Correlation and clinical relevance of animal models for inhaled pharmaceuticals and biopharmaceuticals.

Nonclinical studies are fundamental for the development of inhaled drugs, as for any drug product, and for successful translation to clinical practice. They include in silico, in vitro, ex vivo and in vivo studies and are intended to provide a comprehensive understanding of the inhaled drug beneficial and detrimental effects. To date, animal models cannot be circumvented during drug development programs, acting as surrogates of humans to predict inhaled drug response, fate and toxicity. Herein, we review the animal models used during the different development stages of inhaled pharmaceuticals and biopharmaceuticals, highlighting their strengths and limitations.

In vitro-in vivo correlations (IVIVCs) of deposition for drugs given by oral inhalation.

Conventional in vitro tests to assess the aerodynamic particle size distribution (APSD) from inhaler devices use simple right-angle inlets ("mouth-throats", MTs) to cascade impactors, and air is drawn through the system at a fixed flow for a fixed time. Since this arrangement differs substantially from both human oropharyngeal airway anatomy and the patterns of air flow when patients use inhalers, the ability of in vitro tests to predict in vivo deposition of pharmaceutical aerosols has been limited. MTs that mimic the human anatomy, coupled with simulated breathing patterns, have yielded estimates of lung dose from in vitro data that closely match those from in vivo gamma scintigraphic or pharmacokinetic studies. However, different models of MTs do not always yield identical data, and selection of an anatomical MT and representative inhalation profiles remains challenging. Improved in vitro - in vivo correlations (IVIVCs) for inhaled drug products could permit increased reliance on in vitro data when developing new inhaled drug products, and could ultimately result in accelerated drug product development, together with reduced research and development spending.

Incidental focal uptake in oropharynx due to lingual thyroid on diagnostic 131I whole-body scan after total thyroidectomy.

After total thyroidectomy for papillary thyroid carcinoma, a 37-year-old woman underwent a 2-mCi (131)I whole-body scan which demonstrated focal uptake in the anterior neck and in the oropharynx. Preoperative contrast-enhanced neck computed tomography demonstrated a small enhancing nodule typical for ectopic thyroid at the tongue base. She was then treated with 150 mCi (131)I. Small asymptomatic lingual thyroid remnants typically do not affect high-dose (131)I therapy.

Natural capsaicinoids improve swallow response in older patients with oropharyngeal dysphagia.

OBJECTIVE: There is no pharmacological treatment for oropharyngeal dysphagia (OD). The aim of this study was to compare the therapeutic effect of stimulation of oropharyngeal transient receptor potential vanilloid type 1 (TRPV1) with that of thickeners in older patients with OD. DESIGN: A clinical videofluoroscopic non-randomised study was performed to assess the signs of safety and efficacy of swallow and the swallow response in (1) 33 patients with OD (75.94 ± 1.88 years) while swallowing 5, 10 and 20 ml of liquid (20.4 mPa.s), nectar (274.4 mPa.s), and pudding (3930 mPa.s) boluses; (2) 33 patients with OD (73.94 ± 2.23 years) while swallowing 5, 10 and 20 ml nectar boluses, and two series of nectar boluses with 150 µM capsaicinoids and (3) 8 older controls (76.88 ± 1.51 years) while swallowing 5, 10 and 20 ml nectar boluses. RESULTS: Increasing bolus viscosity reduced the prevalence of laryngeal penetrations by 72.03% (p < 0.05), increased pharyngeal residue by 41.37% (p < 0.05), delayed the upper esophageal sphincter opening time and the larynx movement and did not affect the laryngeal vestibule closure time and maximal hyoid displacement. Treatment with capsaicinoids reduced both, penetrations by 50.% (p < 0.05) and pharyngeal residue by 50.% (p < 0.05), and shortened the time of laryngeal vestibule closure (p < 0.001), upper esophageal sphincter opening (p < 0.05) and maximal hyoid and laryngeal displacement. CONCLUSION: Stimulation of TRPV1 by capsaicinoids strongly improved safety and efficacy of swallow and shortened the swallow response in older patients with OD. Stimulation of TRPV1 might become a pharmacologic strategy to treat OD.

