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Les glucocorticoïdes sont largement utilisés pour le traitement de diverses maladies et affections dans un certain nombre de spécialités. Les effets néfastes des glucocorticoïdes oraux sur la santé osseuse sont bien documentés et l'ostéoporose cortico-induite est la cause la plus répandue d'ostéoporose provoquée par des médicaments et de fractures. On ne sait toutefois pas avec certitude si, ni dans quelle mesure, les glucocorticoïdes administrés par d'autres voies ont des effets sur le squelette. Cette revue présente les résultats disponibles à propos des effets des glucocorticoïdes administrés par voie inhalée, épidurale, intra-articulaire et topique sur les paramètres osseux. Bien que les données probantes soient limitées et peu robustes, il semble qu'une petite proportion des glucocorticoïdes administrés puisse être absorbés, pénétrer dans la circulation systémique et avoir des effets néfastes sur le squelette. Les glucocorticoïdes puissants, les fortes doses et une longue durée de traitement pourraient entraîner un risque accru de perte osseuse et de fractures. On trouve peu de données, et celles qui sont disponibles concernent uniquement les glucocorticoïdes inhalés, sur l'efficacité des anti-ostéoporotiques chez les patients recevant une corticothérapie administrée par d'autres modes que la voie orale. Des études complémentaires sont nécessaires pour clarifier la relation entre les différentes voies d'administration des glucocorticoïdes et les paramètres osseux et contribuer à formuler des recommandations de prise en charge optimale de ces patients. Glucocorticoids (GCs) are widely used by several specialties for the treatment of a variety of diseases and conditions. The unfavorable effect of oral GCs on bone health is well-documented. The ensuing from their use glucocorticoid-induced osteoporosis (GIOP) is the most common cause of medication-induced osteoporosis and fractures. It is uncertain, however, if, and in what extent, GCs administered by other routes affect the skeleton. In the present review, we quote current evidence on the effect of inhaled GCs, epidural and intra-articular steroid injections, and topical GCs on bone outcomes. Although evidence is limited and weak, it seems that a small proportion of the administered GCs may be absorbed, enter the systemic circulation, and adversely affect the skeleton. Potent GCs, higher doses, and longer treatment duration seem to infer the greater risk for bone loss and fractures. There are scarce data, and only for inhaled GCs, regarding the efficacy of antiosteoporotic medications in patients receiving GCs through routes other than oral. Further studies are needed to clarify the relationship between GC administration through these routes and bone outcomes and to help establishing guidelines for the optimal management of such patients. [ABSTRACT FROM AUTHOR]

• Inotrope formulations avoiding the burdens of continuous IV infusion are needed. • We tested a novel, concentrated formulation of milrinone for inhalation. • Nebulized milrinone was well tolerated and without adverse events. • Intermittent inhalation of milrinone produced therapeutic serum concentrations. • Nebulized milrinone improved invasive hemodynamic parameters. Nonintravenous inotropic-delivery options are needed for patients with inotropic-dependent heart failure (HF) to reduce the costs, infections and thrombotic risks associated with chronic central venous catheters and home infusion services. We developed a novel, concentrated formulation of nebulized milrinone for inhalation and evaluated the feasibility, safety and pharmacokinetic profile in a prospective, single-arm, phase I clinical trial. We enrolled 10 patients with stage D HF requiring inotropic therapy during a hospital admission for acute HF. Milrinone 60 mg/4 mL was inhaled via nebulization 3 times daily for 48 hours. The coprimary outcomes were adverse events and pharmacokinetic profiles of inhaled milrinone. Acute changes in hemodynamic parameters were secondary outcomes. A concentrated nebulized milrinone formulation was well tolerated, without hypotensive events, arrhythmias or inhalation-related adverse events requiring discontinuation. Nebulized milrinone produced serum concentrations in the goal therapeutic range with a median plasma milrinone trough concentration of 39 (17–66) ng/mL and a median peak concentration of 207 (134–293) ng/mL. There were no serious adverse events. From baseline to 24 hours, mean pulmonary artery saturation increased (60% ± 7%–65 ± 5%; P = 0.001), and mean cardiac index increased (2.0 ± 0.5 mL/min/1.73m2–2.5 ± 0.1 mL/min/1.73m2; P = 0.001) with nebulized milrinone. In a proof-of-concept study, a concentrated, nebulized milrinone formulation for inhalation was safe and produced therapeutic serum milrinone concentrations. Nebulized milrinone was associated with improved hemodynamic parameters of cardiac output in a population with advanced HF. These promising results require further investigation in a longer-term trial in patients with inotrope-dependent advanced HF. [ABSTRACT FROM AUTHOR]

