Pectin and chitosan polymers were selected based on the computational simulation study. SEM analysis revealed that the beads had a spherical shape with a rough outer surface. CSSC-coated beads achieved sustained drug release for up to 24 h. X-ray imaging demonstrated the stability of the beads in acidic pH conditions. In vivo pharmacokinetic studies showed that CSSC-coated beads were more stable in the gastrointestinal tract (GIT) than PEC-CH beads and the pure drug. Histological evaluation confirmed that the beads are nontoxic and safe for use in rats. Based on the findings, it was concluded that CSSC-coated beads of MP exhibited superior release properties, making them suitable for a chronomodulated drug delivery system. [ABSTRACT FROM AUTHOR]

Objective: Mume fructus is commonly used in traditional Chinese medicine to treat nocturnal asthma symptoms. However, the molecular mechanisms underlying its effects on nocturnal asthma have not yet been established. This study evaluated the therapeutic mechanisms of Mume fructus in treating nocturnal asthma. Materials and Methods: Network pharmacology was used to investigate the chemical composition, critical targets, and potential mechanisms of action of Mume fructus in treating nocturnal asthma. “Mume fructus” and “nocturnal asthma” were used as keywords to search the relevant databases. The 16HBE and RAW264.7 cells were treated with various concentrations of Mume fructus and lipopolysaccharides (LPSs). Data provided included analyses of cell viability detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, cell proliferation and apoptosis detected by 5-ethynyl-2’-deoxyuridine and Hoechst 33342, messenger ribonucleic acid (mRNA) levels obtained by real-time polymerase chain reaction, and protein expression detected by Western blotting. Additionally, immunofluorescence was used to detect nuclear translocation. Results: Network pharmacology analyses were mainly enriched in nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) pathway, and interleukin (IL)-6. Mume fructus and LPS had no effect on viability, proliferation, and apoptosis in 16HBE and RAW264.7 cells under certain concentration conditions. Mume fructus counteracted LPS-stimulated mRNA and protein expression of IL-6. In addition, Mume fructus treatment prevented the LPS-induced phosphorylation of NF-κB and MAPK pathways, as well as the nuclear translocation of NF-κB p-p65 in the 16HBE and RAW264.7 cells. Conclusions: Mume fructus can treat nocturnal asthma by regulating the NF-κB and MAPK pathways and counteracting IL-6 expression. These findings provide a scientific basis for the use of Mume fructus in the treatment of nocturnal asthma.

Background: The association between nocturnal Asthma and gastroesophageal reflux disease (GERD) has been widely researched, yet its complexities remain only partially understood. This systematic review aims to elucidate the connection between night-time asthma and the incidence of GERD, with a focus on nocturnal GERD's impact on respiratory function. Methods: Adhering to PRISMA guidelines, a comprehensive search of eight databases- PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, PsycINFO, CINAHL, and Google Scholar was performed to collect studies examining the link between nocturnal Asthma and GERD. Selection criteria were established a priori, and data from relevant studies were extracted and assessed for methodological quality. Results: Our review synthesized data from eleven studies that consistently showed a link between nocturnal GERD and Asthma. Night-time GERD episodes were found to correlate with increased respiratory load and a higher risk of developing respiratory symptoms and Asthma. While all studies supported the detrimental impact of nocturnal GERD on respiratory health, they varied regarding specific respiratory outcomes and the timing of symptom manifestation. Evidence pointed to both immediate and delayed physiological responses to GERD, complicating the asthma management process. Conclusion: The systematic review confirms a significant association between nocturnal GERD and respiratory health issues, including increased respiratory load and the development of Asthma and related symptoms. These findings highlight the importance of considering nocturnal GERD in the management of respiratory conditions, particularly Asthma, and suggest a need for tailored treatment strategies to address this complex interplay. [ABSTRACT FROM AUTHOR]