Unexplained chronic cough and vitamin B-12 deficiency.

BACKGROUND: Chronic cough is characterized by sensory neuropathy. Vitamin B-12 (cobalamin) deficiency (Cbl-D) causes central and peripheral nervous system damage and has been implicated in sensory neuropathy and autonomic nervous system dysfunction. OBJECTIVE: We evaluated whether Cbl-D has a role in chronic, unexplained cough. DESIGN: Laryngeal threshold (histamine concentration that provokes a 25% decrease in the midinspiratory flow), bronchial threshold (histamine concentration that provokes a 20% decrease in the forced expiratory volume in 1 s), and cough threshold (histamine concentration that causes ≥5 coughs) in response to an inhaled histamine were assessed in 42 patients with chronic, unexplained cough [27 Cbl-D patients and 15 patients without Cbl-D (Cbl-N)] before and after intramuscular injections of cobalamin for 2 mo. Laryngeal, bronchial, and cough hyperresponsiveness was diagnosed when histamine concentration thresholds were ≤8 mg/mL. Seven Clb-D and 3 Cbl-N patients underwent an oropharyngeal biopsy before treatment. RESULTS: Cbl-D patients had a higher prevalence of laryngeal hyperresponsiveness than did Cbl-N patients (92.6% compared with 66.7%; P = 0.03), a thinner oropharyngeal epithelium [133.7 µm (95% CI: 95, 172 µm) compared with 230.8 µm (95% CI: 224, 237 µm); P = 0.002], a lower number of myelinated nerve fibers [2.25/mm(2) (95% CI: 1.8, 2.7/mm(2)) compared with 3.44/mm(2) (95% CI: 3, 3.8/mm(2)); P = 0.05], and a higher immunoreactive score for nerve growth factor (NGF) [6.7 (95% CI: 6, 7.3) compared with 2.8 (95% CI: 2.5, 3.1); P = 0.02]. After cobalamin supplementation, symptoms and laryngeal, bronchial, and cough thresholds were significantly improved in Cbl-D but not in Cbl-N patients. CONCLUSIONS: This study suggests that Cbl-D may contribute to chronic cough by favoring sensory neuropathy as indicated by laryngeal hyperresponsiveness and increased NGF expression in pharyngeal biopsies of Cbl-D patients. Cbl-D should be considered among factors that sustain chronic cough, particularly when cough triggers cannot be identified.

Does using a mouthwash instead of water improve the oropharyngeal removal of inhaled flovent (fluticasone propionate)?

Rinsing the mouth with water is recommended to remove inhaled corticosteroid (ICS) deposited on the oropharyngeal mucosa. Given the lipophilicity of fluticasone propionate (FP), an ethanol-based mouthwash was hypothesized to be superior to water. This study's purpose was to compare the effectiveness of water versus Listerine (Warner Lambert, Lititz, PA) in removing FP from the oropharyngeal mucosa. Asthma patients were randomly assigned water or a Listerine-rinsing vehicle. A 440-microgram dose of FP was inhaled. After the second puff, patients rinsed for 30 seconds with 20 mL of the assigned agent and then repeated the process, spitting each "wash" into the same cup. At visit 2, patients used the alternate vehicle and repeated the procedure. Samples were frozen until analyzed using liquid chromatography/mass spectrophotometry (lower limit of detection 0.067 microgram/mL). Thirty-six patients (mean age, 44 years; 66% female) participated. Mean inhaler technique score was 11.3 (scale of 1-12). Eighty-three percent used the closed-mouth technique. The mean concentration of FP removed by Listerine was not statistically different than that removed by water, 1.67 micrograms/mL (range, 0.067-4.195 micrograms/mL) and 1.42 micrograms/mL (range, 0.067-5.107 micrograms/mL), respectively, and the total milliliter returned was assumed to be 40 mL. Regression analysis using sex, age, and inhaler technique showed no statistical relationship with the amount of FP removed. Therefore, Listerine was not more effective than water in removing FP from the oropharyngeal mucosa (p = 0.53). Thus, water is an adequate rinsing vehicle for removal of ICS deposited on the oropharyngeal mucosa. Other factors besides the rinsing vehicle are strong factors in determining the amount of drug removed.