Animal experiments on the safety pharmacology of lofexidine.

These experiments were carried out to supplement the pharmacodynamic profile of 2[1-(2,6-dichlorophenoxy)-ethyl]-2-imidazoline hydrochloride (lofexidine, Lofetensin and Loxacor), a potent hypotensive imidazoline derivative with a central mode of action. Effects indicative of a central sedative action were seen in various experiments on mice and rats. However, comparative studies with clonidine, particularly those involving the interaction with hexobarbital, the effect on motor coordination on a rotating rod, the effect on body temperature and other experiments, indicated that lofexidine had a 10 to 100 fold less sedative effect than clonidine, depending on the test and the route of administration. In rats there was a dose-related, diuretic and saluretic effect. This effect was not seen in dogs. In rabbits and guinea pigs, lofexidine exhibited local anaesthetic effects and its potency and duration of action were comparable to those of the reference compounds (tetracaine or mepivacaine). Lofexidine did not modify gastric secretion in rats. On the other hand, it inhibited chemically induced (phenylbutazone) and stress-induced (swimming) gastric ulcer formation in rats. Antiinflammatory and analgesic activities in rats and mice were, at most, very weak. Lofexidine increased blood glucose levels of normoglycaemic rats; clonidine is known to have the same effect. In order to investigate the possibility of combining lofexidine with a diuretic drug for the treatment of hypertension, the interaction with hydrochlorothiazide was studied in some experiments. The results obtained from these experiments showed that there was no adverse effect and the diuretic and saluretic effects of hydrochlorothiazide were not impaired. No findings militated against the use of lofexidine as an antihypertensive drug. It is likely that lofexidine, in contrast to clonidine, has less marked central sedative effects.