Targeting the site of infection is a promising strategy for improving vaccine effectivity. To date, licensed COVID-19 vaccines have been administered intramuscularly despite the fact that SARS-CoV-2 is a respiratory virus. Here, we aim to induce local protective mucosal immune responses with an inhaled subunit vaccine candidate, ISR52, based on the SARS-CoV-2 Spike S1 protein. When tested in a lethal challenge hACE2 transgenic SARS-CoV-2 mouse model, intranasal and intratracheal administration of ISR52 provided superior protection against severe infection, compared to the subcutaneous injection of the vaccine. Interestingly for a protein-based vaccine, inhaled ISR52 elicited both CD4 and CD8 T-cell Spike-specific responses that were maintained for at least 6 months in wild-type mice. Induced IgG and IgA responses cross-reacting with several SARS- CoV-2 variants of concern were detected in the lung and in serum and protected animals displayed neutralizing antibodies. Based on our results, we are developing ISR52 as a dry powder formulation for inhalation, that does not require cold-chain distribution or the use of needle administration, for evaluation in a Phase I/II clinical trial. [ABSTRACT FROM AUTHOR]

Despite the devastating impact of many lung diseases on human health, there is still a significant unmet medical need in respiratory diseases, for which inhaled delivery represents a crucial strategy. More guidance on how to design and carry out multidisciplinary inhaled projects is needed. When designing inhaled drugs, the medicinal chemist must carefully balance the physicochemical properties of the molecule to achieve optimal target engagement in the lung. Although the medicinal chemistry strategy is unique for each project, and will change depending on multiple factors, such as the disease, target, systemic risk, delivery device, and formulation, general guidelines aiding inhaled drug design can be applied and are summarised in this review. [ABSTRACT FROM AUTHOR]

Air pollutants are a major source of increased risk of disease, hospitalization, morbidity, and mortality worldwide. The respiratory tract is a primary target of potential concurrent exposure to both inhaled pollutants and pathogens, including viruses. Although there are various associative studies linking adverse outcomes to co- or subsequent exposures to inhaled pollutants and viruses, knowledge about causal linkages and mechanisms by which pollutant exposure may alter human respiratory responses to viral infection is more limited. In this article, we review what is known about the impact of pollutant exposure on antiviral host defense responses and describe potential mechanisms by which pollutants can alter the viral infection cycle. This review focuses on evidence from human observational and controlled exposure, ex vivo , and in vitro studies. Overall, there are a myriad of points throughout the viral infection cycle that inhaled pollutants can alter to modulate appropriate host defense responses. These alterations may contribute to observed increases in rates of viral infection and associated morbidity and mortality in areas of the world with high ambient pollution levels or in people using tobacco products. Although the understanding of mechanisms of interaction is advancing through controlled in vivo and in vitro exposure models, more studies are needed because emerging infectious pathogens, such as severe acute respiratory syndrome coronavirus 2, present a significant threat to public health. [ABSTRACT FROM AUTHOR]

To investigate the effects of a heat and moisture exchanger (HME) on the temperature and humidity of inhaled gas in isoflurane-anesthetized dogs. Prospective, interventional study. A total of four experimental dogs and four client-owned dogs weighing 13.9 ± 7.4 kg (mean ± standard deviation). The four experimental dogs were anesthetized on two occasions with and without an intact HME at least 1 week apart. The four client-owned dogs were anesthetized once only for a surgical procedure and assigned to the HME group or no-HME group in alternate order, resulting in six dogs for each group. All dogs were premedicated, anesthetized with propofol and intubated. The HME was connected to the endotracheal tube. Anesthesia was maintained with isoflurane. A digital thermo-hygrometer was placed between the endotracheal tube and HME. The temperature and relative humidity of the inhaled gas were measured every 5 minutes for 60 minutes and the absolute humidity was calculated at each time point. The temperature and absolute humidity of the inhaled gas was significantly higher at 5–60 minutes after intubation in the HME group than in the no-HME group. Absolute humidity was maintained above 29 mg H 2 O L−1 in the HME group. No significant time-dependent effects on temperature, relative humidity or absolute humidity of the inhaled gas were observed. The temperature and absolute humidity of the inhaled gas were higher when an HME was used during isoflurane anesthesia in dogs. The use of an HME may reduce the risk of dehydration and dysfunction of the airway mucosal epithelium. [ABSTRACT FROM AUTHOR]

The increasing prevalence of ventilator-associated pneumonia (VAP) due to either multidrug-resistant (MDR) organisms or infections with limited treatment options (i.e. susceptible to only aminoglycosides or colisitin) coupled with a dearth of new antimicrobials has led clinicians to pursue alternative management strategies including the use of inhaled antibiotics (IA). To review the evidence surrounding the use of IA in the treatment of VAP with a focus on establishing a path whereby adjunctive IA could become a standard therapy for the treatment of specific VAP patient populations. A meta-analysis performed by the 2016 IDSA/ATS Hospital-acquired Pneumonia Guideline Committee; a PubMed and clinicaltrials.gov search for subsequent trials of IA for the treatment of VAP. Based on a meta-analysis of nine studies (RR 1.29; 95% CI 1.13–1.47), the 2016 IDSA/ATS Hospital-acquired Pneumonia Guideline Committee recommended that adjunctive IA be used to treat VAP due to Gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins. Two subsequent randomized trials of adjunctive IA for the treatment of mechanically ventilated patients with pneumonia failed to demonstrate a benefit. Despite these results, an updated meta-analysis (n = 11) including these two recent trials suggests a benefit of adjunctive IA for the treatment of VAP due to MDR and difficult-to-treat infections (RR 1.2; 95% CI 1.05–1.57). Patients with VAP and limited intravenous antibiotic options are the individuals most likely to benefit from adjunctive IA and should be the focus of future investigative studies. Although vibrating mesh nebulizers predominate in pharmaceutical company-sponsored trials, these devices have not been directly compared with the traditional jet nebulizers in terms of efficacy or safety. [ABSTRACT FROM AUTHOR]