Purpose: Nocturnal asthma is a sign of asthma worsening and could be partially due to more fluid drawn into the thorax during sleep by gravitational force and/or pharyngeal collapse in those with obstructive sleep apnea. Wearing compression stockings during the day reduces fluid shift from the legs to the neck overnight. However, the potential effect of wearing compression stockings to reduce fluid accumulation in the leg and to improve nocturnal small airway narrowing in patients with asthma has not been investigated. This study investigates whether reducing leg fluid volume by wearing compression stockings during the day would attenuate small airway narrowing in patients with asthma before and after sleep. Methods: We enrolled 11 participants with asthma. All participants underwent overnight polysomnography with or without wearing compression stockings for 2 weeks. Before and after sleep, leg fluid volume (LFV) was measured by bioelectrical impedance, and airway narrowing was primarily assessed by respiratory system resistance and reactance at 5 Hz (R5 and X5 respectively) using oscillometry. Results: After 2 weeks of wearing compression stockings, the LFV measured in the evening was reduced (∆ = − 192.6 ± 248.3 ml, p = 0.02), and R5 and X5 improved (∆ = − 0.7 ± 0.9 cmH2O/L/s, p = 0.03 and 0.2 ± 1.4 cmH2O/L/s, p = 0.05 respectively). No changes were observed in the morning. Conclusions: Preventing fluid retention in the legs by wearing compression stockings for 2 weeks during the day, reduced LFV and airway narrowing in the evening in all participants with asthma, but not in the morning after sleep. [ABSTRACT FROM AUTHOR]

Mustafa Abdo,1 Frederik Trinkmann,2,3 Anne-Marie Kirsten,4 Heike Biller,1 Frauke Pedersen,1,4 Benjamin Waschki,1 Erika Von Mutius,5 Matthias Kopp,6,7 Gesine Hansen,8 Klaus F Rabe,1 Thomas Bahmer,1,9,&ast; Henrik Watz4,&ast; On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 3Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 4Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 5Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich, German Center for Lung Research (DZL), and Institute of Asthma and Allergy Prevention, Helmholtz Centre, Both Munich, Germany; 6Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 7Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 8Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 9University Hospital Schleswig-Holstein-Campus Kiel, department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany&ast;These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Grosshansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Small airway dysfunction (SAD) is a frequent feature of asthma that has been linked to disease severity and poor symptom control. However, little is known about the role of SAD in nocturnal asthma.Objective: To study the association between the severity of SAD and frequency of nocturnal symptoms compared to conventional lung function testing.Methods: We assessed the frequency of self-reported nocturnal symptoms through the asthma control test. We studied the impact of nocturnal asthma using the Asthma Quality of Life Questionnaire (AQLQ) and the Multidimensional Fatigue Inventory (MFI-20). We assessed the lung function using spirometry, body plethysmography, impulse oscillometry, single and multiple inert gas washout and measured markers of T2-inflammation (blood and sputum eosinophils; fractional exhaled nitric oxide (FeNo)). We stratified the patients according to the presence and frequency of nocturnal asthma.Results: A total of 166 asthma patients were enrolled in the analysis. Eighty-seven patients (52%) reported to have nocturnal symptoms at least once in the last four weeks. The odds ratio of nocturnal asthma correlated with the severity of all non-spirometric measures of SAD, yet neither with airflow obstruction (FEV1 and FEV/FVC) nor with large airway resistance (R20). Patients with frequent nocturnal asthma (n = 29) had a numerical increase of T2 markers and more severe SAD, as indicated by all non-spirometric measures of SAD (all p-values < 0.05), worse overall asthma control, increased fatigue and reduced quality of life (all p-values < 0.01) compared to patients with infrequent nocturnal asthma (n = 58) or patients without nocturnal asthma (n = 79). We identified 63 patients without airflow obstruction, nearly 43% of them (n = 27) had nocturnal asthma. In this subgroup, only markers of air trapping and ventilation heterogeneity were significantly elevated and correlated with the frequency of nocturnal symptoms: LCI (Spearman’s coefficient = − 0.42, p < 0.001), RV% (− 0.32, p = 0.02).Conclusion: SAD is closely associated to asthma with nocturnal symptoms. Spirometry might underestimate the broad spectrum of distal lung function impairments in this population of patients.Keywords: small airway dysfunction, nocturnal asthma, ventilation heterogeneity, air trapping

