Safety and Toxicology of Cyclosporine in Propylene Glycol after 9-Month Aerosol Exposure to Beagle Dogs

Niven, Ralph W.; Lynch, Maryellen; Moutvic, Ronald R.; Gibbs, Seth; Briscoe, Crystal M; Raff, H.

doi:10.1089/jamp.2010.0863

Cited by 13 publications

(8 citation statements)

References 32 publications

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“…Finally, the results of this investigation report only a minor short-term effect of ECIG-generated aerosol on MTV using an ex-vivo system. Aerosolized propylene glycol in intact live animals, as reported by Niven et al ( 2011 ) in Beagle dogs and Suber et al ( 1989 ) in Sprague Dawley rats, are known to have long-term effects on respiratory epithelium, to include histological alterations, dehydration of airways, and nasal hemorrhaging, all of which could affect mucociliary clearance more drastically over time.…”

Section: Discussionmentioning

confidence: 94%

“…They reason that ECIG-generated aerosol has a higher hygroscopic growth rate than does conventional cigarette smoke, thus accounting for the increased droplet size and increased lung deposition. Aerosolized propylene glycol, the main component of the E-liquid used in the present investigation, is hygroscopic (Niven et al, 2011 ). Analysis of aerosol and smoke dynamics within exposure chambers (as used in our study) is simple by comparison to analysis of aerosol and smoke dynamics within intact respiratory airways.…”

Section: Discussionmentioning

confidence: 99%

“…They speculate that dehydration, brought about by long-term exposure to propylene glycol, is responsible for hemorrhaging of the nasal cavity along with subsequent histological changes. Dehydration of the respiratory airways due to the hygroscopic nature of aerosolized propylene glycol, could also explain the compensatory salivation observed in Beagle dogs exposed to long-term inhalation of aerosolized propylene glycol (Niven et al, 2011 ). On the other hand, Fain et al ( 2015 ) demonstrate that exposure of cultured Calu-3 airway epithelial cells to both aerosolized and unaerosolized vegetable glycerin (another major component of E-liquid) inhibit CFTR-dependent ion transport.…”

Section: Discussionmentioning

confidence: 99%

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The Effects of Electronic Cigarette (ECIG)-Generated Aerosol and Conventional Cigarette Smoke on the Mucociliary Transport Velocity (MTV) Using the Bullfrog (R. catesbiana) Palate Paradigm

et al. 2017

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Background: While ECIGs are under scrutiny concerning safety, particularly in reference to the physiological impact that aerosolized ECIG liquid (E-liquid) may have on respiratory tissues, others believe that ECIGs are a “Harm Reduction” alternative to conventional cigarettes. Previous studies investigating ciliated respiratory epithelium indicate that smoking shortens cilia length, reduces cilia beat frequency and disrupts respiratory epithelium, which most likely contributes to the inhibition of mucocilliary clearance. Monitoring mucous clearance of respiratory tissues exposed to ECIG-generated aerosol or conventional cigarette smoke, as indexed by mucous transport velocity (MTV), is one way to gauge the impact aerosol and smoke have on the respiratory tract. Therefore, we designed an experiment to test the effect of ECIG-generated aerosol and smoke on MTV using the frog palate paradigm.Methods: Peristaltic pumps transport ECIG-generated aerosol and conventional cigarette smoke into custom-made chambers containing excised bullfrog palates. MTVs were determined before exposure, immediately after exposure and approximately 1 day following exposure. MTVs were also determined (at the same time points) for palates exposed to air (control). Surface and cross sectional SEM images of palates from all three groups were obtained to support MTV data.Results: The results indicate that ECIG-generated aerosol has a modest inhibitory effect (p < 0.05) on MTV 1 day post-exposure (0.09 ± 0.01) compared to control MTV (0.16 ± 0.03 mm/s). In contrast, smoke completely inhibits MTV from 0.14 ± 0.03 mm/s immediately before exposure to 0.00 mm/sec immediately after exposure and the MTV is unable to recover 1 day later. SEM images of control palates and palates exposed to ECIG-generated aerosol both show cilia throughout their epithelial surface, while some areas of palates exposed to smoke are completely devoid of cilia. Additionally, the epithelial thickness of aerosol-exposed palates appears thicker than control palates while smoke-exposed palates appear to be thinner due to epithelial disruption.Conclusions: These results indicate that ECIG-generated aerosol has only a modest effect on mucocilary clearance of bullfrog palates and aerosol sedimentation accounts for epithelial thickening. In accordance with the primary literature, conventional cigarette smoke dramatically inhibits mucociliary clearance and is, in part, due to decreased number of cilia and disruption of the smoke-exposed epithelium.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Effects of Electronic Cigarette (ECIG)-Generated Aerosol and Conventional Cigarette Smoke on the Mucociliary Transport Velocity (MTV) Using the Bullfrog (R. catesbiana) Palate Paradigm

et al. 2017

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“…Spontaneous regression is usually observed after luteolysis, ovariectomy [ 27 ] or anti-gestagenic treatment [ 28 ]. Although the lesion is assumed to occur only in cats, fibro-epithelial tumors with stromal proliferation and similar morphologic features have been reported in mammary glands of bitches exposed to aerosolized cyclosporine [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoluteoidism in a dog associated with recurrent mammary fibroadenoma stimulated by progestin therapy