• Portion of non-orally administered glucocorticoids is absorbed and may affect bone health. • Higher glucocorticoid doses and longer treatment may induce bone loss and fractures. • Intra-articular glucocorticoid injection is safe while repeat epidural steroid injection may cause bone loss. • High cumulative doses of topical glucocorticoids may adversely affect the skeleton. • The efficacy of osteoporosis treatments in patients under non-oral glucocorticoids is unknown. Glucocorticoids (GCs) are widely used by several specialties for the treatment of a variety of diseases and conditions. The unfavorable effect of oral GCs on bone health is well-documented. The ensuing from their use glucocorticoid-induced osteoporosis (GIOP) is the most common cause of medication-induced osteoporosis and fractures. It is uncertain, however, if, and in what extent, GCs administered by other routes affect the skeleton. In the present review, we quote current evidence on the effect of inhaled GCs, epidural and intra-articular steroid injections, and topical GCs on bone outcomes. Although evidence is limited and weak, it seems that a small proportion of the administered GCs may be absorbed, enter the systemic circulation, and adversely affect the skeleton. Potent GCs, higher doses, and longer treatment duration seem to infer the greater risk for bone loss and fractures. There are scarce data, and only for inhaled GCs, regarding the efficacy of antiosteoporotic medications in patients receiving GCs through routes other than oral. Further studies are needed to clarify the relationship between GC administration through these routes and bone outcomes and to help establishing guidelines for the optimal management of such patients. [ABSTRACT FROM AUTHOR]

Newborn infants born very preterm are at high risk of developing bronchopulmonary dysplasia, which is associated with not only mortality but also adverse long-term neurological and respiratory outcomes in survivors. Postnatal corticosteroids might reduce the risk of developing bronchopulmonary dysplasia, or reduce its severity. However, it is important to minimize exposure to the potentially harmful effects of corticosteroids, particularly on the developing brain. Systemic corticosteroids started after the first week of life have shown the most benefit in infants at highest risk of developing bronchopulmonary dysplasia, whereas inhaled corticosteroids have little effect in children with established lung disease. Systemic corticosteroids in the first week of life are not recommended, but inhaled corticosteroids, or corticosteroids instilled into the trachea using surfactant as a vehicle to distribute the corticosteroids through the lungs, offer promise with respect to prevention of bronchopulmonary dysplasia. [ABSTRACT FROM AUTHOR]

Local pulmonary delivery of biotherapeutics may offer advantages for the treatment of lung diseases. Delivery of the therapeutic entity directly to the lung has the potential for a rapid onset of action, reduced systemic exposure and the need for a lower dose, as well as needleless administration. However, formulation of a protein for inhaled delivery is challenging and requires proteins with favorable biophysical properties suitable to withstand the forces associated with formulation, delivery, and inhalation devices. Nanobodies are the smallest functional fragments derived from a naturally occurring heavy chain-only immunoglobulin. They are highly soluble, stable, and show biophysical characteristics that are particularly well suited for pulmonary delivery. This paper highlights a number of clinical and preclinical studies on antibodies delivered via the pulmonary route and describes the advantages of using Nanobodies for inhaled delivery to the lung. The latter is illustrated by the specific example of ALX-0171, a Nanobody in clinical development for the treatment of respiratory syncytial virus (RSV) infections. [ABSTRACT FROM AUTHOR]

Introduction Off label use of anticoagulants is common. The association between fibrin deposition in the lungs and primary lung disease, injury or prematurity affords a strong theoretical basis for the potential benefit of antithrombotic therapies administered directly to the lung tissue. This review offers a critical appraisal of current evidence related to the inhalational administration of antithrombotic therapy in humans. Materials and methods An interrogation of 2 databases across a 13 year period of time was undertaken using key words selected a priori. Identified publications were categorized according to the following themes: 1. Inhaled antithrombotic therapy in healthy subjects 2. Inhaled antithrombotic therapy for vascular thromboprophylaxis 3. Inhaled antithrombotic therapy in smoke inhalation and lung injury 4. Inhaled antithrombotic therapy in asthma or allergy 5. Inhaled antithrombotic therapy for plastic bronchitis post-Fontan surgery 6. Inhaled antithrombotic therapy for other indications. Results 33 articles were identified consistent with the inclusion criteria developed for this review. Unfractionated heparin, LMWH, activated protein C and thrombolytic agents have been administered via the respiratory track, with asthma and smoke inhalation/lung injury being the most frequently investigated clinical scenarios described. All studies reported had significant methodological limitations. Conclusions The safety and clinical utility of inhaled antithrombotic therapies have not been adequately investigated to support the generation of any firm evidence. This review highlights where inhaled antithrombotic therapies have shown promise and importantly, the further research required to confirm mechanism of action and a definitive risk: benefit profile. [ABSTRACT FROM AUTHOR]

