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• W2034692756 abstract "Therapeutic DeliveryVol. 4, No. 4 EditorialFree AccessImplications of increased nanoparticle absorption by infant lungs: future prospectsLucila Garcia-Contreras & Mariam IbrahimLucila Garcia-Contreras* Author for correspondenceUniversity of Oklahoma Health Sciences Center, 1110 N. Stonewall Ave, Oklahoma City, OK 73126-0901, USA. Search for more papers by this authorEmail the corresponding author at lucila-garcia-contreras@ouhsc.edu & Mariam IbrahimDepartment of Pharmaceutical Sciences, Collage of Pharmacy University of Oklahoma Health Sciences Center, Oklahoma City, USASearch for more papers by this authorPublished Online:4 Apr 2013https://doi.org/10.4155/tde.13.1AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: infantile lung developmentinhalation therapylung depositionnanoparticlesEven though inhaled therapies are currently employed to treat infants and young children with respiratory diseases, pediatric inhaled treatment is still a multidimensional problem that comprises different aspects.The early years of life are a period of great change in terms of growth and development, and these changes have a major impact on aerosol drug delivery in this age group. In addition, parameters such as physical and chemical characteristics of aerosol particles and optimization of the device design for the pediatric population have an influential role in determining the aerosol deposition. Delivery of medication incorporated into nanoparticles by inhalation has been considered to improve existing therapies for infants with the purpose of increasing lung deposition and efficacy of treatments. However, there are numerous factors that need to be analyzed and studied before inhaled therapies with nanoparticles are part of the standard treatment for infants and young children.Lung diseases of infants & young childrenInfants (28 days to 5 months) and toddlers (6–23 months) can suffer from different respiratory tract disorders extending from the upper airway to the pulmonary vasculature, such as asthma and chronic obstructive pulmonary disease [1]. Respiratory distress syndrome is usually observed in prematurely born infants. In such cases, the surfactant production is insufficient, resulting in increased alveoli collapse at expiration followed by reduction in the total surface available for gaseous exchange [2]. In addition, acute respiratory distress syndrome can also be caused by primary pulmonary injury such as severe viral or bacterial infection, inhalation of toxic fumes, or by extrapulmonary events such as systemic inflammation [3]. Cystic fibrosis (CF) is another common disease in infants that is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with this disease have difficulties in clearing pathogens from the lung and experience chronic pulmonary infections and inflammation.Many medications for such lung diseases have been given as an aerosol. Antibiotics have been delivered by aerosol for more than 60 years for treating lung infections in CF patients [4]. Aerosol surfactants have been used in CF and asthma to immobilize the excessive secretions. Other commonly inhaled medications include anti-inflammatory drugs, such as corticosteroids and peptides [4].Current inhaled therapies for infants & young childrenIn order to more effectively treat the diseases that affect young children, it is imperative to understand and define the causative agent of the disease first. One of the major areas of controversy in the field of inhalation therapy for infants is the definition of the respiratory illness. For example, inhaled drugs in infancy are usually indicated for treating airway obstruction resulting in wheezing. However, management of infant and preschool children with wheezing is complicated by the uncertainty of the etiology. Interpretation of the outcomes of therapies designed to treat wheezing is not conclusive or consistent because phenotypes and the parameters designed as ‘outcome’ are not defined and the symptoms are usually short-lived [5]. It is questionable whether the majority of those children who wheeze in this age group would have asthma, since the leading cause of wheezing during early childhood has been reported to be infection with respiratory viruses. In fact, with current molecular diagnostics, a viral pathogen can be identified in at least 90% of wheezing episodes during the first several years of life [6]. Everard classified the respiratory illness at infancy into four subgroups: chronic lung disease due to