In many of those affected, bronchial asthma with or without therapy leads to fairly significant nocturnal symptoms, which indicate a decline in control of the illness and sleep quality. There are many causes of the symptoms. Changes in lung function, heightened nocturnal hyperresponsiveness, cellular transmitter and inflammatory and hormonal processes, but environmental impacts and frequently coexisting diseases have also been identified as causes. Significant connections exist, particularly between bronchial asthma and nocturnal gastroesophageal reflux, obesity, and obstructive sleep apnea syndrome. With regard to guideline-compliant asthma therapy, the symptoms should be examined more closely in order to achieve control of the asthma with targeted treatment. Preventive measures such as avoidance of allergens in the evening and at night should also be considered. [ABSTRACT FROM AUTHOR]

Nocturnal asthma (NA) is increasing in prevalence, affecting millions of people worldwide. In addition to being associated with increased mortality, NA is associated with a decreased quality of life. NA associated sleep disturbances and increased daytime sleepiness are especially important in children due to the accompanying behavioral and developmental difficulties. As diurnal spirometry is not a practical tool for the diagnosis and monitoring of NA, self or parental reports are used. Children underreport and underestimate their NA symptoms and parents are not fully aware of their child’s NA indicators. In addition, there is the lack of physician familiarity regarding the assessment and treatment of NA. Therefore, NA is chronically underreported. The development of a non-invasive, objective, home-based diagnostic tool is crucial in diagnosing and monitoring children with NA. The presence of wheeze during sleep has been successfully employed as a tool to measure NA in children. This review discusses the increasing prevalence of NA, current diagnostic tools and the consequences of undiagnosed NA in children. In conclusion, this paper suggests that an automated wheeze detective device is an objective and practical tool to aid the diagnosis and monitoring of NA.

Self-management improves quality of life among adolescents with nocturnal asthma. This study aimed to identify sleep disturbances and self-managements regarding asthmatic attack among adolescents with nocturnal asthma. Therefore, a cross sectional study was conducted at the Emergency Department in Al- Najaf, during the period October 15th 2017 to September 18th 2018. The study included 100 adolescents with nocturnal asthma who met the inclusion criteria, a pre-structured validated questionnaire was used, including demographic information, sleep disturbances variables and self-managements questionnaire. Data were managed and analyzed using the statistical package for social sciences software version 25 and appropriate statistical tests were applied accordingly. The findings revealed that (66.6%) of patients had moderate and (30%) had severe sleep disturbances. Also, (77.7%) of patients had a poor and (22.2%) had fair self-management. It had been significantly found that females were less aware for self-management, (P<0.05), other characteristics showed no significant association, (P>0.05). In conclusion, an evidence of sleep disturbances among the adolescents that result from asthmatic attack during the night. Deficit knowledge regarding self-management of asthmatic attack and other female gender can contributed to such attacks. [ABSTRACT FROM AUTHOR]

Background: We have previously shown that when asthmatics go supine, fluid shifts out of the legs, accumulates in the thorax, and exacerbates lower airway narrowing. In the retrospective analysis of our previous work presented here, we test the hypothesis that the sensitivity of this process relates inversely to baseline caliber of the lower airways.Methods: Eighteen healthy (six women) and sixteen asthmatic subjects (nine women) sat for 30 min, and then lay supine for 30 min. While supine, lower body positive pressure (LBPP, 40 mm Hg) was applied to displace fluid from the legs similar in amount to the overnight fluid shift. Respiratory resistance and reactance at 5 Hz (R5 and X5) and leg and thoracic fluid volumes (LFV and TFV) were measured at the beginning and end of the supine period.Results: With LBPP, healthy, and asthmatic subjects had similar changes in the LFV and TFV (p = 0.3 and 0.1, respectively). Sensitivity to fluid shift, defined by ΔR5/ΔTFV, was larger in the asthmatics than in the healthy subjects (p = 0.0001), and correlated with baseline R5 in the supine position in the asthmatics (p = 0.7, p = 0.003). No such association was observed in the healthy subjects (p = 0.6). In the asthmatics, women showed a greater reduction in X5 than men with LBPP (p = 0.009).Conclusions: Smaller baseline airway caliber, as assessed by larger R5, was associated with increased sensitivity to fluid shift in the supine position. We conclude that asthmatics with narrower small airways such as obese asthma patients, women with asthma and those with severe asthma may be more sensitive to the effects fluid shift while supine as during sleep.

