Intranasal Glucagon for the treatment of hypoglycemia - abstracted references:
(1988). "Intranasal glucagon for hypoglycaemia [letter]." Lancet 2(8604): 216-7.
Carstens, S. and I. Andersen (1994). "[Intranasal glucagon in the treatment of hypoglycemia. A therapeutic possibility in the future]." Ugeskr Laeger 156(30): 4339-42.
Nearly 10% of IDDM patients receiving conventional insulin treatment and about three times as many in intensive insulin therapy yearly experience severe hypoglycaemia (requiring external assistance) The conventional treatment of severe hypoglycaemia is glucagon given intramuscularly by a relative or glucose administered intravenously by a physician. These are however not optimal treatments. Obtaining intravenous access requires a medical doctor and glucagon injection is not always properly done by family members. Glucagon administered intranasally has been proven to raise blood glucose levels in volunteers. The effect of intranasal glucagon on blood glucose is similar to that seen after intramuscular administration for the first 15 minutes following administration. However, intranasal glucagon seems more physiological in that is stabilizes blood glucose concentrations at nearfasting levels, whereas glucagon given intramuscularly tends to give hyperglycaemia. Intranasal glucagon is easy to administer, and can thus prevent serious hypoglycaemic crises and thereby make diabetics and their families more secure.
Freychet, L., S. W. Rizkalla, et al. (1988). "Effect of intranasal glucagon on blood glucose levels in healthy subjects and hypoglycaemic patients with insulin-dependent diabetes." Lancet 1(8599): 1364-6.
Glucagon in solution with a surfactant (deoxycholic acid 1% w/v) was administered by intranasal spray to 6 healthy fasting subjects and 6 insulin-dependent diabetics with insulin-induced hypoglycaemia. In the normal subjects, intranasal glucagon increased plasma glucose levels, with a dose-response effect. In the diabetic patients, plasma glucose levels showed a mean increase of 100% above nadir values in approximately 26 min in response to 7.5 mg intranasal glucagon; hypoglycaemic symptoms were relieved within about 7 min. These results suggest that intranasal glucagon is effective and may represent an alternative to parenteral glucagon or glucose or to oral sugar as the first-line treatment of hypoglycaemic episodes in insulin-dependent diabetics.
Hvidberg, A., R. Djurup, et al. (1994). "Glucose recovery after intranasal glucagon during hypoglycaemia in man." Eur J Clin Pharmacol 46(1): 15-7.
We compared the hyperglycaemic effect of intranasal and intramuscular (i.m.) administration of glucagon after insulin-induced hypoglycaemia. Twelve healthy subjects were examined twice, receiving on both occasions an intravenous insulin bolus. Somatostatin and propranolol were administered to block endogenous glucose counterregulation, and glucose turnover was estimated by a 3-[3H]-glucose infusion. When hypoglycaemia was reached, the subjects received either i.m. glucagon of pancreatic extraction (1 mg) or intranasal genetically engineered glucagon (2 mg). The incremental values for plasma glucose concentrations 15 min after intranasal and i.m. administration of glucagon differed marginally. However, after 5 min the glucose appearance rate, as well as the incremental values for plasma glucose, were significantly higher for the i.m. glucagon treatment. The mean time taken for incremental plasma glucose to exceed 3 mmol.l-1 was significantly shorter for i.m. glucagon. The mean plasma glucagon level increased faster after i.m. glucagon than after intranasal glucagon, and the levels remained higher throughout the study period. We conclude that glucose recovery was significantly better after i.m. administration of glucagon than after intranasal administration. However, the differences between the incremental plasma glucose and the time for incremental plasma glucose to exceed 3 mmol.l-1 were not considered of major clinical importance.
Nakazato, M. (2011). "[Development of the novel delivery system of GLP-1 administration for the treatment of diabetes mellitus]." Nihon Rinsho 69(5): 918-922..
