Biosynthetic human growth hormone was injected subcutaneously in rats for 90 days and in cynomolgus monkeys for 30 days. The daily doses were 0.5, 3.3 and 25 IU kg-1 (rats) and 0.3 and 15 IU kg-1 (monkeys). The growth hormone was tolerated well in both rats and monkeys. No drug related deaths occurred and all animals appeared to be normal and also behaved normally throughout the dosing period. Increased body weight gain, increased food utilisation and increased organ weights were seen in the rats in the high and intermediate dose groups. The higher doses of human growth hormone (3.3 and 25 IU kg-1) caused a glandular hyperplasia of the mammary gland in male and female rats with evidence of secretory activity. In the female monkeys secretory activity was seen without any sign of mammary gland hyperplasia. Mucification of the vaginal epithelium and stress induced prostatitis was observed in the rats. Additional treatment related changes in the rats were an increased haematopoietic activity in the spleen and an increase in the amounts of calcium and phosphate excreted in urine. An increase in fasting plasma glucose levels was seen in the male monkeys on the high dose level. The changes observed during the treatment periods presumably represent exaggerated pharmacological effects of the growth hormone.
To furnish a systemic effect after intranasal administration, a formulation must contain the therapeutic dose in no more than 150 μL, the maximum volume that can be applied as a single administration in one nostril in man. The objectives of these studies were to examine the local toxicity of formulations containing benzodiazepines and to document the effects to support clinical trials in man.
After stability, pharmacological and pharmacokinetic studies of several benzodiazepine formulations, we studied nasal toxicity after single and repeated administration to rabbits of poly(ethylene glycol) 200, tetra(ethylene glycol), glycofurolum and mixtures of these vehicles both with and without benzodiazepines. Single‐dose studies with examinations 5 or 10 min after application were undertaken with poly(ethylene glycol), tetra(ethylene glycol), glycofurolum and tetra(ethylene glycol)‐glycofurolum in the ratio 95:5; the reactions were similar to that after physiological saline. A 14‐day repeated‐dose study was conducted with diazepam, lorazepam and flunitrazepam formulations in poly(ethylene glycol), and flunitrazepam in poly(ethylene glycol)‐glycofurolum in the ratio 70:30; the two vehicles without any benzodiazepine were also examined. Microscopic study revealed mild changes only in the treated groups. A final four‐week study was conducted with repeated administration of clonazepam formulated in tetra(ethylene glycol)‐glycofurolum in the ratio 95:5; microscopy revealed mild changes after three 150‐μL doses daily, but no abnormalities after one or three 100‐μL doses daily.
It was concluded that these three solvents individually or as mixtures resulted in only mild local toxicity and might be acceptable as vehicles in nasal preparations of benzodiazepines and other non‐irritating drugs for short‐term use in man.
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