prematurity, viral infections, atopic asthma and acute bronchitis [7]. These subgroups inevitably overlap and there is little guidance as to the appropriateness of various inhaled therapies for a given patient. Therefore, it is important to define the main cause of the disease in young children to determine which patient will benefit from the inhalation therapy, and if possible, to tailor the aerosol generation device and means of aerosol delivery to patients in this age group.Dose calculation for inhaled therapies in infantsMost of the current inhalation therapy in infants is based on adult doses or older children and doses are generally titrated per kilogram of body weight or per square meter of body surface area [8]. However, children are not just miniature adults [9], neither neonates, infants, nor toddlers are just small children [1]. Studies have shown that lung and oropharyngeal deposition increase and decrease with age, respectively [10]. Therefore, adapting the adult dose to a pediatric one may lead to insufficient pulmonary deposition. A more precise way to tailor a pediatric dose is to correct the deposited dose for bodyweight and express it as percentage per kilogram of body weight in order to have an age-independent lung dose [8].Devices & aerosol generation are not specific for infantsNebulizers, metered-dose inhalers, and dry powder inhalers (DPIs) were all originally developed for use by adolescents and adults; however, none of these devices can be used accurately and safely in infants and preschool children without significant modifications. DPIs have not been adapted for use with young children because they cannot provide the coordination or the inspiratory flow rate needed to effectively aerosolize the drug from a DPI [9]. In fact, for young patients the selection of the device is based more on their ability to cooperate and tolerate therapy [11] than on the fraction of the respirable dose emitted from the device [7]. Infants and young children can only tolerate inhaled treatments (with nebulizers or metered dose inhalers/spacer) by using a facemask, while older children can be directed to inhale their medication with specific breathing patterns [8]. For those infants and small children that object to facemasks, the medication is administered while they are sleeping using a hood that covers the child’s head [8]. Another device that incorporates a pacifier into an aerosol mask soothes the child and allows the mask to rest on the face as the infant inhales through the nose. Newer devices are being developed to deliver aerosol therapy using high-flow nasal cannula.In vitro studies have evaluated the aerosol output through nasal cannula to be 8.4 to 18.6% of the loaded dose when an airflow of 3 l/min is used [4]. Effective devices or medical agents for aerosolization to intubated or mechanically ventilated newborn infants are yet to be developed [12].Role of the anatomy & physiology of the respiratory system in infants & young childrenOne variable that makes more complex the task of delivering effective inhaled therapies to this age groups is that the respiratory alveoli are underdeveloped in infants and young children. Even though conducting airways have been fully defined in a human fetus, the length and diameter of the airways continue to change significantly during the first months of a child’s life and continue to change further during childhood [12]. These rapid changes in the airway structure and physiology have an influential role in determining the fraction of the aerosol dose deposited in the different lung regions, which in turn determines the efficacy of the inhaled treatment [7]. Infants have low tidal volume, vital capacity, functional residual capacity and short respiratory cycle, which results in low resident time for aerosol particles and, thus, low pulmonary disposition of aerosol particles [12]. Significant differences were even noted in nose–throat anatomy among four subjects of different stages, (i.e., a newborn, an infant, a child and an adult) [13]. In addition, neonates, infants and toddlers have different breathing patterns when they are asleep, awake and agitated. Sleeping patterns tend to be relatively consistent from breath to breath, while being awake results in substantial changes in all parameters from breath to breath, which become even more pronounced with agitation or crying [1].Understanding the factors that will maximize drug delivery to the lungs in the pediatric population has been improved by studies performed using model lungs to simulate the respiratory