Glucagon-like peptide 1 (GLP-1) is a peptide produced in the endocrine L cells of the distal intestine. GLP-1(7-36)NH2 is a major molecular form that stimulates insulin release, reduces food intake, and has a potential to promote beta-cell regeneration. We have developed a device for intranasal application of GLP-1(7-36)NH2 and completed a double-blind clinical trial of intranasal administration of GLP-1(7-36)NH2 to 26 type II diabetic patients. Intranasal administration of GLP-1 increased its plasma level, stimulated postprandial insulin release, and suppressed glucagon release. Two-week intranasal administration of GLP-1 just before meals significantly decreased serum glycoalbumin level and significantly increased 1,5-AG (1,5-anhydro-D-glucitol) level. Hypoglycemia was not found through this study. Intranasal GLP-1 administration using the novel device and medication improved glycemic control in type 2 diabetic patients without any adverse effects.
Pacchioni, M., C. Orena, et al. (1995). "The hypotonic effect of intranasal and intravenous glucagon in gastrointestinal radiology." Abdom Imaging 20(1): 44-6.
In the present study, following a double-blind, double placebo protocol vs. placebo, we compared the hypotonic effect of intranasal and intravenous glucagon during a double-contrast barium meal examination of the stomach. We found a statistically significant difference between placebo and intranasal or intravenous glucagon in inducing gastric hypomotility, with no significant differences between IN and IV glucagon. The intranasal administration of glucagon has the advantage of being noninvasive and well tolerated by the patients, and might be a valuable aid in upper gastrointestinal examination as well as in CT scan or magnetic resonance imaging of the abdomen.
Pontiroli, A. E. (1998). "Peptide hormones: Review of current and emerging uses by nasal delivery." Adv Drug Deliv Rev 29(1-2): 81-87.
The family of clinically available peptide hormones (PHs) is expanding in an exponential way, and advancement of knowledge of the basic mechanisms of action of PHs has led to multiplication of the possible clinical indications of already known PHs, and appears even more promising for still unknown PHs. A common obstacle to a full routine use of PHs is represented by the fact that PHs cannot be administered by the oral route, since they undergo digestion and inactivation in the gastrointestinal tract and a significant first pass metabolism in the liver. One alternative is represented by intranasal administration of PHs. The intranasal route of administration of PHs is also very attractive because of its convenience, which should assure a good compliance by patients. Luteinizing hormone releasing hormone, the analogues, desmopressin, oxytocin and salmon calcitonin are already marketed for intranasal administration; for salmon calcitonin, studies about bioavailability have been scanty in the past, but should be re-considered in order to fully explore its clinical benefit.Intranasal peptide hormones not yet on the market are insulin, glucagon, growth hormone releasing hormone (GHRH) and GHRP, GH and somatostatin, but the scenario is likely to change in a short period of time. Hexarelin seems very effective and is at a promising stage of development; also, glucagon appears mature enough to undergo extensive clinical evaluation and possibly marketing. The concern is why other peptides have not been further evaluated, as is the case for somatostatin and its analogues.
Pontiroli, A. E., M. Alberetto, et al. (1989). "Nasal administration of glucagon and human calcitonin to healthy subjects: a comparison of powders and spray solutions and of different enhancing agents." Eur J Clin Pharmacol 37(4): 427-30.
The systemic availability of glucagon and human calcitonin given intranasally to healthy volunteers as spray solutions or powders has been examined. Glucagon was absorbed only when surfactants were used, and 9-lauryl ether (as a spray) and sodium glycocholate (as spray or powder) were equally active. Calcitonin was poorly absorbed when given alone but the surfactants dihydrofusinate (as spray or powder) and glycocholate (as a spray) were equally active in promoting absorption. Thus, enhancers are required to obtain significant nasal absorption of glucagon and calcitonin and powders and spray solutions did not differ in terms of systemic availability.
Pontiroli, A. E., M. Alberetto, et al. (1983). "Intranasal glucagon raises blood glucose concentrations in healthy volunteers." Br Med J (Clin Res Ed) 287(6390): 462-3.
Pontiroli, A. E., M. Alberetto, et al. (1985). "Metabolic effects of intranasally administered glucagon: comparison with intramuscular and intravenous injection." Acta Diabetol Lat 22(2): 103-10.
