26502880 A novel nasal powder formulation of glucagon: toxicology studies in animal models. - Evidence Based Medicine on FHIR Implementation Guide v2.0.0-ballot

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Example Citation: 26502880 A novel nasal powder formulation of glucagon: toxicology studies in animal models.

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url: Citation 26502880 A novel nasal powder formulation of glucagon: toxicology studies in animal models.

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title: 26502880 A novel nasal powder formulation of glucagon: toxicology studies in animal models.

status: Active

date: 2024-11-01 10:20:00+0000

publisher: HL7 International / Clinical Decision Support

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identifier: https://pubmed.ncbi.nlm.nih.gov/26502880, https://www.ncbi.nlm.nih.gov/pmc//PMC4621930, https://doi.org/10.1186/s40360-015-0026-9, pii/10.1186/s40360-015-0026-9
Titles
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* Primary title English
A novel nasal powder formulation of glucagon: toxicology studies in animal models.

Abstracts
- Text
*
BACKGROUND: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models. METHODS: The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits. RESULTS: There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included ≥1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading. <AbstractText Label="DISCUSSION" NlmCategory="CONCLUSIONS">The studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes. CONCLUSION: This novel drug product is well tolerated in animal models.

relatesTo
type: cites
classifier: Journal Article
citation:
Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II Diabetes. Diabetologia. 2002;45:937–48. doi: 10.1007/s00125-002-0822-9.

Documents
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* https://pubmed.ncbi.nlm.nih.gov/12136392/
resourceReference: Identifier: https://pubmed.ncbi.nlm.nih.gov/12136392
relatesTo
type: cites
citation:
Deary IJ. Symptoms of hypoglycaemia and effects on mental performance and emotions. In: Frier BM, Fisher M, editors. Hypoglycaemia in clinical diabetes. 2. Chicester, West Sussex, England: John Wiley & Sons Limited; 2007. pp. 25–48.

relatesTo
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classifier: Journal Article
citation:
Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26:1902–12. doi: 10.2337/diacare.26.6.1902.

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classifier: Journal Article
citation:
Leckie AM, Graham MK, Grant JB, Ritchie PJ, Frier BM. Frequency, severity, and morbidity of hypoglycemia occurring in the workplace in people with insulin-treated diabetes. Diabetes Care. 2005;28:1333–8. doi: 10.2337/diacare.28.6.1333.

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Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care. 2005;28:2948–61. doi: 10.2337/diacare.28.12.2948.

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type: cites
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citation:
UK Hypoglycemia Study Group Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50:1140–7. doi: 10.1007/s00125-007-0599-y.

Documents
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citation:
Cryer PE. Hypoglycemia in diabetes: pathophysiology, prevalence, and prevention. Alexandria, VA: American Diabetes Association; 2009. The clinical problem of hypoglycemia in diabetes; pp. 1–15.

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classifier: Journal Article
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American Diabetes Association Standards of medical care in diabetes—2015. Diabetes Care. 2015;38(suppl 1):S1–94.

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Jain MK. Introduction to biological membranes. New York: John Wiley & Sons; 1988. Components of biological membranes; pp. 10–50.

relatesTo
type: cites
citation:
GLUCACON (glucagon for injection, rDNA origin) Product Monograph. Toronto, Ontario: Eli Lilly Canada Inc.; 2012 http://www.lilly.ca/en/pdf/product-monograph/04_rglucagon-pm_9july2012.pdf. Accessed 26 September 2015.

relatesTo
type: cites
citation:
GLUCAGEN® and GLUCAGEN® Hypokit 1 mg (glucagon) Product Monograph. Mississauga, Ontario: Novo Nordisk Canada Inc.; 2014. http://www.paladin-labs.com/our_products/PM_GlucaGen_EN.pdf. Accessed 26 September 2015.

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type: cites
classifier: Journal Article
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resourceReference: Identifier: https://pubmed.ncbi.nlm.nih.gov/13167121
relatesTo
type: cites
classifier: Journal Article
citation:
Eistrup C, Hjortkjaer RK, Pickersgill N, Virgo DM, Woolley AP. Glucagon produced by recombinant DNA technology: repeated dose toxicity studies, intravenous administration to CD rats and beagle dogs for four weeks. Pharmacol Toxicol. 1993;73:103–8. doi: 10.1111/j.1600-0773.1993.tb01544.x.

Documents
- Url
* https://pubmed.ncbi.nlm.nih.gov/8248004/
resourceReference: Identifier: https://pubmed.ncbi.nlm.nih.gov/8248004
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type: cites
classifier: Journal Article
citation:
Merkus FW, Verhoef JC, Marttin E, Romeijn SG, van der Kuy PH, Hermens WA, et al. Cyclodextrins in nasal drug delivery. Adv Drug Deliv Rev. 1999;36:41–57. doi: 10.1016/S0169-409X(98)00054-4.

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- Url
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Documents
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* https://pubmed.ncbi.nlm.nih.gov/12270606/
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title: BMC pharmacology & toxicology
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articleDate: 2015-10-26
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