Long-Term Nonclinical Pulmonary Safety Assessment of Afrezza, a Novel Insulin Inhalation Powder

2020 ◽  
pp. 019262332096042
Author(s):  
Stephanie F. Greene ◽  
Kristen J. Nikula ◽  
Dominic Poulin ◽  
Kevin McInally ◽  
Jack A. Reynolds
Keyword(s):  
Nuclear Antigen ◽  
Cell Hyperplasia ◽  
Mucus Cell ◽  
Carcinogenicity Study ◽  
Inhaled Insulin ◽  
Carcinogenic Potential ◽  
Safety Studies ◽  
Proliferating Cell ◽  
Microscopic Findings

Afrezza delivers inhaled insulin using the Gen2 inhaler for the treatment of patients with type 1 and type 2 Diabetes. Afrezza was evaluated in long-term nonclinical pulmonary safety studies in 2 toxicology species. Chronic inhalation toxicology studies in rat (26 weeks) and dog (39 weeks) and an inhalation carcinogenicity study in rats were conducted with Technosphere insulin (Afrezza) and with Technosphere alone as a vehicle control. Respiratory tract tissues were evaluated by histopathology and cells expressing proliferating cell nuclear antigen (PCNA) were quantified in lungs of rats. Microscopic findings in rats exposed to Afrezza were attributed to the Technosphere particle component, were confined to nasal epithelia, and consisted of eosinophilic globules and nasal epithelial degeneration. There were no Afrezza-related changes in pulmonary PCNA labeling indices in alveoli, large bronchioles, or terminal bronchioles. Microscopic findings in rats exposed to Technosphere particles included eosinophilic globules, mucus cell hyperplasia, and epithelial degeneration in the nasal cavities. PCNA labeling indices were increased in large bronchioles and terminal bronchioles but not in alveoli. There were no Technosphere particle-related findings in the dog study. Afrezza did not exhibit carcinogenic potential in the 2-year study in rats. These nonclinical inhalation studies support the use of Afrezza in humans over extended periods.

scholarly journals Parathyroid Gland Carcinoma in a Wistar Rat

2003 ◽  
Vol 40 (2) ◽  
pp. 203-206 ◽  
Author(s):  
V. Pace ◽  
S. Scarsella ◽  
E. Perentes
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Proliferative Activity ◽  
Wistar Rat ◽  
Anaplastic Carcinoma ◽  
Nuclear Antigen ◽  
Ki 67 ◽  
Carcinogenicity Study ◽  
Thyroid Transcription Factor ◽  
Gland Carcinoma ◽  
Proliferating Cell

An anaplastic carcinoma was found in one of the two parathyroids of a 2-year-old male Wistar rat, which was sacrificed at the end of a carcinogenicity study. Morphologically, it was characterized by the presence of nodular areas of pleomorphic and dense cells with numerous atypical mitoses and large regions of smaller and dark monomorphic cells devoid of mitoses and forming small cystic spaces. Local invasion of the capsule and pronounced compression of the parenchyma of the thyroid gland were observed. Immunohistochemically, the tumor was markedly positive for the parathyroid hormone and negative for the thyroid transcription factor. The proliferative activity was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67, and the proliferating cell nuclear antigen. The diagnosis of carcinoma of the parathyroid was made on the basis of microscopic and immunohistochemical findings.

scholarly journals Effect of long-term glucocorticoid treatment on oestradiol-induced proliferation in the uterus of ovariectomized rats

1998 ◽  
Vol 157 (3) ◽  
pp. 481-488 ◽  
Author(s):  
AG Gunin
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Term Treatment ◽  
Labelling Index ◽  
Ovariectomized Rats ◽  
Nuclear Antigen ◽  
Glucocorticoid Treatment ◽  
Initial Reduction ◽  
Long Term Treatment ◽  
Proliferating Cell

The aim of this study was to examine the effect of long-term treatment with glucocorticoids on the uterine response to oestradiol. Ovariectomized rats were treated with crystal triamcinolone acetonide (0.1 mg/100 g, i.m.) or saline (0.1 ml/100 g i.m.) for 29 days. Over this period five injections were administered, one per week. On the second day after the last triamcinolone injection, rats were treated with a single injection of oestradiol dipropionate (5 micrograms/100 g, s.c.) or vehicle (olive oil, 0.1 ml/100 g, s.c.). The effects of oestradiol in the uterus were determined by measuring mitotic index, bromodeoxyuridine (BrdU)-labelling index (BrdU was injected 2 h before the rats were killed; 2 mg/100 g, i.p.), and proliferating cell nuclear antigen (PCNA)-labelling index 24, 36 and 48 h after the injection of oestradiol or vehicle. Long-term treatment with glucocorticoids resulted in dissimilar changes in oestradiol-induced proliferation in epithelial and connective-tissue (stroma) components of the uterus. In luminal and glandular epithelia, there was an initial reduction in proliferation at 24 h, followed by an increase at 36 h and a further reduction at 48 h after the oestradiol injection. In stromal cells of the endometrium, triamcinolone treatment caused a large constant increase in oestradiol-induced proliferation throughout the experiment. The glucocorticoid treatment had no effect on the parameters without oestradiol administration.

Adrenocortical Ultrastructure in Ectopic Acth Syndrome

1976 ◽  
Vol 34 ◽  
pp. 238-239
Author(s):  
K. Kovacs ◽  
E. Horvath ◽  
W. Singer
Keyword(s):  
Adrenal Cortex ◽  
Zona Glomerulosa ◽  
Ectopic Acth Syndrome ◽  
Pituitary Neoplasms ◽  
Electron Microscopic ◽  
Adrenocortical Cells ◽  
Cell Hyperplasia ◽  
Ectopic Acth ◽  
Ectopic Acth Production ◽  
Microscopic Findings

Secretion of ACTH by non-pituitary neoplasms is recognized with increasing frequency. While the clinical and biochemical changes associated with ectopic ACTH production have been extensively studied recently, relatively little attention was focused on the morphology of the adrenal cortex and, to our knowledge, the fine structure of the adrenocortical cells in cases of ectopic ACTH syndrome has not been described so far. We report here the electron microscopic findings in the adrenal cortex of a 50-year-old man with a pancreatic apudoma. The patient showed the characteristic clinical and biochemical features of ectopic ACTH syndrome and because of extensive hypercorticism, underwent bilateral adrenalectomy.By light microscopy, the adrenal cortices showed extensive compact cell hyperplasia and lipid depletion. The zona glomerulosa was present in small foci and, except for a few places, fasciculata cells were noted under the fibrous capsule.

scholarly journals Proliferating cell nuclear antigen antibody testing – getting them all

Pathology ◽  
2021 ◽  
Vol 53 ◽  
pp. S47
Author(s):  
Christine Bundell ◽  
Mathew Krummenacher ◽  
Elina Tan ◽  
Paul Sjollema ◽  
Nick Acquarola ◽  
...  
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Antibody Testing ◽  
Antigen Antibody ◽  
Proliferating Cell
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