4 June 2015
Insulin signaling is impaired in Alzheimer’s disease [1]. In the SNIFF Trial, Claxton et al. have reported that long-acting intranasal insulin Detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease [2]. Adverse effects included mild rhinitis. In an earlier publication, Craft et al. note 8.3% nosebleeds and 16.7% rhinitis with a 20 IU intranasal insulin dose [3]. The SNIFF trial has been “temporarily suspended” (http://www.nia.nih.gov/alzheimers/clinical-trials/study-nasal-insulin-fi...). Insulin glulisine (Apidra) failed to have an acute impact on cognition in APOE4 carriers with mild-moderate Alzheimer’s disease, but other intranasal insulin preparations were also ineffective in ApoE4 carriers [4,5].
Off the shelf injectable insulins, such as Detemir, Humalog, Apidra, etc., contain various excipients that may be responsible for rhinitis, nosebleeds, and allergic reactions [6]. Chief among these are cresol, meta-cresol, and phenol. These three compounds are added to injectable insulin to stabilize it and extend its shelf life. But their potential for causing severe allergic reactions is well documented [7].
Zinc, another component of Detemir and Humalog but not Apidra, has less potential for harm. Zinc is added to insulin preparations to prolong their action by causing the insulin monomers to form hexamers.
Zicam, a homeopathic nasal gel for the common cold containing 33 mM zinc, was ineffective [8] and was associated with anosmia [9]. However, the concentration of zinc in Detemir is 1 mM, or 3% of the zinc concentration in Zicam. Moreover, there were no reports of anosmia as an adverse effect in the SNIFF study.
In sum, an intranasal insulin preparation containing no cresol, metacresol, or phenol might be a better formulation for treatment of Alzheimer’s disease than regular injectable insulins.
Steven Lehrer, MD, Fermata Pharma Inc., 30 West 60th Street, New York, NY 10023, USA. E-mail: steven@fermatapharma.com
Disclosure: Dr. Lehrer has filed a patent application on the use of preservative-free nasal insulin for the treatment of Alzheimer’s disease.
References:
[1] Candeias E, Duarte AI, Carvalho C, Correia SC, Cardoso S, Santos RX, Placido AI, Perry G, Moreira PI (2012) The impairment of insulin signaling in Alzheimer's disease. IUBMB Life 64, 951-957.
[2] Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S (2015) Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis 44, 897-906.
[3] Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69, 29-38.
[4] Rosenbloom MH, Barclay TR, Pyle M, Owens BL, Cagan AB, Anderson CP, Frey WH, Hanson LR (2014) A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease. CNS Drugs 28, 1185-1189.
[5] Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S (2006) Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 27, 451-458.
[6] Ghazavi MK, Johnston GA (2011) Insulin allergy. Clin Dermatol 29, 300-305.
[7] Rajpar SF, Foulds IS, Abdullah A, Maheshwari M (2006) Severe adverse cutaneous reaction to insulin due to cresol sensitivity. Contact Dermatitis 55, 119-120.
[8] Turner RB (2001) Ineffectiveness of intranasal zinc gluconate for prevention of experimental rhinovirus colds. Clin Infect Dis 33, 1865-1870.
[9] D'Cruze H, Arroll B, Kenealy T (2009) Is intranasal zinc effective and safe for the common cold? A systematic review and meta-analysis. J Prim Health Care 1, 134-139.