Intranasal administration of glucagon, 1 mg, plus sodium glycocholate 15 mg as a surfactant, raised blood glucose levels and plasma levels of immunoreactive glucagon (IRG) and immunoreactive insulin (IRI). Spray solutions were more effective than drops, and neither the surfactant alone nor glucagon alone had any effect. Blood glucose levels were similarly affected by intravenous glucagon, while intramuscular glucagon was slightly more effective. The highest IRG concentrations were reached after intravenous administration, while intramuscular injection of glucagon was accompanied by the highest IRI release. These data indicate that intranasal administration of glucagon exerts metabolic effects similar to intramuscular and intravenous administrations. Further studies are needed to improve bioavailability and efficacy of intranasally administered glucagon.
Pontiroli, A. E., A. Calderara, et al. (1989). "Intranasal glucagon as remedy for hypoglycemia. Studies in healthy subjects and type I diabetic patients." Diabetes Care 12(9): 604-8.
Intranasal glucagon can raise blood glucose levels in healthy subjects. The aims of this study were to 1) compare the hyperglycemic effect of intranasal and intramuscular glucagon in healthy subjects and type I (insulin-dependent) diabetes patients during euglycemic conditions and 2) test the efficacy of intranasal and intramuscular glucagon in counteracting hypoglycemic episodes in insulin-treated diabetic patients. Intranasal glucagon raised blood glucose levels in both healthy subjects and type I diabetic patients, the effect of intramuscular glucagon being similar for the first 30 min and higher thereafter. Intranasal glucagon was also quicker acting than oral glucose in healthy subjects. Intranasal glucagon raised blood glucose levels in patients with hypoglycemic episodes, although less effectively than intramuscular glucagon. These data indicate intranasal glucagon as a possible emergency remedy for self-medication in insulin-treated patients prone to hypoglycemic episodes.
Pontiroli, A. E., A. Calderara, et al. (1993). "Pharmacokinetics of intranasal, intramuscular and intravenous glucagon in healthy subjects and diabetic patients." Eur J Clin Pharmacol 45(6): 555-8.
The pharmacokinetics of intranasal, an intravenous infusion, and intramuscular glucagon has been studied in 5 healthy subjects and 11 patients with insulin-dependent diabetes mellitus. After infusion the elimination half-life was significantly longer in diabetics (11.9 vs 6.6 min) and the apparent volume of distribution was twice as high in diabetics (0.19 vs 0.37 l.kg-1). The metabolic clearance rates were the same in the two groups (18.9 and 21.3 ml.min-1.kg-1 in controls and in diabetics) and were about twice those previously reported. After 1 mg intranasally the Cmax of immunoreactive glucagon (IRG) was similar in diabetic and in healthy subjects. Administration of a higher dose (2 mg) to diabetic patients produced a higher plasma level, although not proportionately so. The AUC after 1 mg was also similar in controls and in diabetics. The elimination half-life in both groups was similar to the value found after i.v. infusion; it was significantly shorter in controls (5.5 min) than in diabetics (13.8 min). In both groups, mean Cmax was significantly lower than after IM glucagon, the relative bioavailability of 1 mg intranasally vs IM injection being less than 30%. After IM administration, the Cmax and AUC of IRG in controls and in diabetic patients, were identical. The apparent elimination half-life was also similar in the two groups, and was three- to four-times longer (28.6 and 31.4 min) than after infusion or intranasal administration, possibly because estimation of the t1/2 was affected by slow release of the hormone from the site of injection.
Pontiroli, A. E., A. Calderara, et al. (1989). "Intranasal drug delivery. Potential advantages and limitations from a clinical pharmacokinetic perspective." Clin Pharmacokinet 17(5): 299-307.
Pontiroli, A. E. and G. Pozza (1990). "Intranasal administration of peptide hormones: factors affecting transmucosal absorption." Diabet Med 7(9): 770-4.
Rosenfalck, A. M., I. Bendtson, et al. (1992). "Nasal glucagon in the treatment of hypoglycaemia in type 1 (insulin-dependent) diabetic patients." Diabetes Res Clin Pract 17(1): 43-50.
