The Role of Biologics in the Management of Asthma in the Pediatric Patient

The management of pediatric patients with asthma continues to be a major health issue. For many patients, traditional therapies have been very effective, but for a large number of patients asthma remains poorly controlled. This leads to significant morbidity and impairment to quality of life. Recently, several new biologics, as well as new dosage forms of combination inhaled drugs, have been made available for use adding to the armamentarium of therapy for specific asthma phenotypes. Biologics have shown promise in the more difficult to manage asthma patient. Approved in children, omalizumab, an anti–immunoglobulin E (anti-IgE) antibody, has been available for several years. New agents, like mepolizumab and benralizumab, directed against interleukin (IL) 5, have indications for children >6 and >12 years of age, respectively. Dupilumab, an IL-4– and IL-13–directed antibody, has been studied as well in eosinophilic asthma, with positive results. A thorough understanding of the clinical data of these agents is key, as they may greatly improve the quality of life in children with difficult-to-manage asthma.

The way of life of the unhoused people as an enhance for COVID-19 care

ABSTRACT Objective: To analyze the way of life of the unhoused people to enhance health care in the pandemic. Methods: A qualitative, interdisciplinary research, with participant observation and 24 interviews with the unhoused people. Empirical categories and bibliographic search on this population and COVID-19 guided simple actions aimed at care. Results: The group at greatest risk for COVID-19 use drugs compulsively; starves constantly; discontinues drug treatment for tuberculosis, HIV, and diabetes; has underdiagnosis of Depression; has difficulty sheltering and uses inhaled drugs. This way of life increases the risk of worsening COVID-19 and brings great challenges to health services. Several proposals to guide care considered these results and the new routine caused by the pandemic. Final considerations: The way of life of the studied population increased their vulnerability in the pandemic, as well as the perception of risk of disease transmission by the population in general.

The value of “General Practitioners–Specialists” mode: A focus group study of patients with asthma in mastering inhalation skills

This study focused on using “General Practitioners–Specialists” (GP-S) mode to teach the patients with asthma to master inhalation skills. 200 patients with asthma being admitted to the respiratory department of Shanghai Changhai Hospital were included in the study from January to December in 2018. There were 100 cases in the control group and 100 cases in the experimental group. The control groups received routine instruction and the experimental group adopted GP-S mode education, respectively, to learn mastering dry powder inhaler skills. The level of mastery and errors in the use of inhaled medications were recorded after each guidance. After four times’ instruction in two different ways, the patient’s mastery of inhalation skills gradually improved. After the guidance through the GP-S mode, the incidence of inhalation errors after each times instruction was 67%, 28%, and 7%, respectively. The later one was significantly lower than the previous one (67% vs. 28%, χ2 = 30.496, p < 0.001; 28% vs. 7%, χ2 = 15.273, p < 0.001). After twice instructions, the GP-S mode was associated with the lower incidence of inhaler device operating errors versus the regular guidance method (10% vs. 26%, χ2 = 8.672, p = 0.005); the same as the third guidance (2% vs. 11%, χ2 = 6.664, p = 0.018). Similarly, after thrice instructions, the incidence of inhalation method errors in the GP-S mode group was significantly lower than the regular guidance mode group (4% vs. 15%, χ2 = 7.037, p = 0.018), and there was still existing statistical difference of inhalation method errors between the two groups after four times instructions (3% vs. 11%, χ2 = 4.916, p = 0.049). General Practitioners–Specialists mode can effectively improve the patient’s mastery of inhalation skills, which significantly reduced the incidence of errors in the use of inhaled drugs and improved the overall management effectivity of asthma and patients’ compliance.

A mechanistic framework for a priori pharmacokinetic predictions of orally inhaled drugs

The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Even though each single process has been systematically investigated, a quantitative understanding on the interaction of processes remains limited and therefore identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models. However, existing modeling attempts considerably simplify these processes or are not systematically evaluated against (clinical) data. In this work, we developed a mathematical framework based on physiologically-structured population equations to integrate all relevant pulmonary processes mechanistically. A tailored numerical resolution strategy was chosen and the mechanistic model was evaluated systematically against data from different clinical studies. Without adapting the mechanistic model or estimating kinetic parameters based on individual study data, the developed model was able to predict simultaneously (i) lung retention profiles of inhaled insoluble particles, (ii) particle size-dependent pharmacokinetics of inhaled monodisperse particles, (iii) pharmacokinetic differences between inhaled fluticasone propionate and budesonide, as well as (iv) pharmacokinetic differences between healthy volunteers and asthmatic patients. Finally, to identify the most impactful optimization criteria for orally inhaled drugs, the developed mechanistic model was applied to investigate the impact of input parameters on both the pulmonary and systemic exposure. Interestingly, the solubility of the inhaled drug did not have any relevant impact on the local and systemic pharmacokinetics. Instead, the pulmonary dissolution rate, the particle size, the tissue affinity, and the systemic clearance were the most impactful potential optimization parameters. In the future, the developed prediction framework should be considered a powerful tool for identifying optimal drug and formulation characteristics.