Background: We have previously shown that when asthmatics go supine, fluid shifts out of the legs, accumulates in the thorax, and exacerbates lower airway narrowing. In the retrospective analysis of our previous work presented here, we test the hypothesis that the sensitivity of this process relates inversely to baseline caliber of the lower airways. Methods: Eighteen healthy (six women) and sixteen asthmatic subjects (nine women) sat for 30min, and then lay supine for 30min. While supine, lower body positive pressure (LBPP, 40mm Hg) was applied to displace fluid from the legs similar in amount to the overnight fluid shift. Respiratory resistance and reactance at 5Hz (R5 and X5) and leg and thoracic fluid volumes (LFV and TFV) were measured at the beginning and end of the supine period. Results: With LBPP, healthy, and asthmatic subjects had similar changes in the LFV and TFV (p = 0.3 and 0.1, respectively). Sensitivity to fluid shift, defined by ΔR5/ΔTFV, was larger in the asthmatics than in the healthy subjects (p = 0.0001), and correlated with baseline R5 in the supine position in the asthmatics (p = 0.7, p = 0.003). No such association was observed in the healthy subjects (p = 0.6). In the asthmatics, women showed a greater reduction in X5 than men with LBPP (p = 0.009). Conclusions: Smaller baseline airway caliber, as assessed by larger R5, was associated with increased sensitivity to fluid shift in the supine position. We conclude that asthmatics with narrower small airways such as obese asthma patients, women with asthma and those with severe asthma may be more sensitive to the effects fluid shift while supine as during sleep. [ABSTRACT FROM AUTHOR]

Inhaled β2-adrenergic receptor (β2-AR) agonists are the mainstay of treatment of acute asthma. Polymorphisms of the β2-AR, especially codons 16, 27, and 164, may affect the functions of the receptor. This study was conducted to investigate whether different polymorphisms of the β2-AR are related to the treatment responses of an inhaled β2-AR agonist in children with nocturnal and nonnocturnal asthma in Taiwan. Methods: The nocturnal asthma group consisted of 27 children (mean age of 10.3±2.4 years), and the nonnocturnal asthma group consisted of 24 patients (mean age of 9.9±3.0 years). Allele-specific polymerase chain reaction was performed to determine 16, 27, and 164 loci alleles of β2-AR genetic polymorphisms, and peak expiratory flow (PEF) was measured before and 1 hour after inhalation of 0.2 mg/kg/dose of terbutaline to determine the treatment response in these patients. Results: The polymorphisms of β2-AR 27 but not 16 or 164 were significantly associated with the response to terbutaline nebulizer (p

Introduction: Many inflammatory conditions, such as asthma, show circadian symptoms that are worse at night. Delayed-release prednisone was developed for bedtime administration to optimize inhibition of nocturnally elevated pro-inflammatory cytokines. A proof-of-concept study was undertaken to examine the impact of delayed-release prednisone on nocturnal awakenings in patients with asthma requiring treatment with oral steroids. Methods: In this single-center, open-label study, patients receiving long-term treatment with conventional prednisone administered at 08:00 h were switched to 4 weeks of treatment with the same dose of delayed-release prednisone given at 22:00 h. The primary efficacy endpoint was the change in number of nocturnal awakenings during the final 2 weeks of each treatment phase. Results: Seven patients received treatment with delayed-release prednisone. Mean nocturnal awakenings because of asthma decreased from 10.0 ± 5.45 with conventional prednisone to 2.1 ± 4.41 with delayed-release prednisone, a mean reduction of −7.9 ± 6.07 (82.7% reduction). Delayed-release prednisone was generally well tolerated, and there were no unexpected safety findings. Conclusions: Although the size of the efficacy population was too small to detect any statistically significant changes in nocturnal asthma control, this proof-of-concept study suggests that nighttime administration of delayed-release prednisone provides better asthma symptom control compared with morning administration of conventional prednisone. Funding: Horizon Pharma, Inc (formerly Nitec Pharma GmbH). [ABSTRACT FROM AUTHOR]

The field of chronobiology and chronotherapy in medicine is in its relative infancy. However, important knowledge has been gained so as to better understand both the pathophysiology of diseases and the corresponding therapeutic interventions. Asthma is one of the disease entities that has been studied in detail in regard to both time related alterations in pathophysiology and treatment. This article reviews the nocturnal worsening of asthma.

