Halotherapy—An Ancient Natural Ally in the Management of Asthma: A Comprehensive Review

The increasing production of modern medication emerges as a new source of environmental pollution. The scientific community is interested in developing alternative, ecological therapies in asthma. Halotherapy proved its benefits in asthma diagnosis, treatment, and prevention and may represent a reliable therapeutic addition to the allopathic treatment, due to its ecological and environment-friendly nature, in order to prevent or prolong the time to exacerbations in patients with asthma. We aimed to review up-to-date research regarding halotherapy benefits in asthma comprehensively. We searched the electronic databases of PubMed, MEDLINE, EMBASE for studies that evaluated the exposure of asthmatic patients to halotherapy. Eighteen original articles on asthma were included. Five studies in adults and five in children assessed the performance of hypertonic saline bronchial challenges to diagnose asthma or vocal cord dysfunction in asthmatic patients. Three papers evaluated the beneficial effects of halotherapy on mucociliary clearance in asthmatic adults. The therapeutic effect of halotherapy on acute or chronic asthma was appraised in three studies in adults and one in children. The preventive role was documented in one paper reporting the ability of halotherapy to hinder nocturnal asthma exacerbations. All studies seem to sustain the overall positive effects of halotherapy as adjuvant therapy on asthma patients with no reported adverse events. Halotherapy is a crucial natural ally in asthma, but further evidence-based studies on larger populations are needed.

Melatonin MT2 receptor is expressed and potentiates contraction in human airway smooth muscle

Nocturnal asthma is characterized by heightened bronchial reactivity at night, and plasma melatonin concentrations are higher in patients with nocturnal asthma symptoms. Numerous physiological effects of melatonin are mediated via its specific G protein-coupled receptors (GPCRs) named the MT1 receptor which couples to both Gq and Gi proteins, and the MT2 receptor which couples to Gi. We investigated whether melatonin receptors are expressed on airway smooth muscle, whether they regulate intracellular cyclic AMP (cAMP) and calcium concentrations ([Ca2+]i) which modulate airway smooth muscle tone, and whether they promote airway smooth muscle cell proliferation. We detected the mRNA and protein expression of the melatonin MT2 but not the MT1 receptor in native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by RT-PCR, immunoblotting, and immunohistochemistry. Activation of melatonin MT2 receptors with either pharmacological concentrations of melatonin (10 - 100 µM) or the non-selective MT1/MT2 agonist ramelteon (10 µM) significantly inhibited forskolin-stimulated cAMP accumulation in HASM cells, which was reversed by the Gαi protein inhibitor pertussis toxin or knockdown of the MT2 receptor by its specific siRNA. Although melatonin by itself did not induce an initial [Ca2+]i increase and airway contraction, melatonin significantly potentiated acetylcholine-stimulated [Ca2+]i increases, stress fiber formation through the MT2 receptor in HASM cells, and attenuated the relaxant effect of isoproterenol in guinea pig trachea. These findings suggest that the melatonin MT2 receptor is expressed in ASM, and modulates airway smooth muscle tone via reduced cAMP production and increased [Ca2+]i.

An Unidentified Monster in the Bed – Assessing Nocturnal Asthma in Children

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.

Effectiveness of beclometasone dipropionate and formoterol in an extrafine particle formulation for asthma therapy depending on patient smoking status: the CASPER noninterventional, observational trial

Background: The goal of asthma treatment, outlined by GINA experts, is to achieve and maintain full control of the disease. One critical risk factor for poor asthma control is exposure to tobacco smoke. The purpose of this analysis isto assess the effectiveness and safety of long-term therapy with an extrafine combined aerosol formulation of beclometasone dipropionate and formoterol (BDP/F) in asthmatics for current and ex-smokers vs non-smokers. Methods: The CASPER study was an observational, noninterventional, prospective, multicentre trial. Asthmatics currently being managed long-term with BDP/F pressurized metred-dose inhaler (pMDI) were divided based on smoking status into three groups: current smokers, ex-smokers, and non-smokers. The subjects were evaluated at 0, 3, and 6 months for symptom intensity, asthma control, frequency of exacerbations and dose of inhaled corticosteroids. Adverse drug reactions were also monitored. Results: Out of 16,844 patients, 2833 (16.8%) were ex-smokers and 3312 (19.7%) were current smokers. At the beginning of the observation, the current smokers were the most symptomatic subgroup of patients with the greatest limitation on life activity. During long-term treatment with extrafine BDP/F-pMDI , diurnal and nocturnal asthma symptoms, rescue medication use, and limitations of activity secondary to asthma were markedly decreased in all subgroups, with a statistically significant effect in smokers and ex-smokers, albeit at the end of the observation, a higher percentage of symptomatic patients remained in the groups of current smokers and ex-smokers while a lower percentage of symptomatic patients was observed among the non smokers. At the 6-month follow-up, an improvement in asthma control compared to baseline, according to GINA criteria, was reported in 77.1% of current smokers, 75.2% of exsmokers, and 75% of non-smokers, but full asthma control was more frequently achieved in non smokers (64.0% fulfilled GINA criteria of asthma control) compared to current smokers and ex-smokers (54.9% and 51.5%, respectively). A total of 525 nonserious ADRs were reported in 422 patients (3.2%), all of which were within expectations. Conclusions: Combination therapy with extrafine BDP/F-pMDI is an effective therapy across a broad spectrum of asthmatics, irrespective of smoking status,albeit the overall asthma control is worse in those with a smoking history.