The aim of this study was to compare the effect of nasally administered glucagon in doses of 1 (A) and 2 mg (B), with 1 mg glucagon administered intramuscularly (C) in 12 C-peptide-negative IDDM patients. Spontaneous recovery (D) from insulin-induced hypoglycaemia in the same patients was used as reference. The mean age was 31.1 (21-48) years, diabetes duration 10.8 (2.7-31) years and HbA1c 7.7 (6.5-9.8)%. Hypoglycaemia was induced by i.v. insulin infusion. When blood glucose (BG) reached about 2 mmol/l either glucagon was administered or the patients recovered spontaneously. BG nadir was 1.6 (1.1-2.3) mmol/l. BG increments during the first 15 min after glucagon administration were: (A) 1.9 +/- 0.7 (0.4-3.0); (B) 2.5 +/- 0.7 (1.5-3.5); (C) 2.5 +/- 1.0 (1.2-4.7); and (D) 0.3 +/- 0.4 (0-1.0) mmol/l, respectively. All treatments were more effective, measured as increments in BG, than spontaneous recovery, P less than 0.00001. There was no difference between nasal treatment with 2 mg (B) and i.m. treatment (C), both being more effective than 1 mg (A) nasal treatment, P less than 0.1. BG continued to increase up to 10 mmol/l 90 min after i.m. glucagon administration, whereas it stabilized at a level of 4.6-6 mmol/l, 30-45 min after nasal administration. Eighty percent of the patients had side-effects to nasal administration - local irritation, rhinitis or sneezing. Half of the patients sneezed, without correlation with the delivered dose of glucagon. None of the patients had side-effects which would preclude further treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Sibley, T., R. Jacobsen, et al. (2012). "Successful Administration of Intranasal Glucagon in the Out-of-Hospital Environment." Prehosp Emerg Care.
Abstract We present a case of successful prehospital treatment of hypoglycemia with intranasal (IN) glucagon. Episodes of hypoglycemia can be of varying severity and often requires quick reversal to prevent alteration in mental status or hypoglycemic coma. Glucagon has been shown to be as effective as glucose for the treatment of hypoglycemia. The inability to obtain intravenous (IV) access often impairs delivery of this peptide and is therefore frequently given via the intramuscular (IM) route. Intranasal administration of glucagon has been shown to be as effective as the IV route and may be used for rapid correction of hypoglycemic episodes where IV access is difficult or unavailable and IM administration is undesirable. We describe the first documentation in the peer-reviewed literature of the successful treatment and reversal of an insulin-induced hypoglycemic episode with IN glucagon in the prehospital setting. We also present a review of the literature regarding this novel medication administration route.
Slama, G., C. Alamowitch, et al. (1990). "A new non-invasive method for treating insulin-reaction: intranasal lyophylized glucagon." Diabetologia 33(11): 671-4.
The main therapeutic indication for glucagon is the treatment of hypoglycaemia in insulin overdosed Type 1 (insulin-dependent) diabetic patients. We have previously shown that an intranasal spray of 7.5 mg glucagon with deoxycholic acid as surfactant was able to correct an i.v. insulin-induced hypoglycaemia in diabetic patients. However, bioavailability and stability needed to be improved before intranasal glucagon could be introduced into clinical practice. This has now been achieved with a freeze-dried mixture of glucagon (1 mg) and glycocholic acid (1 mg) as a surfactant. Kinetics and efficacy have been controlled by (1) comparing subcutaneous and intranasal glucagon in 12 healthy non-hypoglycaemic subjects; (2) testing intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by an i.v. bolus of insulin and (3) comparing subcutaneous and intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by adding extra subcutaneous regular insulin to their usual morning dosage. Our results show that 1 mg of intranasal glucagon is as effective as 1 mg of subcutaneous glucagon in terms of the rise in blood glucose. Differences in kinetics between the subcutaneous and the intranasal routes may be observed: intranasal glucagon initiates the blood glucose rise earlier than does the subcutaneous form but the effect of the latter is more sustained. Glycocholic acid appears to be a perfectly tolerated agent in acute conditions. The use of intranasal lyophylized glucagon, for the reversal of hypoglycaemia in Type 1 diabetes, seems to be a clinically relevant alternative to its parenteral equivalent and should now be ready to be introduced in the market.
Slama, G., L. Freychet, et al. (1988). "Intranasal glucagon for hypoglycaemia [letter]." Lancet 2(8614): 799.