Purpose: To develop and determine the in vivo performance of a capsule-based pulsatile drug delivery system containing salbutamol sulphate Methods: A controlled pulsatile release of drug after a programmed 4 h lag period was achieved from cross-linked gelatin capsule shells containing salbutamol pellets, and sealed with a suitable mixture of sodium alginate and ethyl cellulose as plug. In order to confirm the utility of developed system for the management of nocturnal asthma, a crossover study was conducted six male rabbits were fasted overnight and divided into two groups comprised of 3 rabbits each. The individual rabbits were administered the developed pulsatile capsule and immediate release salbutamol capsule as reference, separately. Blood samples were collected from the ear vein of the animals into heparinized tubes and used to determine pharmacokinetic parameters, namely, maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), and area under the plasma concentration - time curve (AUC0-8) using a validated HPLC method. Results: It was observed that drug release from the optimized time-controlled capsule stopped for a period of approximately 4.25 h with an average Cmax and Tmax of 271.54 ± 58.95 ng/ml and 6.00 ± 0.25 h. The AUC0-8 of salbutamol after administration of the time-controlled pulsatile system was 2494.73 ± 525.95 ng h/ml while that of the immediate-release formulation was 2352.77 ± 432.51 ng h/ml. Using ANOVA at a significant difference of p < 0.05 (CI 95%), there was no significant difference for the AUC0-8 between immediate release and the pulsatile capsule developed. Conclusion: The developed system is capable of releasing salbutamol after a 4 h lag period and can be considered as promising delivery system for time-controlled (pulsatile) delivery of the medication for the management of nocturnal asthma. [ABSTRACT FROM AUTHOR]

Fungal growth indoors is a common problem both in older and modern buildings. Numerous studies demonstrate a deterioration of asthma in environments with fungal growth but precise estimates of exposure levels have not been reported.This study was carried out to investigate whether levels of airborne fungi were higher in homes of subjects with nocturnal asthma as compared to controls. Subjects with nocturnal asthma (n = 42) and non-nocturnal asthma (n = 14) were recruited from an outpatient department. Subjects without disease or respiratory symptoms (n = 24) served as controls. Among the asthmatics, determinations were made of pulmonary function before and after treatment with bronchodilatators. The subjects were equipped with a pump and a filter and instructed to sample air in their bedroom. The filters were analysed for the content of N-acetylhexosaminidase (NAHA) as a marker of fungal cell biomass. In some houses the number of colony forming units was also determined. Patients with asthma had significantly higher activities of NAHA in their bedrooms as compared to controls (31.2 vs. 12.5 U m−3, p = 0.004). When the material was divided according to the 2nd quartile of NAHA (14.0 U m−3), 29 out of 42 subjects with nocturnal asthma had high values compared to 5 out of 24 for the controls (p<0.0001). The results support the hypothesis that patients with nocturnal asthma have high levels of fungi in their homes. This provides a basis for treatment and exposure diminution. Whether that exposure is causative for their disease; or if it aggravates already existing airway symptoms remains to be elucidated. [ABSTRACT FROM PUBLISHER]