Background Oral glucocorticoids can prevent acute mountain sickness (AMS). Whether inhaled budesonide (BUD) can prevent AMS remains unknown. Objective Our aim was to investigate the effectiveness of BUD in AMS prevention. Methods Eighty subjects were randomly assigned to receive budesonide (BUD, inhaled), procaterol tablet (PT), budesonide/formoterol (BUD/FM, inhaled), or placebo tablet (n = 20 in each group). Subjects were treated for 3 days before ascending from 500 m to 3700 m within 2.5 h by air. Lake Louis AMS questionnaire, blood pressure, heart rate, and oxygen saturation (SpO 2 ) were examined at 20, 72, and 120 h after high-altitude exposure. Pulmonary function was measured at 20 h after exposure. Results Compared with placebo, BUD significantly reduced the incidence of AMS (70% vs. 25% at 20 h, p < 0.05; both 10% vs. 5% at 72 and 120 h, both p > 0.05) without side effects. The relative risk was 0.357, and the risk difference was 0.45. Mean SpO 2 was higher in BUD, BUD/FM, and PT groups than in the placebo group at 20 h ( p < 0.05). SpO 2 in all 80 subjects dropped after ascent (98.1% to 88.12%, p < 0.01) and increased gradually, but it was still lower at 120 h than at baseline (92.04% vs. 98.1%, p < 0.01). Pulmonary function did not differ among the four groups at 20 h. Conclusion BUD can prevent AMS without side effects. The alleviation of AMS may be related to increased blood oxygen levels rather than pulmonary function. [ABSTRACT FROM AUTHOR]

In the present investigation inhaled isoniazid microparticles (IM) and isoniazid polymeric microparticles (INH-PM) using poly-ɛ-caprolactone polymer were prepared through spray drying techniques. The purpose of this investigation is to evaluate lung deposition of IM and INH-PM through cascade impaction study. The drug release of IM and INH-PM was studied using simulated lung fluids at pH 7.4 representing the interstitial site and at pH 4.5 representing phagocomal site after alveolar macrophage uptake. The kinetic models had also been applied providing the drug release kinetics for IM and INH-PM in simulated lung fluids at pH 7.4 and at pH 4.5. The results of the particles size and surface characteristics showed the spherical shape and 1-5 μm size of IM and INH-PM prepared using spray drying which can be suitable for pulmonary drug delivery. The cascade impaction study with mass median aerodynamic diameter ranging from 1.9 to 4 μm confirmed the inhaled characteristics of IM and INH-PM with providing the deep lung deposition where tubercular bacilli reside. From in vitro drug release studies done using simulated lung fluids and goodness of fit with kinetic model applications, it can be concluded that the prepared poly-ɛ-caprolactone microparticles of isoniazid provided the advantage of controlled release characteristics deep inside the lung where tubercular bacilli reside and as suitable for pulmonary drug delivery it may help in improving treatment of tuberculosis through direct administration to site of action. [ABSTRACT FROM AUTHOR]

Purpose: Despite many advances in diabetes care over the last century, some elements of insulin therapy remain inadequate for optimal care of the patient with diabetes. There is a need for improved pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues to mimic physiologic insulin secretion. In addition, a major barrier to successful insulin therapy has been patient resistance. Alternative routes of insulin administration, including inhaled insulin, have been under investigation for several years. This review discusses the rationale for pulmonary delivery of insulin, compares previous inhaled insulin products, reviews the literature on the safety and efficacy of a current inhaled insulin formulation under investigation, and compares this product with other prandial insulin products. Methods: English-language studies and reviews of inhaled insulin were searched in MEDLINE, the ClinicalTrials.gov registry (through May 2014), and the US Food and Drug Administration Website. Findings: Inhaled insulin has several favorable characteristics due to pulmonary anatomy/physiology and the lack of injections. Pharmacokinetic and pharmacodynamic studies have shown a time-action profile suitable for prandial insulin use. Inhaled insulin seems to be safe and effective compared with other prandial insulin products and may be preferable to subcutaneous rapid-acting insulin analogues in terms of time-action profiles and rates of hypoglycemia. Small decreases in forced expiratory volume in 1 second (FEV1) have been shown with inhaled insulin, although this finding is not progressive over time and reverses with cessation of the medication. Implications: Although several inhaled insulin products have been under investigation, only one (Exubera ® [Nektar Therapeutics, San Carlos, California/ Pfizer Inc, New York, New York]) was approved by the US Food and Drug Administration, and it was pulled from the market after only a short period of time. Technosphere® insulin (MannKind Corporation, Valencia, California) is currently the only inhaled insulin that remains under investigation. A review of the past and present literature on inhaled insulin is pertinent in understanding the current status of inhaled insulin and its risks and benefits. The current literature suggests that inhaled insulin could be a valuable option for prandial insulin administration, with a favorable risk to benefit ratio in some patients. [ABSTRACT FROM AUTHOR]