et al. 2017

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BackgroundHypoluteoidism in the bitch is characterized by insufficient production and secretion of progesterone by the corpora lutea. It is a rare pathologic condition and during pregnancy, it leads to embryonic resorption or fetal abortion. Supplementary therapy with progestins is indicated during pregnancy to obtain delivery of vital puppies but unwarranted side effects of such treatment are poorly documented.Case presentationA 4-year-old, nulliparous, female Istrian Shorthaired Hound dog had been mated repeatedly in six heats with different dogs of proven fertility but signs of pregnancy did not develop. Estrous cycles, mating and pregnancies were monitored as hypoluteoidism or genital disease was suspected. During the first monitored estrus, the bitch was mated and on day 18 [day 0, day of estimated peak of luteinizing hormone (LH)], ultrasound examination showed three amniotic vesicles that were however found to be resorbed between day 20 and 23. Progesterone concentrations, measured by ELISA, were >8 ng/mL until day 12 and 1–2.5 ng/mL on days 20, 23 and 26. Primary hypoluteoidism was therefore suspected. In the second monitored estrus, the bitch was mated and during pregnancy, progesterone concentrations were >8 ng/mL until day 17 and 1–2.5 ng/mL on day 19. On days 20 and 22, two out of three embryonic vesicles had been resorbed. The bitch was treated with progesterone in oil from day 19 to day 58. Increase in the size of 2nd left thoracic mammary gland (T2-L) was observed and on day 46, ultrasound evaluation and biopsy were performed revealing a low-cellularity fibroadenoma. Parturition started spontaneously at day 65 but due to dystocia caused by fetal macrosomia, a Caesarean section was performed. During the next (third) monitored estrus, the bitch was bred again and during pregnancy, early decrease in progesterone concentration confirmed the diagnosis of primary hypoluteoidism. The bitch was treated with synthetic progestin (altrenogest) from day 8 to day 57. Five amniotic vesicles were detected by ultrasonography. Recurrence of swelling of T2-L was observed. On day 60, the bitch whelped five pups, two males and three females. As reported later by the owner, the latter did not show any sign of heat over the past 3 years. In one of them, clitoral hypertrophy and a blind ending vagina were diagnosed.ConclusionsThis is the first description of early hypoluteoidism in a pregnant bitch developing a mammary fibroadenoma under progestin treatment.

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“…CIS is a propylene glycol suspension that had been demonstrated pre-clinically to be safe, with favorable pharmacokinetics, in dogs and rats. 49, 50 Building on this, CIS entered Phase III trials, but failed to show efficacy in disease free survival or overall mortality. 51, 52 However, that trial did produce valuable information, including the finding that this aerosolized mechanism of delivery can produce high percentages of pulmonary delivery, and substantially lower systemic levels of cyclosporine than oral administration.…”

Section: Introductionmentioning

confidence: 99%

Nanotechnological Approaches to Immunosuppression and Tolerance Induction

et al. 2017

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Purpose of review Several preclinical studies have engineered nanoparticles for immune regulation, and have shown promising results in the fields of autoimmunity and cancer. In solid organ transplantation, the use of nanoparticle-based immune regulation has only just begun to emerge but holds significant promise for the improvement of our current standard of care immunosuppressive regimens. In this review, we will shed light on the current status of nanoparticle-engineered immunotherapeutics, and the potential application of these technologies to the field of organ transplantation. Further we discuss different strategies for delivery and potential cellular targeting moieties that could be utilized to obviate the need for high dose systemic immunosuppressive regimens. Recent Findings Recent studies have shown the potential of immunosuppressive laden nanoparticles to increase bioavailability, drug release, and specifically target immune cell compartments as methods to provide recipient immunosuppressive sparing strategies. Summary Nanoparticle centered immunosuppressive strategies hold the potential to usher in a new era in transplant recipient management and could hold the key to minimizing off-target effects of immunosuppressants, along with prolonging transplant survival.

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Safety and Toxicology of Cyclosporine in Propylene Glycol after 9-Month Aerosol Exposure to Beagle Dogs

Abstract: The study supports the pulmonary and systemic safety of aerosolized CIS at expected lung dose levels/kg of up to 12 times greater than the average dose patients are receiving in the CYCLIST trial.

Cited by 13 publications

References 32 publications

The Effects of Electronic Cigarette (ECIG)-Generated Aerosol and Conventional Cigarette Smoke on the Mucociliary Transport Velocity (MTV) Using the Bullfrog (R. catesbiana) Palate Paradigm

The Effects of Electronic Cigarette (ECIG)-Generated Aerosol and Conventional Cigarette Smoke on the Mucociliary Transport Velocity (MTV) Using the Bullfrog (R. catesbiana) Palate Paradigm

Hypoluteoidism in a dog associated with recurrent mammary fibroadenoma stimulated by progestin therapy

Nanotechnological Approaches to Immunosuppression and Tolerance Induction

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