Inhaled tyrosine kinase inhibitors for pulmonary hypertension: a possible future treatment

Abstract

Georgia Pitsiou,1 Paul Zarogoulidis,1 Dimitris Petridis,2 Ioannis Kioumis,1 Sofia Lampaki,1 John Organtzis,1 Konstantinos Porpodis,1 Antonis Papaiwannou,1 Theodora Tsiouda,3 Wolfgang Hohenforst-Schmidt,4 Stylianos Kakolyris,5 Konstantinos Syrigos,6 Haidong Huang,7 Qiang Li,7 J Francis Turner,8 Konstantinos Zarogoulidis1 1Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, 2Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, 3Internal Medicine Department, Thegenio Anticancer Hospital, Thessaloniki, Greece; 4II Medical Department, Coburg Regional Hospital, Coburg, Germany; 5Oncology Department, Sotiria Hospital of Chest Diseases, University of Athens, Athens, 6Oncology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece; 7Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People’s Republic of China; 8Division of Interventional Pulmonology and Medical Oncology, Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ, USA Abstract: Pulmonary hypertension is a disease with severe consequences for the human body. There are several diseases and situations that induce pulmonary hypertension and are usually underdiagnosed. Treatments include conventional medical therapies and oral, inhaled, intravenous, and subcutaneous options. Depending on its severity, heart or lung transplant may also be an option. A possible novel treatment could be tyrosine kinase inhibitors. We conducted experiments with three jet nebulizers and three ultrasound nebulizers with erlotinib, gefitinib, and imatinib. Different residual cup designs and residual cup loadings were used in order to identify the best combination to produce droplets of less than 5 µm in mass median aerodynamic diameter. We found that gefitinib could not be transformed into a powder, so conversion to an aerosol form was not possible. Our experiments indicated that imatinib is superior to erlotinib with regard to small droplet size formation using both inhaled technologies (1.37 µm <2.23 µm and 1.92 µm <3.11 µm, jet and ultrasound, respectively) and, at jet devices (1.37 µm <1.92 µm). Cup designs C and G contribute best to small droplet creation uniquely supporting and equally well the activity of both drugs. The disadvantage of the large droplets formed for erlotinib was offset when combined with residual cup C (1.37 µm instead of 2.23 µm). At a 2 mL dose, the facemask and cone mouthpieces performed best and evenly; the facemask and low dose were the best choice (2.08 µm and 2.12 µm, respectively). Erlotinib and imatinib can be administered as an aerosols, and further in vivo experimentation is necessary to investigate the positive effects of these drugs in the treatment of pulmonary hypertension. Keywords: erlotinib, gefitinib, imatinib, jet nebulizers, ultrasound nebulizers