Optimized chronomodulated dual release bilayer tablets of fexofenadine and montelukast: quality by design, development, and in vitro evaluation

Background The conventional oral dosage forms are not effective in dealing with chronopathological conditions, such as nocturnal asthma. Therefore, there is an unmet need to develop a delivery system that can deliver drug as per the chronopharmacology of the diseases. The purpose of the study is to use quality by design (QbD) technique and pulsatile principles for the development of Eudragit-coated dual release bilayer tablets. The dual layer consists of immediate release layer of fexofenadine HCl and sustained release layer of montelukast sodium. Results The quality target product profile of the formulation was developed, and the critical quality attributes were identified. Three-level, three-factor Box-Behnken design was used for the optimization of the bilayer tablets. Based on the design, a total of 13 formulation combinations (F1–F13 and M1–M13) were made having acceptable micromeritic properties. The developed immediate and sustained release layers were evaluated for physicochemical properties. Depending upon the value of the diffusion exponent, the Fickian diffusion mechanism is dominant among immediate and sustained release tablet layers. Response curve for immediate release layer showed that concentrations of sodium starch glycolate and sodium bicarbonate had a negative effect on disintegration time and a positive effect on drug release. For sustained release tablet layer, concentrations of HPMC E 5 LV and magnesium stearate had a significant effect on drug release. The ANOVA and diagnostic plots confirmed the significance and goodness of fit of the used model. Based on desirability plot values, optimized formulation was developed and coated with Eudragit coat. The coated bilayer tablet showed met the requirement of providing an immediate release during the first hour and a sustained release action for a period of more than 8 h after passing the gastric region. Conclusions The formulation can be fruitful in curbing the menace of nocturnal asthma and providing a high degree of patient compliance as the patient will not have to wake up at night to take the medication.

Bilayer Tablet Based Chronotherapeutics in the Management of Nocturnal Asthma: An Overview

Background: Asthma is a common ailment with a larger circadian difference. Nocturnal Asthma (NA) is an inconstant exacerbation of asthmatic condition related to the rise in warning sign during the night time and there is a need for its treatment addressing air route alertness and decline in lung functions. These symptoms are linked to sleep or known as circadian events. Chronotherapeutics is a management system based on an in-vivo drug accessibility programmed to check the rhythms of ailment in a direction to improve the therapeutic outcomes by suppressing the side effects. This review aims to provide an overview of NA, chronotherapeutics for the treatment of NA, bilayer tablets, and advanced techniques involved in the fabrication of bilayer tablets. The review also discusses some of the related patents. Methods: Relevant literature about the latest developments and updated information related to NA, chronotherapeutics and bilayer tablets has been very widely searched on different biomedical literature programs such as Google, Web of Science, PubMed portals, etc. Bilayer tablet mediated chronotherapy has gained significant attention and consideration as it is developed and fabricated based on the body’s circadian rhythm. Bilayer tablets can deliver the bioactive compounds at an appropriate time, place as well as amount and site. Results: Available literature advocated that the bilayer matrix tablet containing a single drug in the sustained release film and fast releasing film, may be beneficial for the chronic diseases like asthma, migraine, diabetes, hypertension and inflammation which usually require immediate as well as maintained therapeutic effect. Conclusion: The application of nanotechnology in the arena of medicine will transform the diagnosis and treatment strategies of a wide range of diseases in the upcoming years. The findings of this review confirm the importance of bilayer tablet based chronotherapy in nocturnal asthma.