Safety and toxicology of cyclosporine in propylene glycol after 9-month aerosol exposure to beagle dogs

Journal of Aerosol Medicine and Pulmonary Drug Delivery

Volumn 24, Issue 4, 2011, Pages 205-212

  Niven, Ralph ^a   Lynch, Maryellen ^b   Moutvic, Ronald ^b   Gibbs, Seth ^b   Briscoe, Crystal ^b   Raff, Howard ^a  

^a APT Pharmaceuticals ^*  (United States)

^b BATTELLE MEMORIAL INSTITUTE   (United States)

Author keywords

aerosol; cyclosporine; inhalation; propylene glycol; toxicity

Indexed keywords

CYCLOSPORIN; PROPYLENE GLYCOL;

AEROSOL; ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; BREAST TUMOR; CHRONIC TOXICITY; CONTROLLED STUDY; CONVALESCENCE; DOG; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG EXPOSURE; DRUG INDUCED DISEASE; DRUG MEGADOSE; DRUG SAFETY; DRUG TISSUE LEVEL; FEMALE; FIBROADENOMA; IMMUNOSUPPRESSIVE TREATMENT; LOW DRUG DOSE; LUNG MINUTE VOLUME; MALE; MAXIMUM PLASMA CONCENTRATION; MEAN RESIDENCE TIME; NEBULIZER; NONHUMAN; PARTICLE SIZE; SALIVATION DISORDER; TIME TO MAXIMUM PLASMA CONCENTRATION; TOXICOKINETICS; TOXICOLOGY; TREATMENT DURATION;

ADMINISTRATION, INHALATION; ADMINISTRATION, INTRANASAL; AEROSOLS; ANIMALS; CYCLOSPORINE; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; IMMUNOSUPPRESSIVE AGENTS; MALE; PROPYLENE GLYCOL; SIALORRHEA;

EID: 79961093474     PISSN: 19412711     EISSN: 19412703     Source Type: Journal    
DOI: 10.1089/jamp.2010.0863     Document Type: Article

References (38)