Abstract: A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing. [Copyright &y& Elsevier]

Abstract: A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald–Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs. [Copyright &y& Elsevier]

[Display omitted] • Currently available therapeutics for COVID-19 include repurposed, and a few novel drugs. • Current treatments for COVID-19 are mainly given orally or intravenously. • The key limitations of these treatments include high oral dose, low efficacy, potential side effects and - more importantly - low drug concentrations at the site of infection. • Inhaled treatments ensure higher drug concentration in the target site and avoid unwanted adverse effects as lower doses are required. • The rightly chosen cocktail drugs can show better antiviral effects with synergistic activity and lower unwanted drug resistance. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for the COVID-19 pandemic, has outspread at full tilt across the world. Although several effective vaccines continue to be deployed, reliable antiviral treatments have yet to be developed against this disease. Currently, available therapeutics for COVID-19 include repurposed, and a few novel drugs. Many drugs have been promising in preclinical studies, but a majority of these drugs have shown little or no efficacy in clinical studies. One of the major reasons is the insufficient drug concentration in the lung, the primary target site of infection for SARS-CoV-2, from the administration of drugs through oral or intravenous routes. Higher effective doses administered through these routes could also lead to adverse side effects. For this reason, inhaled treatments are being tested as an efficient approach for COVID-19, allowing lower doses of drugs ensuring higher concentrations of the drug(s) in the lung. The inhaled treatment combining two or more antiviral drugs will increase potency and reduce the possibility of selecting for SARS-CoV-2 variants with reduced drug susceptibility. Finally, the appropriate drug combination needs to be delivered using a suitable system. Here, we review the current treatment for COVID-19 and their limitations, discussing the advantages of mono and combinational inhaled therapy with a brief outline of the recently reformulated anti-SARS-CoV-2 agents as inhaled formulations. The selection of appropriate delivery devices for inhalation and associated key considerations including the formulation challenges are also discussed. [ABSTRACT FROM AUTHOR]

Abstract: Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction. [Copyright &y& Elsevier]

Abstract: A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction. [Copyright &y& Elsevier]

Abstract: A multivalent approach was applied to the design of long-acting inhaled β2-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β2-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C 2-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection. [Copyright &y& Elsevier]

Abstract: Libraries of dibasic compounds designed around the molecular scaffold of the DA2/β2 dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β2-agonist with high selectivity and a duration of action commensurable with once daily dosing. [Copyright &y& Elsevier]

Abstract: In this Letter we present data for a novel series of ICS for the treatment of asthma. ‘Inhalation by design’ principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma. [Copyright &y& Elsevier]

Abstract: Starting with the molecular scaffold of the DA2/β2 dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full β2-agonist with high selectivity and long duration capable of being dosed once daily has been discovered. [Copyright &y& Elsevier]

Abstract: The design and synthesis of a new series of high efficacy β2 -agonists devoid of the key benzylic alcohol present in previously described highly efficacious β2 -agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β2-adrenoceptor crystal structure, other biophysical data and modeling studies. [Copyright &y& Elsevier]

Abstract: We sought to design dual pharmacology bronchodilators targeting both the M3 muscarinic acetylcholine and beta-2 adrenergic (β2) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors. [Copyright &y& Elsevier]

Simultaneously Manufactured Nano-In-Micro (SIMANIM) particles for the pulmonary delivery of antibodies have been prepared by the spray-drying of a double-emulsion containing human IgG (as a model antibody), lactose, poly(lactide-co-glycolide) (PLGA) and dipalmitoylphosphatidylcholine (DPPC). The one-step drying process involved producing microparticles of a diameter suitable for inhalation that upon contact with aqueous media, partially dissolved to form nanoparticles, ∼10-fold smaller than their original diameter. Continuous release of the model antibody was observed for 35 days in pH 2.5 release media, and released antibody was shown to be stable and active by gel electrophoresis, field-flow fractionation and enzyme linked immunosorbent assay. Adding 1% L-leucine to the emulsion formulation, and blending ‘SIMANIM’ particles with 1% magnesium stearate, achieved a fine particle fraction of ∼60%, when aerosolised from a simple, capsule-based, dry powder inhaler device. ‘SIMANIM’ particles could be beneficial for the delivery of antibodies targeted against inhaled pathogens or other extracellular antigens, as well as having potential applications in the delivery of a wide range of other biopharmaceuticals and certain small-molecule drugs. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4055–4068, 2009 [ABSTRACT FROM AUTHOR]