Purpose: To develop an oral capsule-based chronomodulated drug delivery system of salbutamol sulphate for the treatment of nocturnal asthma. Methods: The basic design of the proposed dosage form entails an insoluble cross-linked capsule body filled with drug-loaded pellets sealed with hydrocolloid plug and a soluble capsule cap. Various hydrocolloid polymers, namely, hydroxypropyl methylcellulose, (HPMC), hydroxypropyl cellulose (HPC), sodium alginate, polyethylene oxide (PEO) and guar gum. were used to optimize the plug material in the delivery in order to modulate lag period To avoid gastric transit time variability, the entire system was coated with Eudragit S100/Eudragit L100 dispersion (4:1), an enteric polymer system that dissolves at pH 6.8. Results: Time-specific pulsatile release with 4 h lag period was achieved with crosslinked insoluble gelatin capsule shells containing pellets prepared from Avicel PH 101/lactose (80: 10) and 3 % Acidisol as disintegrant. In vitro data indicate that the developed pulsatile system released almost 98 % of the drug shoertly after the predetermined lag time of 4 h. Conclusion: The developed system is capable of releasing the drug after a 4-h lag period. However, in vivo studies need to be carried out to ascertain the effectiveness of the formulation. [ABSTRACT FROM AUTHOR]

Asthma is a lung disease characterized by inflammation and remodeling of the airways. It is now widely accepted that airway inflammation and remodeling occur not only in the central airways but also in the small airways and even in the lung parenchyma. Inflammation of the distal lung can be observed even in mild asthmatics with normal or noncompromised lung function. Moreover, the small airways and the lung parenchyma can produce many Th2 cytokines and chemokines involved in initiation and perpetuation of the inflammatory process. In addition, the distal parts of the bronchial tree have been recognized as a predominant site of airflow obstruction in many asthmatics. In fact, the inflammation at this distal site has been described as more severe when compared to the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance, highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The purpose of this study was to prepare a pressure-controlled colon delivery capsule (PCDC) containing theophylline (TPH) dispersion in a lipid matrix as a chronotherapeutic drug delivery system for the treatment of nocturnal asthma. The system was made by film coating using Eudragit S100- based formula over the sealed-hard gelatin capsules containing the drug-lipid dispersion. The lipid formula was composed mainly of Gelucire 33/01 (G33) with different ratios of surfactants (1--10%). The efficiency of the prepared system was evaluated in vitro for its ability to withstand both the gastric and intestinal medium. In addition, the drug plasma concentrations were monitored after single administration to Beagle dogs and compared to that obtained after administration of a reference marketed, generic, sustained-release TPH tablets, Avolen®® SR. It was found that the optimum lipid formula was GL2 containing 90% G33 and 10% Labrasol. The film-coated capsules showed complete resistance to both the acidic environment (pH 1.2) for 2 hours and phosphate buffer pH 6.8 for 3 hours at 37°°C. In vivo evaluation of the TPH-based PCDCs showed longer lag time compared TO the marketed formula followed by sudden increase in TPH blood levels, which recommends the high potential of this system as a chronotherapeutic drug delivery for nocturnal asthma. The prepared PCDCs exhibited a significantly higher Cmax and Tmax and a nonsignificantly different AUC compared with Avolen®® SR. Higher TPH blood levels from 1 to 8 hours postadministration was detected in the case of the prepared PCDCs. [ABSTRACT FROM AUTHOR]

Background: Inhaled β2-adrenergic receptor (β2-AR) agonists are the mainstay of treatment of acute asthma. Polymorphisms of the β2-AR, especially codons 16, 27, and 164, may affect the functions of the receptor. This study was conducted to investigate whether different polymorphisms of the β2-AR are related to the treatment responses of an inhaled β2-AR agonist in children with nocturnal and nonnocturnal asthma in Taiwan. Methods: The nocturnal asthma group consisted of 27 children (mean age of 10.3±2.4 years), and the nonnocturnal asthma group consisted of 24 patients (mean age of 9.9±3.0 years). Allele-specific polymerase chain reaction was performed to determine 16, 27, and 164 loci alleles of β2-AR genetic polymorphisms, and peak expiratory flow (PEF) was measured before and 1 hour after inhalation of 0.2mg/kg/dose of terbutaline to determine the treatment response in these patients. Results: The polymorphisms of β2-AR 27 but not 16 or 164 were significantly associated with the response to terbutaline nebulizer (p <0.05). The polymorphism of β2-AR 16 was associated with nocturnal asthma (p =0.027). The Gly16 allele was more prevalent in the nocturnal asthma group (9/27; 33.3%) than in the nonnocturnal asthma group (3/24; 12.5%). Arg16 allele was less prevalent in the nocturnal asthma (3/27; 11.1%) than in the nonnocturnal asthma group (10/24; 41.7%). There was also a linkage disequilibrium found between β2-AR 16 (Arg/Arg) and β2-AR 27 (Gln/Gln). Conclusion: These findings suggest that polymorphisms of β2-AR 16 are related to nocturnal asthma and polymorphisms of β2-AR 27 are associated with the variable responses to the inhaled terbutaline in children with nocturnal and nonnocturnal asthma. [ABSTRACT FROM AUTHOR]

