Rabbits insulin administration

H) In vivo studies The studies in vitro discussed above clearly showed that for mammalian glycogen synthase (or at least for the rabbit muscle enzyme) the important phosphorylation sites for inactivation were site 2 and (2a SerlO), sites 3a and 3b. However, it is of interest to know which are the important phosphorylation sites under hormonal control in vivo. In rabbit muscle enzyme, intravenous insulin administration doubles the Glc-6-P activity ratio, with a decrease in phosphorylation of all the sites. " " Epinephrine, which increases the phosphate content of the glycogen synthase, increases the phosphorylation at practically all the phosphorylation sites." " " ... 

Dosing presents difficulties in animal investigations, and most studies of pulmonary insulin administration have been performed by instillation of an insulin solution into the lung of rats or rabbits (Table VI). However, drug is absorbed to a greater extent when inhaled as an aerosol than when... 

Table 7.12 Effects of polyoxyethylene (POE)(n) fatty alcohol ethers in insulin suppositories on blood glucose level in rabbits. Insulin suppositories contained 0.5% polyoxyethylene (n) fatty alcohol ethers and 1 U kg insulin in corn oil. The initial blood glucose concentration was 118.3 6.2 mg/100 ml. Each value represents the blood glucose concentration at 30,60,90 and 120 min after rectal administration of insulin suppositories and mean of three rabbits s.e.m.

Figure 13. Normalized reduction of serum glucose in normal rabbits by oral administration of bovine insulin imbibed into a poly(acrylic acid) matrix.

Somatostatin. Somatostatin is an endogenous peptide hormone involved in e.g. the control of the release of Somatomedin, Insulin and Pancreatin. Due to its biological role, Somatostatin has a very low biological stability. The half-life in the rabbit after intravenous administration has been determined to approximately 90 seconds in this investigation. After sc or im administration, the apparent half-life is somewhat longer, close to 10 minutes, probably due to the absorption of the peptide from the injection site into the systemic circulation. 

Colthorpe P, Farr SJ, Taylor G, Smith IJ, Wyatt D (1992) The pharmacokinetics of pulmonary delivered insulin a comparison of intratracheal and aerosol administration to the rabbit. Pharm Res 9 764-768. 

Colthorpe, R, Farr, S.J., Taylor, G., Smith, I.J., and Wyatt, D. (1992). Pharmacokinetics of pulmonary-delivered insulin Comparison of intratracheal and aerosol administration to the rabbit. Pharmaceut. Res., 9, 764—768. 

Soybean-derived sterol mixture (SS), soybean-derived steryl glucosides (SG), and their individual components have been extensively studied for their ability to promote the nasal absorption of drugs, particularly insulin [79,80], Maitani et al. [79] demonstrated that the nasal administration of SG plus insulin to rabbits resulted in significant reductions in blood glucose. The effect of SG was dose dependent to 1%, with a plateau being reached thereafter. Muramatsu et al. [81] have demonstrated that SG perturbs the phospholipids in artificial membranes (i.e., liposomes). Furthermore, circular dichroism studies with insulin in the presence or absence of SG have indicated that the enhancer had little effect on the dissociation of insulin hexamers to monomers. These results suggest that the action of SS and SG involves interaction with the nasal membrane rather than interaction with insulin molecules. 

In addition, the buccal delivery of insulin in rabbits has been shown to be increased from approximately 3-5% by co-administration of edetate (least effective), sodium dextransulfate, sodium methoxysalicylate, sodium deoxycholate, sodium lauryl sulfate, sodium taurocholate and Brij 35 (most effective) with Brij 35 increasing the bioavailability of insulin to 12% by this route. 

Rapid dose-related changes in the plasma glucose and insulin levels have been demonstrated in alloxan-induced diabetic rats and rabbits, after vaginal administration of insulin suspended in a poly(acrylate) aqueous gel (0.1%, pH 6.5). 

Crystalline cellulose, hydroxypropyl cellulose, and Carbopol 934 have been studied in combination with lyophilized insulin as bioadhesive powder dosage forms for nasal delivery. Each formulation tested resulted in an decrease in plasma glucose level after nasal administration in dog and rabbit models. The most effective formulation, crystalline cellulose blended with insulin, decreased the plasma glucose level to 49% of the control value. In ternary systems the lyophilized Carbopol 934 and insulin blend with crystalline cellulose powder has been the most effective, leading to a hypoglycemia on the order of one-third of the effect obtained after intravenous injection of the same dose of insulin. The plasma glucose levels obtained in the volunteers after administration of the insulin-Carbopol-crystalline cellulose powder formulation were quite variable [38],... 

Human insulin was acidified and added to appropriate amounts of sodium palmitate solution containing deoxycholate salt. Oral administration of these insulin-containing deoxycholate-palmitic acid dispersions at doses from 10 to 40U/kg to rats and rabbits resulted in a significant reduction of blood glucose level in 30 min. The glucose-lowering effect lasted for 4h. 

Degim Z, Degim T, Acarturk F, et al. (2005). Rectal and vaginal administration of insulin-chitosan formulations An experimental study in rabbits. J. Drug. Target. 13 563-572. 

In rabbits with moderate or severe diabetes, oral administration of 100 mg/kg of an ethanol extract of jambolan seed daily for 15 days resulted in a significant reduction in fasting blood glucose and peak blood glucose and an increase in serum insulin levels (Sharma et al. 2003). 

Eudragit SlOO microspheres were prepared using water-in-oil-in-water emulsion solvent-evaporation technique, and their application toward oral insulin delivery was evaluated. Oral administration of PVA-stabilized microspheres in normal albino rabbits (equivalent to 6.6 lU insulin/kg of animal weight) demonstrated a 24% reduction in blood glucose level, with maximum plasma glucose reduction of 76% 3.0% in 2 h, and the effect continued up to 6 h. 

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