Abstract: Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625mg (low dose group) or 31.25mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85±0.63μg/g wet lung weight and 0.58±0.30μg/mL, with low dose group lung and plasma concentrations of 0.38±0.01μg/g wet lung weight and 0.09±0.06μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation. [Copyright &y& Elsevier]

Abstract: Invasive fungal infections in immunocompromised patients have high mortality rates despite current treatment modalities. This study was designed to evaluate the suitability of an aqueous solution of voriconazole solubilized with sulfobutyl ether-β-cyclodextrin for targeted drug delivery to the lungs via nebulization. A solution was prepared such that the inspired aerosol dose was isotonic with an acceptable mass median aerodynamic diameter of 2.98μm and a fine particle fraction of 71.7%. Following single and multiple inhaled doses, high voriconazole concentrations were observed within 30min in the lung tissue and plasma. Drug solubilization with sulfobutyl ether-β-cyclodextrin contributed to the rapid and high drug concentrations in plasma following inhalation. Maximal concentrations in the lung and plasma were 11.0±1.6μg/g wet lung weight and 7.9±0.68μg/mL, respectively, following a single inhaled dose with a corresponding tissue/plasma concentration ratio of 1.4 to 1. Following multiple inhaled doses, peak concentrations in lung tissue and plasma were 6.73±3.64μg/g wet lung weight and 2.32±1.52μg/mL, respectively. AUC values in lung tissue and plasma were also high. The clinically relevant observed pharmacokinetic parameters of inhaled aqueous solutions of voriconazole suggest that therapeutic outcomes could be benefitted through the use of inhaled voriconazole. [Copyright &y& Elsevier]

Abstract: Therapeutic antibodies offer a potential treatment for, or means of protection against, airborne infections. For this application, it may be desirable to deliver the antibody directly into the nasal cavity, one of its potential sites of action, since this would be more efficient and convenient than systemic administration. Formulations of a model antibody (human IgG) were developed using albumin, sodium chloride and disaccharides. A combination of these excipients allowed the efficient spray-drying (yield>70%) of the antibody into a microparticulate (1–15 µm) dry powder that was rapidly soluble in aqueous media. The water content and crystallinity of the formulations were also measured, with both properties being affected by the substitution of some of the sodium chloride in the formulation, with lactose. The antibody was found to be stable following the formulation process, as determined by gel-electrophoresis, field-flow-fractionation and enzyme-linked immunosorbent assay. Incubation of an in vitro epithelial cell line in the presence of solutions of the formulations (at concentrations of up to 2500 µg/mL) was found not affect cell viability. The aerosolisation properties of the formulations were tested using Bespak''s “Unidose-DP™”, dry-powder nasal device. The powder aerosol was analysed by laser diffraction, high-speed video and dose deposition in Bespak''s nasal cast model. For the latter experiment, a range of additional excipients were either dissolved in the spray-drying liquid feed (leucine), or blended with the spray-dried powder formulation (magnesium stearate, Aerosil® and lactose). The major dose deposition site of the standard spray-dried formulation was the nasal vestibule (~55%). The addition of leucine and Aerosil® resulted in a 10% increase in the deposition beyond the nasal vestibule, with ~45% of the delivered dose being deposited in the turbinates, olfactory region, and nasal-pharynx. [Copyright &y& Elsevier]

Summary: Background: Ventilator-associated pneumonia (VAP) remains the leading cause of death in patients with intensive care unit (ICU) acquired infections associated with an attributable mortality around 30%. Increasing antimicrobial resistance in patients with VAP challenges intensivists to search for alternative therapeutic options. There is scarcity of data in the literature concerning the administration of aerosolized colistin in critically ill patients with VAP due to multidrug-resistant (MDR) Gram-negative pathogens. Methods: To assess the safety and effectiveness of aerosolized colistin as an adjunctive to the intravenous antimicrobial therapy for the treatment of VAP due to MDR Gram-negative pathogens, we prospectively examined all patients, who received inhaled colistin. Results: Sixty critically ill patients with a mean APACHE II score 16.7, received aerosolized colistin for the treatment of VAP due to MDR pathogens [Acinetobacter baumannii (37/60 cases), Pseudomonas aeruginosa (12/60 cases) and Klebsiella pneumoniae strains (11/60 cases)]. Half of the isolated pathogens were susceptible only to colistin. Mean (±SD) daily dosage of aerosolized colistin was 2.2 (±0.7) million international units (IU). All patients received 2946 inhalations of colistin and the mean duration of administration was 16.4 days. Fifty-seven patients received concomitant intravenous treatment with colistin or other antimicrobial agents. Bacteriological and clinical response of VAP was observed in 50/60 (83.3%) patients. No adverse effects related to inhaled colistin were recorded. All cause hospital mortality was 25% while mortality attributable to VAP was 16.7%. Conclusions: Aerosolized colistin may be considered as adjunctive to intravenous treatment in patients with VAP due to MDR Gram-negative bacteria susceptible to colistin in critically ill patients. Although colistin is safe and effective, the best route of administration remains unclear. In addition, controlled comparative studies are needed to establish its effectiveness and safety. [Copyright &y& Elsevier]

