Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

Hereditary mucoepithelial dysplasia and severe respiratory distress.

Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant disorder characterized by mucoepithelial disruption of the skin, hair and mucous membranes. It results from defective gap junction formation and leads to non-scarring alopecia, mucosal erythema, perineal erythematous intertrigo, involvement of the conjunctival mucosa, and pulmonary disease. We present a case of severe respiratory distress in an initially healthy full term infant born to a mother with HMD. This infant later developed signs and symptoms of HMD. A high index of suspicion for pulmonary infection with atypical organism is essential in infants with a family history of HMD who present with respiratory distress.

Successful use of bronchoscopic lung insufflation to treat left lung atelectasis.

We report first use of bronchoscopic lung insufflation in a child to treat acute left lung collapse. The patient is a 6-year old male asthmatic who was hospitalized with a 2-day history of cough, chest pain, and abdominal pain. He was tachypneic and hypoxemic on room air. Chest exam revealed diminished breath sounds on the left side. Chest X-ray and Chest CT showed complete left lung collapse. He underwent bronchoscopic lung insufflation procedure by injecting total of 200 ml air via flexible bronchoscope in the left upper lobe using 50cc syringe aliquots followed by similar injection of 200 ml of air in left lower lobe. After air insufflations, 6 ml of bovine surfactant (calfactant) were instilled in each lobe. Chest fluoroscopy was done immediately after procedure and showed expansion of entire left lung with no pneumothorax. The procedure was well tolerated. The patient's symptoms and hypoxemia resolved soon after procedure. However, left lower lobe atelectasis recurred next day and persisted for 6 days despite treatments with chest physical therapy, systemic steroids, oral azithromycin, nebulized dornase alpha, and endoscopic removal of secretions from left lower lobe. Bronchoscopic insufflation of left lower lobe was repeated resulting in immediate expansion of that lobe as demonstrated by intraoperative fluoroscopy. The patient was discharged home next day. This case suggests that brochoscopic lung insufflation can be safe and effective in treating acute lung collapse and in treating atelectasis which is refractory to conventional therapy.

Achalasia: unusual cause of chronic cough in children.

Achalasia is a rare motility disorder of the esophagus which results from lack of enervation of the lower esophageal sphincter muscles and leads to dilatation of proximal esophagus. Patients with achalasia presents typically with dysphagia, vomiting of undigested food and failure to thrive. Cough can be present in achalasia patients due to aspiration of food or due to airway compression by the dilated esophagus. We report two cases of achalasia presenting primarily with prolonged cough. Diagnosis of achalasia in both cases was delayed due to this atypical presentation. This highlights the importance of recognizing achalasia as a potential cause of chronic cough in order to avoid delayed diagnosis and mismanagement.