Mesoporous Silica as an Alternative Vehicle to Overcome Solubility Limitations.

Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates.

Insulin glargine: a reevaluation of rodent carcinogenicity findings.

The 1995 to 1997 lifetime carcinogenicity studies of insulin glargine in rats and mice were reanalyzed and reassessed for their validity according to current guidelines. In 2-year studies, 50 animals per sex and per group were used. Survival rates between weeks 80 and 90 in female mice and rats were greater than 20 animals in all groups, fulfilling current Food and Drug Administration requirements that enough animals lived long enough to provide adequate exposure to glargine and to be at risk of forming late-developing tumors. Exposure to 5 or 12.5 IU/kg glargine was similar to or 2 to 3 times greater than 5 IU/kg neutral protamine Hagedorn insulin, respectively. Using statistical methods recommended by current guidelines, no significant effect of glargine on mammary gland neoplastic lesions in female rodents was found, confirming earlier results. Thus, both studies can be considered valid according to contemporary standards. Insulin glargine does not present a carcinogenic risk.

Insulin glulisine--a comprehensive preclinical evaluation.

Receptor binding and signaling and the mitogenic potential of insulin glulisine (glulisine), regular human insulin (RHI), and Asp(B10) were compared in vivo and in vitro. Insulin and insulin-like growth factor 1 (IGF-1) receptor binding was studied with human insulin receptors (293HEK cells) and the human osteosarcoma-derived cell line B10. Insulin receptor-mediated signaling was assessed in rat-1 fibroblasts overexpressing insulin receptors. Activation of insulin receptor substrates 1 and 2 (IRS-1/ IRS-2) was studied in rat and human myoblasts and rat cardiomyocytes. DNA synthesis induction was assessed by [3H] thymidine incorporation in the human epithelial breast cell line MCF10. Interaction with the IGF-1 receptor, DNA synthesis, and intracellular signal transduction were assessed in cardiac K6 myoblasts. Immunohistochemical examination of Sprague-Dawley rat tissue treated with glulisine for 6 months (n = 40), and glulisine and RHI for 12 months (n = 60), was performed. Steady-state insulin receptor binding affinity was slightly lower for glulisine versus RHI (approximately 0.70). IGF-1 receptor binding affinity was lower (four- to fivefold) for glulisine, but significantly higher (four-fold) for Asp(B10) versus RHI. Glulisine, Asp(B10), and RHI showed similar insulin receptor-association kinetics; however, Asp(B10) revealed increased insulin receptor affinity. Glulisine and RHI showed similar insulin receptor-mediated phosphorylation and IRS-2 activation. Activation of IRS-1 was 6- to 10-fold lower with glulisine; glulisine was less potent and Asp(B10) slightly more potent in stimulating DNA synthesis versus RHI. Stimulation of DNA synthesis was comparable for glulisine and RHI in K6 myoblasts. At 12 months, there was no significant difference between glulisine and RHI in proliferative activity. This preclinical evaluation suggests that structural changes in glulisine versus RHI are not associated with any safety issues.

Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice.

Insulin glargine (LANTUS) is a new, long-acting insulin analogue with a stable profile of action. The purpose of these studies was to evaluate the carcinogenic potential of insulin glargine in rats and mice. General toxicity studies were conducted in NMRI mice (3 months' duration) and rats (Wistar rats in the 3- and 6-month studies and Sprague-Dawley rats in the 12-month study) to determine the optimal dose of insulin glargine for long-term carcinogenicity studies. Based on these results, groups of Sprague-Dawley rats or NMRI mice (50 male, 50 female) received a daily subcutaneous dose of 2, 5, or 12.5 IU/kg of insulin glargine or 12.5 (mice) or 5 IU/kg (rats) of the reference insulin (NPH insulin) in a lifetime study. Similarly treated control and vehicle-control animals received isotonic sodium chloride (NaCl) solution or the vehicle solution, respectively. In mice, the mortality rate was comparable between all groups. In rats, the mortality rate compared with the NaCl control was significantly increased in the following groups: males treated with the vehicle control, all insulin glargine and NPH insulin groups, and in females in the high-dose insulin glargine and NPH insulin groups. There was no difference in the incidence of mammary tumors reported in both mice and rats when comparing the insulin glargine groups with the NaCl, vehicle-control, or the NPH insulin groups. In rats and mice, the distribution of subcutaneous malignant fibrous histiocytomas found at the injection site were not dose-dependent. These lesions are a rodent-specific event and were related to chronic tissue irritation and inflammation. In rats, neuronal necrosis of the cerebrum was attributed to persistent repeated episodes of hypoglycemia induced by high doses of insulin. In these studies, there were no neoplastic findings to indicate that insulin glargine had a systemic carcinogenic potential in mice or rats.

Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits.

Insulin glargine (LANTUS) is a new insulin analog that has a prolonged duration of action with no pronounced peak of activity, rendering it an ideal basal insulin for the treatment of diabetes. The aim of these studies was to assess the reproductive and embryotoxicity of insulin glargine. Reproductive toxicity was assessed in 25 male and 25 female Wistar rats per group treated with a daily subcutaneous injection of control; 1 IU/kg, 3 IU/kg, and 10 IU/kg insulin glargine; or 3 IU/kg NPH insulin in the premating and mating periods, and throughout pregnancy and lactation in the females. Embryotoxicity was assessed in 20 female rats per group injected with daily subcutaneous doses of control; 2 IU/kg, 6.3 IU/kg, and 20 IU/kg insulin glargine; or 6.3 IU/kg NPH insulin from the 7th to 18th day of pregnancy. Embryotoxicity was also assessed in 20 female rabbits per group treated with 0 IU/kg, 0.5 IU/kg, 1 IU/kg, and 2 IU/kg insulin glargine, or 1 IU/kg NPH insulin from the 6th to 18th day of pregnancy. The data demonstrated that, with the exception of toxicologic effects induced by hypoglycemia in response to high doses of insulin glargine and NPH insulin (including the premature dropout of female rats in the reproductive toxicity study, and increased incidence of abortions, early intrauterine deaths, and single anomalies in the rabbit embryotoxicity study), insulin glargine had no effects on reproduction, embryofetal development, and postnatal development in rats. Maternal and embryofetal toxicity in rabbits treated with middle and high doses of insulin glargine was related to the hypoglycemic effect of insulin.