Slama, G., G. Reach, et al. (1992). "Intranasal glucagon in the treatment of hypoglycaemic attacks in children: experience at a summer camp." Diabetologia 35(4): 398.Slama, G., G. Reach, et al. (1992). "Intranasal glucagon in the treatment of hypoglycaemic attacks in children: experience at a summer camp [letter]." Diabetologia 35(4): 398.
Stenninger, E. and J. Aman (1993). "Intranasal glucagon treatment relieves hypoglycaemia in children with type 1 (insulin-dependent) diabetes mellitus." Diabetologia 36(10): 931-5.
The aim of the present study was to compare intra-nasal glucagon with subcutaneous glucagon as a treatment of insulin-induced hypoglycaemia in 11 children, 7-12 years old, with Type 1 (insulin-dependent) diabetes mellitus. Hypoglycaemia (1.6 +/- 0.1 vs 1.8 +/- 0.2 mmol/l) was induced twice in each child by continuous insulin and variable glucose infusions. One milligram of intranasal glucagon or 0.5 mg of subcutaneous glucagon was given in a randomized order. At 15 min after the administrations of either intranasal or subcutaneous glucagon, the blood glucose concentration increased by 1.5 +/- 0.2 mmol/l or 1.7 +/- 0.2 mmol/l above the glucose nadir, respectively. After nasal administration, the maximal rise in blood glucose was seen after 25 min. Subcutaneous injections induced higher and more sustained plasma glucagon concentrations but the children suffered more often from nausea than when they were treated intranasally. In conclusion, treatment with intranasal glucagon seems to be efficient and results in a rapid correction of insulin-induced hypoglycaemia with few side-effects.
Teshima, D., A. Yamauchi, et al. (2002). "Nasal glucagon delivery using microcrystalline cellulose in healthy volunteers." Int J Pharm 233(1-2): 61-6.
We developed an intranasal powder form of glucagon to improve metabolic status and fatty liver in patients with pancreatectomy. Microcrystalline cellulose, which is commonly used in commercial preparations for allergic rhinitis was used as an absorption enhancer. We compared the intranasal powder form with some spray solutions of glucagon with regard to glucagon absorption, concentration of blood glucose, stability and nasal irritation. The absorption of glucagon from the spray solution including 1.5% sodium glycocholate or 1% sodium caprate was 1.3- and 2.6-fold higher than that from the powder form mixed with microcrystalline cellulose at a ratio of 1:69, respectively. The C(max) values of plasma glucose were 2.18, 3.39 and 1.56 mmol l(-1) in the spray solutions including sodium glycocholate and sodium caprate and in the powder form, respectively. However, glucagon in spray solutions was unstable, but that in the powder form was stable at 5 and 25 degrees C for at least 84 days. The spray solution caused strong irritation, but the powder form did not. These results suggested usefulness of the powder form of glucagon for treatment of pancreatectomized patients.
Yanai, O., M. Phillip, et al. (2005). "IDDM patients' opinions on the use of glucagon emergency kit in severe episodes of hypoglycemia." Practical Diabetes 14(2): 40-42.This study investigated the coping strategies of IDDM patients with mild and severe episodes of hypoglycaemia. One hundred and two IDDM patients, aged 4-62 years old, 59% male and 41% female, were interviewed by telephone using a structured questionnaire. Most of the patients recognised the symptoms of hypoglycaemia and accordingly treated their mild episodes with either Coca Cola or fruit juice (61%), sweets (32%), milk (26%), or a slice of bread (23%). Forty two per cent of the patients treated themselves with additional chocolate, fruit or honey. While 83% of the patients reported that they had received an explanation regarding the use of the glucagon emergency kit, only 60% actually owned it. In only 19% of the patients who had ever experienced a severe episode of hypoglycaemia had this mode of treatment actually been used. Most of the patients (67%) said they would prefer the intranasal route if available and 82% assumed that the people surrounding them would prefer to administer an intranasal spray or drops in emergency hypoglycaemic situations. We conclude that only in a small percentage of patients is subcutaneous or intramuscular glucagon used in an emergency situation, and speculate that other modes of glucagon administration such as the intranasal route would increase the use of glucagon and prevent some of the IDDM patients from waiting for the emergency paramedic teams or from being referred to hospitals.