The aim of the present study was to develop theophylline fast release enteric-coated pellets as a pulsatile drug delivery to the colon. The novelty of this work is the combination of pH and time-dependant enteric polymers as a single coating for the development of multiparticulate formulation. Theophylline pellets were optimized by applying a 2-factors 3-levels full factorial design. Continuous dissolution studies were carried out in simulated gastric, intestinal, and colonic fluid with pH 1.2 (0.1 N HCl), pH 7.4 and pH 6.8 (phosphate buffer), respectively. The lag time prior to the drug release was highly affected by combination of two factors, i.e. the percentage of Eudragit RL100 in polymer mixture and coating level. The formulation containing Eudragit RL100 and Eudragit S100 with a ratio of 4:1 and coating level of 12%w/w was found to be optimum. The results of serum study in New Zealand rabbits showed that the developed formulation provided a significant lag phase of 5 h. The present study demonstrates that the theophylline enteric-coated pellets could be successfully colon targeted by the design of pH- and time-dependant modified chronopharmaceutical formulation. In conclusion, pulsatile drug release over a period of 3–12 h is consistent with the requirements for chronopharmaceutical drug delivery. [ABSTRACT FROM AUTHOR]

Nocturnal asthma indicates poor overall control of asthma and adversely affects the quality of life of the patient. The purpose of the present study was to compare the objective measurement of nocturnal wheeze with clinical state, recall of symptoms, and changes in lung function. Nine asthmatic children aged 9 to 16 years were followed with an asthma diary and diurnal measurement of peak flow for a week before the nocturnal study; all but two were apparently well controlled. Breath sounds were recorded and analyzed continuously overnight to quantify wheeze using a phonopneumography sensor attached over the trachea. The analytical system (PulmoTrack) utilized an algorithm to detect wheeze and reject interference. The wheeze rate (Tw/Ttot = duration of wheeze/duration of recording) was calculated minute by minute throughout the night. Recordings lasted over 8 hours and all but two children had wheeze lasting for a total time of between 11 and 87 minutes. The pattern of wheezing was very variable during sleep, with episodes of wheeze separated by periods of quiet breathing. There was no relationship between subjective perception of nocturnal asthma, forced expiratory volume in 1 s (FEV1) next morning, and the objective measurement of wheeze. Total overnight wheeze was significantly related to the total diary symptom score and to the (small) diurnal variability of peak expiratory flow (PEF). Four of the seven children with asthma who were apparently well controlled had considerable amounts of wheeze during the night that was episodic in nature and unrelated to conventional measures of lung function or nocturnal symptoms. [ABSTRACT FROM AUTHOR]

Background. Asthmatics with glucocorticoid dependent asthma should be treated with systemic steroids. Cyclosporine is in many ways a potent anti-inflammatory drug. Cyclosporine is sometimes very effective in treating asthmatics and could allow us to lower the dose of oral steroid. In some randomized, double blind studies steroid dependent asthmatics were treated 12–36 weeks with cyclosporine in dose 5 mg/kg/day. We tried cyclosporine in steroid dependent asthmatics in shorter course and in lower dose.Methods. 13 steroid dependent asthmatics were in the first four weeks of the study treated by their own drugs (phase 1). Then they were for the next four weeks (phase 2) randomly and in double blind fashion treated with either cyclosporine (mean 1.7 mg/kg/day, SD 0.5, 6 patients – group 1) or by identical placebo (7 patients – group 2). To the patients in the group 2 serum concentration of cyclosporine was measured on the eight day of the study.Results. Morning peak expiratory flow (PEF) raised significantly in group 1 (200 L/sec to 247 L/sec or for 23%). Patients in group1 had significantly less episodes of nocturnal asthma (2.2 episodes/night to 1.5 episodes/night or for 32%). In group 2 were not found any changes between first phase and second phase of the study. Steroid consumption did not change in any group. Mean serum concentration of cyclosporine in patients of group1 was 35.7 µg/L. We did not find any adverse effects of cyclosporine or placebo.Conclusions. Cyclosporine could have dangerous side effects, which are dependent on its serum concentration. So it should be administered in the lowest possible dose and for the most possible short period. In our study it was found that it is possible to successfully treat steroid dependent asthmatics with lower daily dose and for shorter time, than was found in other similar studies.