Humidified Warmed CO2 Treatment Therapy Strategies Can Save Lives With Mitigation and Suppression of SARS-CoV-2 Infection: An Evidence Review

The coronavirus disease (COVID-19) outbreak has presented enormous challenges for healthcare, societal, and economic systems worldwide. There is an urgent global need for a universal vaccine to cover all SARS-CoV-2 mutant strains to stop the current COVID-19 pandemic and the threat of an inevitable second wave of coronavirus. Carbon dioxide is safe and superior antimicrobial, which suggests it should be effective against coronaviruses and mutants thereof. Depending on the therapeutic regime, CO2 could also ameliorate other COVID-19 symptoms as it has also been reported to have antioxidant, anti-inflammation, anti-cytokine effects, and to stimulate the human immune system. Moreover, CO2 has beneficial effects on respiratory physiology, cardiovascular health, and human nervous systems. This article reviews the rationale of early treatment by inhaling safe doses of warmed humidified CO2 gas, either alone or as a carrier gas to deliver other inhaled drugs may help save lives by suppressing SARS-CoV-2 infections and excessive inflammatory responses. We suggest testing this somewhat counter-intuitive, but low tech and safe intervention for its suitability as a preventive measure and treatment against COVID-19. Overall, development and evaluation of this therapy now may provide a safe and economical tool for use not only during the current pandemic but also for any future outbreaks of respiratory diseases and related conditions.

Clinical Relevance of the Anti-inflammatory Effects of Roflumilast on Human Bronchus: Potentiation by a Long-Acting Beta-2-Agonist

Background: Roflumilast is an option for treating patients with severe COPD and frequent exacerbations despite optimal therapy with inhaled drugs. The present study focused on whether the phosphodiesterase (PDE) 4 inhibitor roflumilast and its active metabolite roflumilast N-oxide affect the release of tumor necrosis factor (TNF)-α and chemokines by lipopolysaccharide (LPS)-stimulated human bronchial explants. We also investigated the interactions between roflumilast, roflumilast N-oxide and the β2-agonist formoterol with regard to cytokine release by the bronchial preparations.Methods: Bronchial explants from resected lungs were incubated with roflumilast, roflumilast N-oxide and/or formoterol and then stimulated with LPS. An ELISA was used to measure levels of TNF-α and chemokines in the culture supernatants.Results: At a clinically relevant concentration (1 nM), roflumilast N-oxide and roflumilast consistently reduced the release of TNF-α, CCL2, CCL3, CCL4, CCL5 and CXCL9 (but not CXCL1, CXCL5, CXCL8 and IL-6) from human bronchial explants. Formoterol alone decreased the release of TNF-α, CCL2, and CCL3. The combination of formoterol with roflumilast (1 nM) was more potent than roflumilast alone for inhibiting the LPS-induced release of TNF-α, CCL2, CCL3, CCL4, and CXCL9 by the bronchial explants.Conclusions: At a clinically relevant concentration, roflumilast N-oxide and its parent compound, roflumilast, reduced the LPS-induced production of TNF-α and chemokines involved in monocyte and T-cell recruitment but did not alter the release of chemokines involved in neutrophil recruitment. The combination of formoterol with roflumilast enhanced the individual drugs’ anti-inflammatory effects.

Clinical appearance of oral lesions in bronchial asthma patients using inhalation drug

Introduction: Inhalation therapy has become the first-line treatment for bronchial asthma patients. Studies have proved that not all of the inhaled drugs reach the target organ, but mostly are deposited in the mouth and cause local immunosuppressant and decrease saliva secretion. These conditions are closely linked to some adverse effects in the mouth. The purpose of this study was to describe the clinical appearance of oral lesion in bronchial asthma patients using inhalation drugs. Methods: This study was descriptive and conducted on 30 bronchial asthma patients that have been using inhalation drug for at least one year, free of other systemic diseases, not using denture and orthodontic appliances. Oral mucosa was examined, and any oral lesion was recorded. Results: The most number of oral lesions found in patients through clinical examinations were plaque (73.3%), followed by a fissure (36.7%), atrophy (30%), and the least oral lesions found were pigmentation (3.3%), bullae (3.3%), and petechiae (3.3%). The lesions found in patients using inhalation drugs in a range of up to 10 years were found more varyingly. Conclusion: Plaque, fissure, atrophy, pigmentation, bullae, and petechiae are oral lesions that are clinically found in bronchial asthma patients using inhalation drugs.

Emerging antibody-based therapeutics against SARS-CoV-2 during the global pandemic

SARS-CoV-2 antibody therapeutics are being evaluated in clinical and preclinical stages. As of 11 October 2020, 13 human monoclonal antibodies targeting the SARS-CoV-2 spike protein have entered clinical trials with three (REGN-COV2, LY3819253/LY-CoV555, and VIR-7831/VIR-7832) in phase 3. On 9 November 2020, the US Food and Drug Administration issued an emergency use authorization for bamlanivimab (LY3819253/LY-CoV555) for the treatment of mild-to-moderate COVID-19. This review outlines the development of neutralizing antibodies against SARS-CoV-2, with a focus on discussing various antibody discovery strategies (animal immunization, phage display and B cell cloning), describing binding epitopes and comparing neutralizing activities. Broad-neutralizing antibodies targeting the spike proteins of SARS-CoV-2 and SARS-CoV might be helpful for treating COVID-19 and future infections. VIR-7831/7832 based on S309 is the only antibody in late clinical development, which can neutralize both SARS-CoV-2 and SARS-CoV although it does not directly block virus receptor binding. Thus far, the only cross-neutralizing antibody that is also a receptor binding blocker is nanobody VHH-72. The feasibility of developing nanobodies as inhaled drugs for treating COVID-19 and other respiratory diseases is an attractive idea that is worth exploring and testing. A cocktail strategy such as REGN-COV2, or engineered multivalent and multispecific molecules, combining two or more antibodies might improve the efficacy and protect against resistance due to virus escape mutants. Besides the receptor-binding domain, other viral antigens such as the S2 subunit of the spike protein and the viral attachment sites such as heparan sulfate proteoglycans that are on the host cells are worth investigating.