Journal of Aerosol Medicine and Pulmonary Drug Delivery最新文献

Background: To assess the effectiveness of inhalation therapy, it is important to evaluate the lungs' structure; thus, visualization of the entire lungs at the level of the alveoli is necessary. To achieve this goal, the applied visualization technique must satisfy the following two conditions simultaneously: (1) it has to obtain images of the entire lungs, since one part of the lungs is influenced by the other parts, and (2) the images have to capture the detailed structure of the alveolus/acinus in which gas exchange occurs. However, current visualization techniques do not fulfill these two conditions simultaneously. Segmentation is a process in which each pixel of the obtained high-resolution images is simplified (i.e., the representation of an image is changed by categorizing and modifying each pixel) so that we can perform three-dimensional volume rendering. One of the bottlenecks of current approaches is that the accuracy of the segmentation of each image has to be evaluated on the outcome of the process (mainly by an expert). It is a formidable task to evaluate the astronomically large numbers of images that would be required to resolve the entire lungs in high resolution. Methods: To overcome this challenge, we propose a new approach based on machine learning (ML) techniques for the validation step. Results: We demonstrate the accuracy of the segmentation process itself by comparison with previously validated images. In this ML approach, to achieve a reasonable accuracy, millions/billions of parameters used for segmentation have to be optimized. This computationally demanding new approach is achievable only due to recent dramatic increases in computation power. Conclusion: The objective of this article is to explain the advantages of ML over the classical approach for acinar imaging.

Background: Intravenous liposomal amphotericin B (L-AMB) has accompanying side effects that may be diminished when administering an inhaled form. Delivery systems for inhaled or aerosolized L-AMB vary, and there has not been a recent comparison of available systems to date. Methods: We compared three differently designed nebulizer delivery systems for the inhaled delivery of L-AMB to determine the best combination of efficient lung dosing and treatment time. Aerosol size was measured using a Malvern Mastersizer, and five separate nebulizers were tested. For drug output measurements, a Harvard Lung was used, and aerosol was collected using HEPA filters. Results: Overall aerosol size characteristics were similar for all devices with volume median diameters in the 4-5 μm range. The highest inhaled dose was delivered by the AeroEclipse. The Aerogen and the AeroEclipse had similar predicted pulmonary doses, and the AeroEclipse had the highest pulmonary delivery rates. Conclusion: The AeroEclipse nebulizer may provide more efficient delivery in a shorter amount of time; however, human studies are warranted to assess the safety, tolerability, and efficacy of inhaled delivery of L-AMB from this system.

Background: As the COVID-19 pandemic has progressed, numerous variants of SARS-CoV-2 have arisen, with several displaying increased transmissibility. Methods: The present study compared dose-response relationships and disease presentation in nonhuman primates infected with aerosols containing an isolate of the Gamma variant of SARS-CoV-2 to the results of our previous study with the earlier WA-1 isolate of SARS-CoV-2. Results: Disease in Gamma-infected animals was mild, characterized by dose-dependent fever and oronasal shedding of virus. Differences were observed in shedding in the upper respiratory tract between Gamma- and WA-1-infected animals that have the potential to influence disease transmission. Specifically, the estimated median doses for shedding of viral RNA or infectious virus in nasal swabs were approximately 10-fold lower for the Gamma variant than the WA-1 isolate. Given that the median doses for fever were similar, this suggests that there is a greater difference between the median doses for viral shedding and fever for Gamma than for WA-1 and potentially an increased range of doses for Gamma over which asymptomatic shedding and disease transmission are possible. Conclusions: These results complement those of previous studies, which suggested that differences in exposure dose may help to explain the range of clinical disease presentations observed in individuals with COVID-19, highlighting the importance of public health measures designed to limit exposure dose, such as masking and social distancing. The dose-response data provided by this study are important to inform disease transmission and hazard modeling, as well as to inform dose selection in future studies examining the efficacy of therapeutics and vaccines in animal models of inhalational COVID-19.

Background: Greater patient satisfaction with his or her inhalation device is associated with better adherence to pharmacological therapy and better clinical outcomes, such as improved quality of life, greater asthma control, and fewer exacerbations. The objective of this study was to determine the satisfaction level of a group of patients diagnosed with bronchial asthma concerning their devices for inhalation of bronchodilators and glucocorticoids. Methods: This was a cross-sectional study of patients treated in the Colombian health system. Satisfaction with inhalation devices was evaluated with the Feeling of Satisfaction with Inhaler (FSI)-10 questionnaire. A score of ≥44 points indicated high satisfaction. Results: In total, 362 patients from 59 cities were identified, their median age was 55 years, and 74.6% were women. The FSI-10 average score was 44.6; 68.5% of patients showed high satisfaction, especially with pressurized metered-dose inhalers (pMDIs), and 63.4% did not use them with an inhalation chamber. Users of pMDIs (odds ratio [OR]: 1.80; 95% confidence interval [CI]: 1.05-3.10) and those who received training by medical specialists (OR: 2.29; 95% CI: 1.33-3.97) had high satisfaction, while patients who were older (40-64 vs. <40 years: OR: 0.38; 95% CI: 0.19-0.78 and ≥65 vs. <40 years: OR: 0.35; 95% CI: 0.15-0.81), resided in the Caribbean region (OR: 0.48; 95% CI: 0.29-0.81), and had a university education (OR: 0.54; 95% CI: 0.32-0.90) had lower satisfaction. Conclusions: The majority of patients with asthma used pMDIs without an inhalation chamber, and their overall satisfaction was higher than that of patients using other inhalation devices. Patients who received special training from medical specialists showed better satisfaction.