Individual differences in circadian rhythm have been studied since the past century. Chronotypes are a chronobiology classification based on the preferential times for beginning and ending activities throughout the day. Chronotypes can be classified as definitely morning, moderately morning, indifferent, moderately evening, and definitely evening. We aim to assess the distribution of chronotypes in asthmatics and the relationship of chronotype to the presence of nocturnal symptoms. Two hundred subjects were evaluated, 100 asthmatics and 100 non-asthmatics. The Morningness/Eveningness questionnaire was applied for chronotype determination. The asthmatics were subdivided according to the presence or absence of nocturnal symptoms. The chronotype distribution did not differ significantly between asthmatics and non-asthmatics. Thirty-five percent of the asthma group reported nocturnal symptoms. There was a significant difference in chronotype distribution between asthmatics with and without nocturnal worsening. The asthmatics with nocturnal symptoms had a lower prevalence of morning types and had a greater predominance of indifferent chronotype compared to asthmatics without nocturnal symptoms (p = 0.011). In conclusion, asthmatics with nocturnal symptoms present deviation from the chronotype distribution curve when compared to asthmatics without nocturnal symptoms. This is the first study to show the effect of a disease on chronotypes. [ABSTRACT FROM AUTHOR]

A time dependent pulsed release system consisting of an effervescent core surrounded by consecutive layers of swelling and rupturable polymers was prepared and evaluated. The cores containing salbutamol sulphate as bioactive agent were prepared by direct compression method using different ratios of microcrystalline cellulose and effervescent agent and then coated sequentially with an inner swelling layer containing a hydrocolloid, hydroxypropylmethylcellulose E5 and an outer rupturable layer having Eudragit RL/RS (1:1). The effects of various processing and formulative parameters on the performance of system were studied. The rupture and dissolution tests were studied using the USP paddle method at 50 rpm in 0.1 N HCl and phosphate buffer pH 6.8. The lag time of the drug release decreased by increasing the inner swelling layer and increased by increasing the rupturing layer level. All the results obtained in the present study suggest that osmotic pumping effect was involved which eventually lead to the drug release. [ABSTRACT FROM AUTHOR]

Abstract: In this study, investigation of an oral colon specific, pulsatile device to achieve time and/or site specific release of theophylline, based on chronopharmaceutical consideration. The basic design consists of an insoluble hard gelatin capsule body, filled with eudragit microcapsules of theophylline and sealed with a hydrogel plug. The entire device was enteric coated, so that the variability in gastric emptying time can be overcome and a colon-specific release can be achieved. The theophylline microcapsules were prepared in four batches, with Eudragit L-100 and S-100 (1:2) by varying drug to polymer ratio and evaluated for the particle size, drug content and in vitro release profile and from the obtained results; one better formulation was selected for further fabrication of pulsatile capsule. Different hydrogel polymers were used as plugs, to maintain a suitable lag period and it was found that the drug release was controlled by the proportion of polymers used. In vitro release studies of pulsatile device revealed that, increasing the hydrophilic polymer content resulted in delayed release of theophylline from microcapsules. The gamma scintigraphic study pointed out the capability of the system to release drug in lower parts of GIT after a programmed lag time for nocturnal asthma. Programmable pulsatile, colon-specific release has been achieved from a capsule device over a 2–24h period, consistent with the demands of chronotherapeutic drug delivery. [Copyright &y& Elsevier]