Inhaled Medicines: Past, Present, and Future.

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include ß -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

Novel Toxicology Program to Support the Development of Inhaled VentaProst.

Currently, off-label continuous administration of inhaled epoprostenol is used to manage hemodynamics during mitral valve surgery. A toxicology program was developed to support the use of inhaled epoprostenol during mechanical ventilation as well as pre- and postsurgery via nasal prongs. To support use in patients using nasal prongs, a Good Laboratory Practice (GLP), 14-day rat, nose-only inhalation study was performed. No adverse findings were observed at ∼50× the dose rate received by patient during off-label use. To simulate up to 48 hours continuous aerosol exposure during mechanical ventilation, a GLP toxicology study was performed using anesthetized, intubated, mechanically ventilated dogs. Dogs inhaled epoprostenol at approximately 6× and 13× the dose rate reported in off-label human studies. This novel animal model required establishment of a dog intensive care unit providing sedation, multisystem support, partial parenteral nutrition, and management of the intubated mechanically ventilated dogs for the 48-hour duration of study. Aerosol was generated by a vibrating mesh nebulizer with novel methods required to determine dose and particle size in-vitro. Continuous pH 10.5 epoprostenol was anticipated to be associated with lung injury; however, no adverse findings were observed. As no toxicity at pH 10.5 was observed with a formulation that required refrigeration, a room temperature stable formulation at pH 12 was evaluated in the same ventilated dog model. Again, there were no adverse findings. In conclusion, current toxicology findings support the evaluation of inhaled epoprostenol at pH 12 in surgical patients with pulmonary hypertension for up to 48 hours continuous exposure.

Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter.

BACKGROUND AND OBJECTIVE: Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side-effect profiles are poorly understood. METHODS: Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post-injection. RESULTS: Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose-limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)(0-5d) 20- to 50-fold lower than the AUC(0-∞) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post-injection, bronchial PTX tissue concentrations were above a 10-nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX. CONCLUSION: Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow-up period.

Prediction of troponin elevation by means of intracoronary electrocardiogram during percutaneous coronary intervention of coronary bifurcation lesions (from COronary SIde Branch Residual IschemiA and COllateralization Assessment Study; COSIBRIA & Co Study.

BACKGROUND: The influence of periprocedural ischaemia on coronary artery bifurcation stenting (percutaneous coronary intervention [PCI]) remains uncertain. AIM: To determine the differences in rates of end procedural ischaemia after bifurcation lesion PCI detected with intracoronary electrocardiography (icECG). METHODS: Unipolar icECGs were recorded before, during, and after stent placement and at the end of procedure in side branch (SB) and main branch (MB). Coronary wire was placed in all distal vessels with diameter > 1.5 mm to "map" the distal zones of ischaemia. The patient population consisted of patients with stable/unstable angina with troponin I evaluated before and after PCI. RESULTS: We studied 147 patients (68% males) with mean age of 64 ± 9 years. One hundred and forty-two patients had icECG recordings at the end of PCI from all locations of the treated region; 36% of patients had MB ST segment elevation (STE) and 31% had icECG STE in the SB region (p = 0.378). The icECG had sensitivity of 82% and specificity of 81% to detect troponin I elevation, with positive predictive value of 81% and negative predictive value of 83%. The independent predictors of troponin increase (> 5 × N) were: sex (for female gender, OR = 0.130, CI 0.017-0.995, p = 0.049), previous myocardial infarction (OR = 33.23, CI 2.802-394.1, p = 0.005), and icECG STE in MB or SB or occlusion of secondary SB (OR = 7.877, CI 2.474-25.07, p < 0.001) and for any troponin elevation were double product - SBPxHR (OR = 0.999, CI 0.999-1.00, p = 0.022) and icECG STE in MB or SB or occlusion of secondary SB (OR = 9.762, CI 3.273-29.12, p < 0.001). CONCLUSIONS: Intracoronary electrocardiography is a highly sensitive and specific method for determination of ischaemic regions and prediction of elevated troponin I.

Dynamics and control of biofilms of the oligotrophic bacterium Caulobacter crescentus.

Caulobacter crescentus is an oligotrophic alpha-proteobacterium with a complex cell cycle involving sessile-stalked and piliated, flagellated swarmer cells. Because the natural lifestyle of C. crescentus intrinsically involves a surface-associated, sessile state, we investigated the dynamics and control of C. crescentus biofilms developing on glass surfaces in a hydrodynamic system. In contrast to biofilms of the well-studied Pseudomonas aeruginosa, Escherichia coli, and Vibrio cholerae, C. crescentus CB15 cells form biphasic biofilms, consisting predominantly of a cell monolayer biofilm and a biofilm containing densely packed, mushroom-shaped structures. Based on comparisons between the C. crescentus strain CB15 wild type and its holdfast (hfsA; DeltaCC0095), pili (DeltapilA-cpaF::Omegaaac3), motility (motA), flagellum (flgH) mutants, and a double mutant lacking holdfast and flagellum (hfsA; flgH), a model for biofilm formation in C. crescentus is proposed. For both biofilm forms, the holdfast structure at the tip of a stalked cell is crucial for mediating the initial attachment. Swimming motility by means of the single polar flagellum enhances initial attachment and enables progeny swarmer cells to escape from the monolayer biofilm. The flagellum structure also contributes to maintaining the mushroom structure. Type IV pili enhance but are not absolutely required for the initial adhesion phase. However, pili are essential for forming and maintaining the well-defined three-dimensional mushroom-shaped biofilm. The involvement of pili in mushroom architecture is a novel function for type IV pili in C. crescentus. These unique biofilm features demonstrate a spatial diversification of the C. crescentus population into a sessile, "stem cell"-like subpopulation (monolayer biofilm), which generates progeny cells capable of exploring the aqueous, oligotrophic environment by swimming motility and a subpopulation accumulating in large mushroom structures.