Abstract: Orally active phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of asthma and chronic obstructive pulmonary disorders (COPD) although their full development has been limited by adverse side effects. Administration of PDE4 inhibitors by inhalation may improve their therapeutic index, but limited information exists on the efficacy of inhaled PDE4 inhibitors to improve lung function. In this study in ovalbumin-sensitized Brown Norway rats, roflumilast was given either intratracheally or by nose-only inhalation and changes in lung function (forced vital capacity, FVC; peak expiratory flow, PEF) and inflammatory cell influx (total cells, eosinophils and neutrophils) into the bronchoalveolar lavage (BAL) fluid were evaluated 24 h after allergen challenge. Intratracheal roflumilast, given 5 h before antigen challenge, inhibited the antigen-induced reductions in FVC (ED50 = 140 μg/kg, i.t.) and total cells appearing in the bronchoalveolar lavage fluid (ED50 = 50 μg/kg, i.t.). By the nose-only inhalation route, roflumilast reduced the bronchoalveolar lavage fluid total cells (ED50 = 10 μg/kg, estimated pulmonary deposition). Intratracheal roflumilast (600  μg/kg, i.t.) was also given to rats 24 h after the antigen challenge and reversed the antigen-induced reductions of FVC by 38% at 1 h, 54% at 5 h and 71% by 16 h. Intratracheal roflumilast also reduced the number of inflammatory cells in the bronchoalveolar lavage fluid and reduced the interstitial airway edema caused by the antigen challenge. These results support the development of inhaled PDE4 inhibitors for the treatment of asthma and COPD, particularly for the improvement of lung function. [Copyright &y& Elsevier]

Summary: Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammatory process in the large and small airways, as well as in the lung parenchyma. Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented, its role in stable COPD is not clear. We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 (IL-8) levels in bronchoalveolar lavage (BAL) and their correlation with spirometry and symptom scores. Twenty-six patients with stable COPD were randomised, in a double-blinded, placebo-controlled trial with either 800μg of inhaled budesonide or placebo for a 6-month period. The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy (mean±sem, 1.53±0.72 at baseline vs. 0.70±0.48ng/ml at 6 months, ) and a reduction in the mean percentages of neutrophils (17.16±2.67% vs. 13.25±2.28% ). The improvement in sputum production was of borderline () significance but there was no improvement in lung function. In stable patients with COPD, treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation, as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL. [Copyright &y& Elsevier]

Objective: The effects of inhaled nitric oxide (NO) on cardiac pathology and energy metabolism were studied in a canine model of smoke inhalation injury. Material and method: Twenty-one dogs were randomly divided into three groups: four dogs constituted the normal control group (group N), eight dogs subjected to smoke inhalation followed by O2 inhalation (FiO2=0.45) constituted the injury control group (group C), and nine dogs inhaling a mixture of O2 and 45 ppm nitric oxide after smoke exposure served as the treatment group (group T). Myocardial zymograms were continuously measured, and ventricular muscles were examined for histopathology in the end of the experiment. Results: Lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (alpha-HBD), creatine kinase (CK) and glutamic oxalacetic transaminase (GOT) in group T were less than those in group C(P<0.05, or P<0.01). ATP content and energy charge (EC) in group T were higher significantly than those in group C(P<0.01). Light microscopy and electron microscopy indicated that the ventricular pathologic changes in group T were milder than in control group. Conclusion: Nitric oxide inhalation relieved myocardial damage and improved energy metabolism. [Copyright &y& Elsevier]

The effects of inhaled nitric oxide (NO) on pulmonary hypertension and their mechanisms were studied in a canine model of smoke inhalation injury. Twenty-one dogs were randomly divided into three groups: four dogs constituted the normal control group, eight dogs subjected to smoke inhalation followed by O2 inhalation (FiO2=0.45) constituted the injury control group, and nine dogs inhaling a mixture of O2 and 45 ppm nitric oxide after smoke exposure served as the treatment group. The levels of cyclic guanosine monophosphate (cGMP) in arterial plasma of the treatment group were higher than that of the control group at 5, 8, and 12 h after smoke exposure, while the levels of cGMP in lung tissue were also significantly higher compared with that of the control group (P<0.01). The levels of cGMP of injury control group were decreased significantly compared with normal controls (P<0.05). Pulmonary vasoconstriction following smoke inhalation was significantly attenuated by inhalation of NO (P<0.05), which exerted no apparent effect on the systemic circulation (P>0.05). Inhalation of NO may lower pulmonary hypertension induced by smoke inhalation injury in dogs. The selective effect of NO on pulmonary circulation may be attributed to an increase in level of cGMP in smooth muscle cells of the lung tissue after inhalation of NO. [Copyright &y& Elsevier]