pattern, pharmacokinetic studies and radiolabeled deposition studies. These studies have determined the influence of deposition on the identification of causality and assessment of dose–outcome response, and of potential side effects for these young patients [13].In vitro models are the most common and convenient method to study aerosol delivery for infants; however, they usually result in a higher estimate of the respirable dose thanin vivo testing due to their inability to simulate exhalation for aerosol [12]. Gamma scintigraphy was initially employed to assess total body deposition, lung deposition and pulmonary deposition of inhaled radiolabeled aerosols in infants [12]. However, because of the ethical issues and lack of safety guidelines involving radiolabeling in this population, small mammals are now used as models.The stages of lung growth and development have been studied in laboratory animals, since it is ethically impossible to use human babies and fetuses for this purpose. The rat model has been useful to study these stages, since it exhibits similar stages of lung development as those in humans, but in a shorter time frame, comparable to its shorter lifespan in contrast to that of humans [14]. However, the relevance of animal models to study the deposition of inhaled medications is still limited because of the anatomical and physiological differences between animal models and humans, as well as the differences and similitudes in the methods of aerosol generation and delivery between these two species. There are a numerous marked anatomical and physiological differences between rats and humans, including airway branching, respiratory bronchioles, pleurae and respiratory parameters. The airway branching in rats is strongly monopodial wheras it is relatively symmetric in humans [15]. Respiratory bronchioles are absent or present in a single short generation in rats, but humans have several generations of respiratory bronchioles [16]. The pleura in rats are thin, whereas humans have thick pleurae [17]. Most importantly, all rodents, including rats, are obligated nose breathers and the cut-off diameter of particles inhaled by their nose is less than 3 µm, whereas humans (including small infants) can breathe through the nose and mouth, and the cut-off diameter is significantly larger [17]. Rats have a respiratory rate of 85 breaths per minute and a tidal volume of 1.5 ml, whereas humans breathe 12–20 times per minute and have a tidal volume of 400–616 ml [16]. These anatomical and physiological differences between rats and humans have significant implications in the particle size and amount of aerosol inhaled, as well as the site of aerosol deposition and the fraction deposited in each lung region. All these variables and differences should be carefully considered for an accurate interpretation of inhalation studies performed in animal models.Toxicological studies to assess the safety of nanoparticle inhalation by infant lungsMature human lungs have a complex and efficient set of mechanisms, including the hair in the nasal cavity, the mucociliary escalator and the alveolar macrophages, to protect human body from inhaled toxic materials. In addition, the human lungs are equipped with innate and adaptive immune responses that aid in its protection against bacterial and viral pathogens. Despite these efficient mechanisms of protection, recurrent exposure to ultrafines and nanoparticles, such as those from diesel fumes, can induce undesired immune responses that may ultimately lead to lung diseases such as severe asthma, bronchiolitis, sarcoidosis and chronic obstructive pulmonary disease [18]. The enhanced deposition of nanoparticles observed in the lungs of infants may result in more severe and life-threatening diseases should they be exposed to toxic nanomaterials, such as diesel nanoparticles [19].Another issue to consider with regard to the therapeutic application of nanomaterials is the need for the nanocarrier material to be biomimetic/biocompatible/biodegradable to reduce toxicity from the carrier [11]. There are challenges in selecting pediatric excipients since there are no pediatric inactive ingredients guide list. The choice of excipients and their associated toxicities therefore needs to be justified before inclusion.Future perspectiveAlthough the manufacture of inhaled medications is a multibillion dollar industry, very few pharmaceutical drug/device combinations have been approved for inhalation across the range of pediatric patient ages and sizes [1]. Therefore, in order to consider the use of inhaled nanoparticles in this underserved population, several important questions concerning the use of therapeutic aerosols in infants should be considered. These are: ▪ Are there enough drugs approved by the US FDA for the treatment of lung diseases in infants?