Vamsi P. Guntur

How Best to Deliver Aerosol Medications to Mechanically Ventilated Patients

Pressurized metered-dose inhalers (pMDIs) and nebulizers are employed routinely for aerosol delivery to ventilator-supported patients, but the ventilator circuit and artificial airway previously were thought to be major barriers to effective delivery of aerosols to patients receiving mechanical ventilation. In the past two decades, several investigators have shown that careful attention to many factors, such as the position of the patient, the type of aerosol generator and its configuration in the ventilator circuit, aerosol particle size, artificial airway, conditions in the ventilator circuit, and ventilatory parameters, is necessary to optimize aerosol delivery during mechanical ventilation. The best techniques for aerosol delivery during noninvasive positive-pressure ventilation are not well established as yet, and the efficiency of aerosol delivery in this setting is lower than that during invasive mechanical ventilation. The most efficient methods of using the newer hydrofluoroalkane-pMDIs and vibrating mesh nebulizers in ventilator-supported patients also require further evaluation. When optimal techniques of administration are employed, the efficiency of aerosolized drug delivery in mechanically ventilated patients is comparable to that achieved in ambulatory patients.

The potential use of tyrosine kinase inhibitors in severe asthma

Purpose of reviewSevere asthma comprises heterogeneous phenotypes that share in common a poor response to traditional therapies. Recent and ongoing work with tyrosine kinase inhibitors suggests a potential beneficial role in treatment of severe asthma. Recent findingsVarious receptor and nonreceptor tyrosine kinase pathways contribute to aspects of airway inflammation, airway hyperresponsiveness, and remodeling of asthma. Selective and nonselective tyrosine kinase inhibitors may be useful to block pathways that are pathologically overactive or overexpressed in severe asthma. Recent in-vivo studies have demonstrated the utility of inhibitors against specific tyrosine kinases (epidermal growth factor receptor, c-kit/platelet derived growth factor receptor, vascular endothelial growth factor receptor, spleen tyrosine kinase, and janus kinase) in altering key aspects of severe asthma. SummaryAsthma and even severe asthma does not consist of a single phenotype. Targeting key inflammatory and remodeling pathways engaged across subphenotypes with tyrosine kinase inhibitors appears to hold promise.

The Tyrosine Kinase Inhibitor Masitinib Blunts Airway Inflammation and Improves Associated Lung Mechanics in a Feline Model of Chronic Allergic Asthma

Background: Blockade of tyrosine kinase signaling by masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, can modulate allergic airway inflammation, but effects on lung mechanics have not been well characterized. We hypothesized masitinib would decrease airway eosinophilia and consequently improve pulmonary mechanics in a feline allergic asthma model. Methods: Asthma was induced in 12 cats using Bermuda grass allergen (BGA). Cats received 50 mg/day oral masitinib or placebo. Bronchoalveolar lavage fluid (BALF) was analyzed for eosinophils, total protein (TP) and BGA-specific IgE. Ventilator-acquired mechanics after methacholine (MCh) challenge determined MCh concentration needed to increase baseline airway resistance by 200% (EC200Raw), positive end expiratory occlusion pressure (PEEP) and end inspiratory breath hold pressure (Pplat). An inverse correlate of respiratory system compliance Pplat-PEEP was also calculated. Data were analyzed using the Wilcoxon test, with one-tailed significance set at p < 0.1. Results: After 4 weeks, percent eosinophils in BALF was lower in masitinib-treated cats (7 ± 9%) versus controls (30 ± 27%, p = 0.023). BALF TP significantly differed (p = 0.047) between groups, decreasing with masitinib and increasing with placebo. BALF BGA-specific IgE was unaffected by masitinib. Both groups showed an improvement in EC200Raw (masitinib, p = 0.015; control, p = 0.078) but no significant change in PEEP after 4 weeks. Masitinib-treated cats demonstrated decreased Pplat (p = 0.033) and Pplat-PEEP (p = 0.075) at week 4, suggesting an improvement in respiratory compliance. Conclusions: Masitinib reduced BALF eosinophilia and TP, indicating improved airway inflammation and edema, and improved Pplat and Pplat-PEEP, suggesting benefit to respiratory compliance influenced by airway inflammation/edema. Masitinib deserves further study in humans with chronic allergic asthma.

Endotracheal nebulization of N-acetylcysteine increases airway resistance in cats with experimental asthma

N-acetylcysteine (NAC), a mucolytic and antioxidant, is speculated to cause bronchoconstriction in cats when delivered via aerosol. We hypothesized that in cats with experimental asthma, aerosol delivery of NAC (400 mg cumulative dose) via an endotracheal tube would increase airflow limitation as measured by ventilator-acquired mechanics. After endotracheal drug delivery, airway resistance and inspiratory plateau pressure (Pplat) measurements were obtained in six mechanically ventilated asthmatic cats. Results demonstrated significantly increased airway resistance (P=0.0007) compared with aerosolized saline control; Pplats were not significantly different (P=0.059). All cats exhibited at least one adverse effect: excessive airway secretions (n=3), spontaneous cough (n=2), unilateral strabismus (n=1) and post-anesthetic death (n=1). No adverse reactions were noted with saline aerosol; cough was noted in one cat with methacholine challenge. In conclusion, airway resistance and adverse reactions were documented in all cats after NAC aerosol delivery. Further studies must be performed to evaluate if it is an effective mucolytic and/or antioxidant in cats and to determine if bronchodilator pre-treatment will negate NAC-induced bronchoconstriction.