Anti-inflammatory treatment options for cystic fibrosis (CF) patients are currently limited and as such, there is an imperative need to develop new anti-inflammatory agents to reduce the persistent inflammation present within CF lungs. This study explored the potential of Diclofenac (DICLO) as a novel inhaled anti-inflammatory drug for CF treatment. The anti-inflammatory activity of DICLO on an air–liquid interface (ALI) cell culture model of healthy (NuLi-1) and CF (CuFi-1) airways showed a significant reduction in the secretion of pro-inflammatory cytokines, IL-6 and IL-8. Therefore, pressurized metered dose inhaler (pMDI) DICLO formulations were developed to allow targeted DICLO delivery to CF airways. As such, two pMDI DICLO formulations with varying ethanol concentrations: 5% (w/w) equating to 150 µg of DICLO per dose (Low dose), and 15% (w/w) equating to 430 µg of DICLO per dose (High dose) were developed and characterized to determine the optimum formulation. The Low dose pMDI DICLO formulation showed a significantly smaller particle diameter with uniform distribution resulting in a greater aerosol performance when compared to High dose formulation. Consequently, the Low dose pMDI DICLO formulation was further evaluated in terms of in vitro transport characteristics and anti-inflammatory activity. Importantly, the DICLO pMDI displayed anti-inflammatory activity in both healthy and CF in vitro models, highlighting the potential of an aerosolized low-dose DICLO formulation as a promising inhaled anti-inflammatory therapy for CF treatment. [ABSTRACT FROM AUTHOR]

Whenever a paediatric airway foreign body (PAFB) is suspected, decisions may be difficult without a clearly defined or accepted treatment algorithm. History and examination are commonly non-diagnostic and the risks associated with either watchful waiting or proceeding to MLB are significant. This paper reviews a 10 year cohort of suspected PAFBs for the predictive utility of history, examination and investigations and subsequent positive findings at MLB. 1. To review cases of suspected PAFB undergoing MLB in Perth, Western Australia over 10 years 2. To examine the relative strengths of history, examination and imaging for predicting the presence of a foreign body, and their utility in treatment decision making 3. To characterise the epidemiology of our cohort and to Evaluate our complication rate 4. To consider the limitations and benefits of the use of CT imaging in such cases The medical records of 127 children who underwent MLB for suspected PAFB between 2007 and 2016 were examined. The data was retrospectively reviewed for epidemiological details, history, examination, radiological findings and MLB outcomes. Sensitivity for PAFB on MLB with all three; history, examination and imaging (x-ray) positive for PAFB was 87.7%. Of the patients who were both symptom and sign positive (n = 96), chest x-ray findings did not significantly alter the chance of finding a PAFB. Chest x-ray had a low specificity (17%) in symptom and sign positive patients. Conversely, sensitivity of chest x-ray was high (88%), for symptom and sign positive patients. For a child with both signs and symptoms, xray is unlikely to assist in decision making around suspected PAFB. When only sign or symptom is present, positive imaging may significantly increase the chance that PAFB is the cause.For patients with a low suspicion of PAFB, consideration of a CT can be a helpful means of excluding a PAFB and avoiding an unnecessary general anaesthetic in this potentially high-risk group.A greater level of public awareness is needed with regards to appropriate food types for children and the importance of eating seated and supervised in order to reduce the risk of PAFB. [ABSTRACT FROM AUTHOR]

Summary: The course of COPD has traditionally been equated with an accelerated decline in the forced expiratory volume in one second (FEVi) over time in patients with COPD, compared to healthy individuals. However, other important clinical outcomes associated with COPD also worsen over time and should also be considered in conceptualizing the course of COPD. These include health status, breathlessness related to activities of daily living, exercise capacity, the frequency of exacerbations, and peripheral muscle weakness. These outcomes are often quite responsive to therapy of COPD. Presently there is no evidence that any treatment other than smoking cessation can normalise the rate of decline of FEVi, and therefore be considered as modifying the physiologic course of the disease. Thus, smoking cessation reigns as the primary disease modifying strategy in COPD. Even though there are a number of smoking cessation products on the market and smoking prevalence continues to decrease marginally each year, more needs to be done to provide comprehensive programmes to help people quit smoking. In the US in 2004, 37.5% of preventable deaths were found to be tobacco-related. The FEVi does not reflect the clinical manifestations or the total burden of this multidimensional illness. As novel therapeutic agents become available that may alter the underlying pathology of COPD, additional markers and outcomes of disease progression will be needed to provide a more comprehensive assessment. There has been increasing interest in predicting and assessing mortality as it is the final outcome of disease progression. In this review we have considered three approaches toward modifying the course of COPD: smoking cessation, reduction in lung hyperinflation through medical and surgical approaches, and long-term pharmacotherapy. [Copyright &y& Elsevier]