Background: As an anti-inflammatory and antioxidant, sodium pyruvate significantly reduces inflammatory cytokines and oxygen radicals such as interleukin (IL) IL-6, IL-8, Monocyte Chemoattractant Protein-1, and hydrogen peroxide. Thus, sodium pyruvate holds promise as a treatment for many respiratory diseases, including allergic rhinitis (AR). Novel treatments for AR are needed as current medications, including steroids, often fail to treat severe symptoms. Methods: The data from five human clinical studies were analyzed to determine the effect of 20 mM sodium pyruvate nasal spray (N115) in patients with AR. Nasal inflammation scores were compared to a placebo control or a no-treatment baseline control. Three studies were open-labeled and two were appropriately blinded to both patients and clinicians using computer randomization of subjects. Results: The intranasal administration of sodium pyruvate significantly improved nasal inflammation scores in all five clinical trials of patients with AR (p < 0.0001 in all trials). Conclusions: These results give credence to the overall ability of sodium pyruvate, administered by nasal spray, to treat inflammation of the nasal airways.

Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD^®), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use.

Several imaging modalities have been employed to quantify lung dose and the distribution of the dose of orally inhaled aerosols in vivo. Two-dimensional (2D, or planar) imaging using gamma scintigraphy is the most widely used of these modalities. Two-dimensional gamma scintigraphy studies are accomplished using a single- or dual-headed gamma camera. The formulation to be tested is admixed with the gamma emitting radioisotope ^99mtechnetium, which serves as a surrogate for the drug. This article provides details as to how 2D gamma scintigraphy images should be acquired and analyzed using recently standardized methods. Based on the new guidelines, the investigator should confirm that the drug formulation is unchanged with the addition of the radioisotope, determine the amount of radioactivity needed for inhalation to obtain appropriate radioactivity counts in the lungs, perform quality control procedures for the gamma camera, identify the lung borders of the study subject using a reference image such as an X-ray computed tomography scan, a ventilation scan, or a transmission scan, acquire a lung transmission image to correct for attenuation of radioactivity by lung tissue, instruct the subject how to inhale the radiolabel-drug mixture and record associated breathing parameters, acquire anterior and/or posterior views of the lungs and any other regions of interest (i.e., oropharynx, stomach) and assess the acquired images for total and regional dose to the lungs. Total dose should be assessed after identification of the right lung border and appropriate correction for tissue attenuation. Regional dose should be quantified as a normalized outer/inner deposition ratio (O/I) and expressed as the penetration index (PI). Mass balance should be performed as needed. By following the standardized methods, 2D gamma scintigraphy data from studies in different laboratories may be compared and combined, leading to multi-center studies and more rapid development of new medications and devices for inhaled therapies.

Background: Suboptimal use of pressurized metered dose inhaler (pMDI) remains a major barrier to inhaled therapy success. Verbal inhaler technique training (VT) fails to maintain patients' good pMDI use, thus training tools might help. Trainhaler^® (THR device) and Flo-Tone^® CR (FTCR device), two novel pMDI technique training tools, were evaluated and compared in terms of relative lung and systemic bioavailability and oropharyngeal deposition of salbutamol inhaled from Ventolin^® Evohaler^® (GlaxoSmithKline) either alone following THR or connected to FTCR. Methods: Sixteen healthy adults inhaled 2 × 100 μg salbutamol puffs (1 minute apart) from Ventolin using the THR device or FTCR device in a two-period, randomized crossover study. A 7-day washout separated THR and FTCR approaches. Immediately after each puff inhalation, each subject gargled with 20 mL water for oropharyngeal deposition determination. Urine samples were collected 0.5 hour (pre-inhalation) and 0.5, 1.0, and 2.0 hours post-inhalation. Urine was then pooled till 24-hour post-inhalation. The relative lung bioavailability (0- to 0.5-hour urinary salbutamol excretion-USAL0.5) and relative systemic bioavailability (0- to 24-hour urinary excretion of salbutamol and its metabolite-USALMET24) were determined. Results: The mean (standard deviation [SD]) USAL0.5 of the THR and FTCR groups was 5.70 (6.43) and 11.39 (9.67) μg, respectively. The mean (SD) oropharyngeal deposition was 11.11 (4.37) and 6.09 (1.89) μg, respectively. The THR and FTCR devices were statistically significantly different in USAL0.5 and oropharyngeal deposition (p < 0.001), whereas there was no statistically significant difference in USALMET24. Conclusion: The THR device and the FTCR device showed positive impact on inhaled pMDI delivery. Indeed, the FTCR device doubled the relative lung bioavailability and minimized the unwanted oropharyngeal deposition of inhaled salbutamol. In practice, these pMDI trainers would complement and maintain VT. Study Registration: The study was registered on the ISRCTN registry (Reference: ISRCTN88332465-06/12/2017 [Prospectively Registered]).