Targeted Combined Aerosol Chemotherapy in Dogs and Radiologic Toxicity Grading

BACKGROUND We investigated whether combination chemotherapy, targeted with the AeroProbe® Intracorporeal Nebulizing Catheter (INC), could be safely administered, and developed a radiologic grading scheme to monitor subclinical effects on the lungs. METHODS In anesthetized and mechanically ventilated healthy dogs (n = 3), we introduced the INC via a flexible bronchoscope into the right caudal lung lobe and administered escalating dosages of gemcitabine (1, 2, 3, or 6 mg/kg) followed by cisplatin (10 mg/m(2)). Treatments were performed every 2 weeks for 4 treatments and dogs were monitored weekly with physical examination, biochemical tests, and thoracic radiographs. Dogs were sacrificed 2 weeks after the final treatment and tissues examined histologically. A radiologic grading scheme was developed to monitor subclinical pulmonary toxicity. RESULTS No significant side effects occurred in any dog. All dogs developed focal pneumonitis radiographically, and chronic, severe pneumonia with fibrosis histologically limited to the treated portion of the lung. Radiologic scores increased over time following increasing doses of chemotherapy. CONCLUSIONS Targeted aerosol delivery of gemcitabine and cisplatin by INC was clinically well tolerated. This minimally invasive method is promising for lung cancer treatment, especially given the lack of clinical toxicity. The proposed radiologic grading scheme provides a method to monitor subclinical local drug toxicity.

Nebulized lidocaine blunts airway hyper-responsiveness in experimental feline asthma

Nebulized lidocaine may be a corticosteroid-sparing drug in human asthmatics, reducing airway resistance and peripheral blood eosinophilia. We hypothesized that inhaled lidocaine would be safe in healthy and experimentally asthmatic cats, diminishing airflow limitation and eosinophilic airway inflammation in the latter population. Healthy (n = 5) and experimentally asthmatic (n = 9) research cats were administered 2 weeks of nebulized lidocaine (2 mg/kg q8h) or placebo (saline) followed by a 2-week washout and crossover to the alternate treatment. Cats were anesthetized to measure the response to inhaled methacholine (MCh) after each treatment. Placebo and doubling doses of methacholine (0.0625–32.0000 mg/ml) were delivered and results were expressed as the concentration of MCh increasing baseline airway resistance by 200% (EC200Raw). Bronchoalveolar lavage was performed after each treatment and eosinophil numbers quantified. Bronchoalveolar lavage fluid (BALF) % eosinophils and EC200Raw within groups after each treatment were compared using a paired t-test (P <0.05 significant). No adverse effects were noted. In healthy cats, lidocaine did not significantly alter BALF eosinophilia or the EC200Raw. There was no difference in %BALF eosinophils in asthmatic cats treated with lidocaine (36±10%) or placebo (33 ± 6%). However, lidocaine increased the EC200Raw compared with placebo 10 ± 2 versus 5 ± 1 mg/ml; P = 0.043). Chronic nebulized lidocaine was well-tolerated in all cats, and lidocaine did not induce airway inflammation or airway hyper-responsiveness in healthy cats. Lidocaine decreased airway response to MCh in asthmatic cats without reducing airway eosinophilia, making it unsuitable for monotherapy. However, lidocaine may serve as a novel adjunctive therapy in feline asthmatics with beneficial effects on airflow obstruction.

Abstract LB-89: A combined epigenetic and genetic biomarker panel for detection of lung cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Lung cancer is the leading cause of cancer-related deaths in human. However, there is no valid screening procedure or test available at the present time. Although National Lung Screening Trial (NLST) demonstrated, for the first time, that low-dose helical CT screening in high-risk population reduced lung cancer mortality by 20%, the procedure is associated with over 95% false positive results (Aberle DR et al. N Engl J Med. 2011, 365:395). A confirmatory test is urgently needed. We have been developing a combined epigenetic and genetic molecular biomarker panel to verify the presence of lung cancer on the blood samples. Methods: Lung cancer cell lines NCI-H69 (small cell carcinoma), NCI-H1299 and NCI-H460 (large cell lung cancer), NCI-H1781 and A549 (adenocarcinoma), NCI- H358 (bronchioalveolar carcinoma) and NCI-H520 (squamous cell carcinoma) were obtained from ATCC (Manassas, VA). Blood samples of patients with lung cancer (n=105) and non-cancer patients were collected at MU Health Care System with an IRB approval. Genomic DNA was extracted from cell lines, mononuclear cell fraction and plasma using QIAamp DNA mini kit and circulating nucleic acid kit (QIAGEN, Valencia, CA), respectively. Isolated DNAs were digested with 4 methylation sensitive restriction enzymes followed by PCR for DNA methylation assay. Genomic DNAs were also subject to allele-specific PCR for PT53, EGFR and BRAF gene mutation assay. All PCR reactions were carried out in an iQ5 Real-time PCR system (Bio-Rad, Hercules, CA). Results: Specific CGI DNA methylation of HOXA7 , HOXA6 and PCDHGA12A was detected in all lung cancer cell lines except NCI-H1299 in HOXA7 . Only NCI-H460 was positive for EGFR L858R mutation. Among patient blood samples, HOXA7 methylation was detectable in 9 out of 105 patient mononuclear cell DNAs, but neither in patient plasma nor in non-cancer patients or normal blood control DNAs. EGFR L858R mutation was detected in only 4 lung cancer patient DNA samples. The sensitivity of HOXA7 DNA methylation assay, determined by serial dilutions of cancer cell DNA into normal DNA, was 0.1%. Conclusion: A combined epigenetic DNA methylation and genetic mutation panel could be utilized for lung cancer detection or verification in patient blood sample. Citation Format: Michael X. Wang, Dan Guo, Mary Andersen, Vamsi Guntur. A combined epigenetic and genetic biomarker panel for detection of lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-89. doi:10.1158/1538-7445.AM2013-LB-89