1. Kahan BD: Forty years of publication of transplantation proceedings-the second decade: the cyclosporine revolution. Transplant Proc. 2009;41:1423-1437.
2. The 2008 OPTN/SRTR Annual Report: Transplant Data 1998-2007; 2008.
3. Al-Githmi I, Batawil N, Shigemura N, Hsin M, Lee TW, He GW, and Yim A: Bronchiolitis obliterans following lung transplantation. Eur J Cardiothorac Surg. 2006;30:846-851. (Pubitemid 44755355)
4. Boehler A, and Estenne M: Post-transplant bronchiolitis obliterans. Eur Respir J. 2003;22:1007-1018. (Pubitemid 37540657)
5. Grossman EJ, and Shilling RA: Bronchiolitis obliterans in lung transplantation: the good, the bad, and the future. Transl Res. 2009;153:153-165.
6. Jaramillo A, Fernandez FG, Kuo EY,Trulock EP, Patterson GA, and Mohanakumar T: Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation. Pediatr Transplant. 2005;9:84-93. (Pubitemid 40238970)
7. Smith-Seiler DA, and Iacono AT: Obliterative bronchiolitis in the lung transplant recipient. A powerful foe. Adv Nurse Pract. 2004;12:69-74.
8. Rezzani R: Cyclosporine A and adverse effects on organs: histochemical studies. Prog Histochem Cytochem. 2004;39: 85-128. (Pubitemid 38902918)
9. Dowling RD, Zenati M, Burckart GJ, Yousem SA, Schaper M, Simmons RL, Hardesty RL, and Griffith BP: Aerosolized cyclosporine as single-agent immunotherapy in canine lung allografts. Surgery. 1990;108:198-204; discussion 204-195.
10. Keenan RJ, Duncan AJ, Yousem SA, Zenati M, Schaper M, Dowling RD, Alarie Y, Burckart GJ, and Griffith BP: Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation. Transplantation. 1992;53:20-25.
11. Mitruka SN, Pham SM, Zeevi A, Li S, Cai J, Burckart GJ, Yousem SA, Keenan RJ, and Griffith BP: Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation. J Thorac Cardiovasc Surg. 1998;115:28-36; discussion 36-27.
12. Mitruka SN, Won A, McCurry KR, Zeevi A, McKaveney T, Venkataramanan R, Iacono A, Griffith BP, and Burckart GJ: In the lung aerosol cyclosporine provides a regional concentration advantage over intramuscular cyclosporine. J Heart Lung Transplant. 2000;19:969-975.
13. Muggenburg BA, Hoover MD, Griffith BP, Haley PJ, Snipes MB, Wolff RK, Yeh HC, Burckart GJ, and Mauderly JL: Administration of cyclosporine by inhalation: a feasibility study in beagle dogs. J Aerosol Med. 1990;3:1-13.
14. Zenati M, Duncan AJ, Burckart GJ, Schaper M, Yousem SA, Griffith BP, and Casarotto D: Immunosuppression with aerosolized cyclosporine for prevention of lung rejection in a rat model. Eur J Cardiothorac Surg. 1991;5:266-271; discussion 272.
15. Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, Fung JJ, Burckart GJ, McCurry KR, and Griffith BP: A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med. 2006;354:141-150. (Pubitemid 43076711)
16. Iacono AT, Keenan RJ, Duncan SR, Smaldone GC, Dauber JH, Paradis IL, Ohori NP, Grgurich WF, Burckart GJ, Zeevi A, Delgado E, O'Riordan TG, Zendarsky MM, Yousem SA, and Griffith BP: Aerosolized cyclosporine in lung recipients with refractory chronic rejection. Am J Respir Crit Care Med. 1996;153:1451-1455. (Pubitemid 26112616)
17. Iacono AT, Smaldone GC, Keenan RJ, Diot P, Dauber JH, Zeevi A, Burckart GJ, and Griffith BP: Dose-related reversal of acute lung rejection by aerosolized cyclosporine. Am J Respir Crit Care Med. 1997;155:1690-1698. (Pubitemid 27216679)
18. Keenan RJ, Iacono A, Dauber JH, Zeevi A, Yousem SA, Ohori NP, Burckart GJ, Kawai A, Smaldone GC, and Griffith BP: Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients. J Thorac Cardiovasc Surg. 1997;113:335-340; discussion 340-331.
19. Wang T, Noonberg S, Steigerwalt R, Lynch M, Kovelesky RA, Rodriguez CA, Sprugel K, and Turner N: Preclinical safety evaluation of inhaled cyclosporine in propylene glycol. J Aerosol Med. 2007;20:417-428.
20. Bide RW, Armour SJ, and Yee E: Allometric respiration/body mass data for animals to be used for estimates of inhalation toxicity to young adult humans. J Appl Toxicol. 2000;20:273-290. (Pubitemid 30601407)
21. Cuddihy RG, BrownStein DG, Raabe OG, and Kanapilly GM: Respiratory tract deposition of inhaled polydisperse aerosols in beagle dogs. J Aerosol Sci. 1973;4:35-45.
22. Burckart GJ, Smaldone GC, Eldon MA, Venkataramanan R, Dauber J, Zeevi A, McCurry K, McKaveney TP, Corcoran TE, Griffith BP, and Iacono AT: Lung deposition and pharmacokinetics of cyclosporine after aerosolization in lung transplant patients. Pharm Res. 2003;20:252-256. (Pubitemid 36269732)
23. Niven RW, and Corcoran T: Impact of pharmacokinetics on the anticipated duration of calcineurin inhibition after inhalation of cyclosporine solution. J Heart Lung Transplant. 2010;29:S140.
24. Wieslander G, Norback D, and Lindgren T: Experimental exposure to propylene glycol mist in aviation emergency training: acute ocular and respiratory effects. Occup Environ Med. 2001;58:649-655. (Pubitemid 32881043)
25. Suber RL, Deskin R, Nikiforov I, Fouillet X, and Coggins CR: Subchronic nose-only inhalation study of propylene glycol in Sprague-Dawley rats. Food Chem Toxicol. 1989;27: 573-583. (Pubitemid 19270915)
26. Venitz J, and Werley MS: Systemic and Pulmonary Pharmacokinetics of Propylene Glycol (PG) after Inhalation of a Condensation Aerosol in Rats for 28 Days. Richmond, VA: Virginia Commonwealth University; 2003.
27. Montharu J, Le Guellec S, Kittel B, Rabemampianina Y, Guillemain J, Gauthier F, Diot P, and de Monte M: Evaluation of lung tolerance of ethanol, propylene glycol, and sorbitan monooleate as solvents in medical aerosols. J Aerosol Med Pulm Drug Deliv. 2010;23:41-46.
28. Ruddick JA: Toxicology, metabolism, and biochemistry of 1,2-propanediol. Toxicol Appl Pharmacol. 1972;21:102-111.
29. Bond JA: Metabolism and elimination of inhaled drugs and airborne chemicals from the lungs. Pharmacol Toxicol. 1993;72(Suppl 3):36-47. (Pubitemid 23226247)
30. Krimer PM, Harvey SB, Blas-Machado U, Lauderdale JD, and Moore PA: Reversible fibroadenomatous mammary hyperplasia in male and female New Zealand white rabbits associated with cyclosporine A administration. Vet Pathol. 2009;46:1144-1148.
31. Petraitiene R, Petraitis V, Bacher J, Das SR, Parlow AF, and Walsh TJ: Cyclosporine A-induced mammary hyperplasia and hyperprolactinemia in New Zealand White rabbits. Comp Med. 2001;51:430-435. (Pubitemid 33097864)
32. Binokay F, Balal M, Demir E, Paydas S, Soyupak S, Sertdemir Y, and Akgul E: Risk of developing fibroadenoma with the use of cyclosporine A in renal transplant recipients. Ren Fail. 2005;27:721-725. (Pubitemid 41748125)
33. Seo YL, Choi CS, Yoon DY, Yun EJ, Lee YJ, Park SJ, Moon JH, Cho SJ, Lee S, Han H, Kim SS, and Lee JY: Benign breast diseases associated with cyclosporine therapy in renal transplant recipients. Transplant Proc. 2005;37:4315-4319. (Pubitemid 43016019)
34. Sangalli L, Bortolotti A, Jiritano L, and Bonati M: Cyclosporine pharmacokinetics in rats and interspecies comparison in dogs, rabbits, rats, and humans. Drug Metab Dispos. 1988;16:749-753.
35. Batiuk TD, Urmson J, Vincent D, Yatscoff RW, and Halloran PF: Quantitating immunosuppression. Estimating the 50% inhibitory concentration for in vivo cyclosporine in mice. Transplantation. 1996;61:1618-1624. (Pubitemid 26190904)
36. Halloran PF, Helms LM, Kung L, and Noujaim J: The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation. 1999;68:1356-1361.
37. Mogayzel PJ Jr, and Wagner TL: Cyclosporin and tacrolimus do not potentiate oxidative damage in pulmonary epithelial cells. Transpl Int. 2003;16:709-712. (Pubitemid 37408590)
38. Neuringer IP, Sloan J, Budd S, Chalermskulrat W, Park RC, Stonebraker JR, O'Neal WK, Aris RM, and Randell SH: Calcineurin inhibitor effects on growth and phenotype of human airway epithelial cells in vitro. Am J Transplant. 2005;5:2660-2670.