▪ How can we calculate accurately the effective dose of an inhaled medication for infants?▪ What are the advantages and disadvantages of the available animal models to study deposition in the lungs of infants? How do we incorporate anatomical and physiological differences between species?▪ Are there any benefit–risk assessment data about long-term treatment with inhaled nanoparticles in infants?Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Fink JB. Delivery of inhaled drugs for infants and small children: a commentary on present and future needs. Clin. Ther.34(11),S36–S45 (2012).Crossref, Medline, CAS, Google Scholar2 Ma CC, Ma S. The role of surfactant in respiratory distress syndrome. Open Respir. Med. J.6,44–53 (2012).Crossref, Medline, Google Scholar3 Gizzi C, Papoff P, Barbàra CS, Cangiano G, Midulla F, Moretti C. Old and new uses of surfactant. J. Matern. Fetal Neonatal Med.23(Suppl. 3),41–44 (2010).Crossref, Medline, Google Scholar4 Rubin BK. Pediatric aerosol therapy: new devices and new drugs. Respir. Care56(9),1411–1421 (2011).Crossref, Medline, Google Scholar5 Boehmer AL, Merkus PJ. Asthma therapy for children under 5 years of age. Curr. Opin. Pulm. Med.12(1),34–41 (2006).Crossref, Medline, Google Scholar6 Jackson DJ, Lemanske RF. The role of respiratory virus infections in childhood asthma inception. Immunol. Allergy Clin. North. Am.30(4),513–522 (2010).Crossref, Medline, Google Scholar7 Everard ML. Aerosol delivery in infants and young children. J. Aerosol Med.9(1),71–77 (1996).Crossref, Medline, CAS, Google Scholar8 Schüepp KG, Straub D, Möller A, Wildhaber JH. Deposition of aerosols in infants and children. J. Aerosol Med.17(2),153–156 (2004).Crossref, Medline, CAS, Google Scholar9 Ahrens RC. The role of the MDI and DPI in pediatric patients: “children are not just miniature adults”. Respir. Care50(10),1323–1328 (2005).Medline, Google Scholar10 Wildhaber JH, Mönkhoff M, Sennhauser FH. Dosage regimens for inhaled therapy in children should be reconsidered. J. Paediatr. Child Health38(2),115–116 (2002).Crossref, Medline, CAS, Google Scholar11 Giacoia GP, Taylor-Zapata P, Zajicek A. Eunice kennedy shriver national institute of child health and human development pediatrics formulation initiative: proceedings from the second workshop on pediatric formulations. Clin. Ther.34(11),S1–S10 (2012).Crossref, Medline, Google Scholar12 Fink JB. Aerosol delivery to ventilated infant and pediatric patients. Respir. Care49(6),653–665 (2004).Medline, Google Scholar13 Xi J, Berlinski A, Zhou Y, Greenberg B, Ou X. Breathing resistance and ultrafine particle deposition in nasal-laryngeal airways of a newborn, an infant, a child, and an adult. Ann. Biomed. Eng.40(12),2579–2595 (2012).Crossref, Medline, Google Scholar14 Bolle I, Eder G, Takenaka S et al. Postnatal lung function in the developing rat. J. Appl. Physiol.104(4),1167–1176 (2008).Crossref, Medline, Google Scholar15 Phalen RF, Oldham MJ. Tracheobronchial airway structure as revealed by casting techniques. Am. Rev. Respir. Dis.128(2 Pt 2),S1–S4 (1983).Crossref, Medline, CAS, Google Scholar16 Cryan SA, Sivadas N, Garcia-Contreras L. In vivo animal models for drug delivery across the lung mucosal barrier. Adv. Drug. Deliv. Rev.59(11),1133–1151 (2007).Crossref, Medline, CAS, Google Scholar17 Garcia-Contreras L. In vivo animal models for controlled release pulmonary drug delivery. In: Controlled Pulmonary Drug Delivery. Smyth HDC, Hickey AJ (Eds). Springer, NY, USA (2011).Google Scholar18 Nanoparticles in Medicine and Environment: Inhalation and Health Effects. Marijnissen JC, Gradon L (Eds). Springer, NY, USA (2010).Google Scholar19 Cooney DJ, Hickey AJ. The generation of diesel exhaust particle aerosols from a bulk source in an aerodynamic size range similar to atmospheric particles. Int. J. Nanomedicine3(4),435–449 (2008).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByNanopharmaceuticals Vol. 4, No. 4 Follow us on social media for the latest updates Metrics Downloaded 523 times History Published online 4 April 2013 Published in print April 2013 Information© Future Science LtdKeywordsinfantile lung developmentinhalation therapylung depositionnanoparticlesFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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