Pharmacological effects and pharmacokinetics of atipamezole, a novel alpha 2‐adrenoceptor antagonist‐a randomized, double‐blind cross‐over study in healthy male volunteers.

Abstract

1. Single doses (10, 30 and 100 mg) of atipamezole (MPV‐1248), a new potent and selective imidazole‐type alpha 2‐adrenoceptor antagonist, and saline placebo were administered as 20 min intravenous infusions to six healthy male volunteers in a randomized double‐blind, cross‐over phase I study. Later, 100 mg atipamezole was given orally to the same subjects in an open fashion. 2. The i.v. doses resulted in linearly dose‐related concentrations of atipamezole in plasma. Pharmacokinetic calculations revealed an elimination half‐life of 1.7‐2.0 h, an apparent volume of distribution of 3.0‐3.5 l kg‐1 and a total plasma clearance of 1.1‐1.5 l h‐1 kg‐1. No atipamezole could be detected in plasma after oral dosing. 3. Subjective drug effects were seen mainly after the largest i.v. dose and included increased alertness and nervousness, coldness and sweating of hands and feet, tremor and shivering, motor restlessness, and increased salivation. Salivation was also quantitated using dental cotton rolls, with dose‐related increases produced by the i.v. doses. 4. The 100 mg i.v. dose increased plasma noradrenaline concentrations on average by 484 +/− 269 (s.d.)%, and also elevated both systolic and diastolic blood pressure (mean increases 17 +/− 7/14 +/− 2 mm Hg). The 30 mg dose had minor and the 10 mg dose no effects on these variables. Adrenaline and cyclic AMP levels in plasma were increased only after the largest dose. No drug effects were observed after oral dosing. 4. Plasma C‐peptide and blood glucose levels were not markedly influenced by the drug, and cortisol secretion was not stimulated. 5. The observed effects are compatible with the presumed alpha 2‐adrenoceptor antagonistic action of atipamezole and are in general concordance with the reported results of other alpha 2‐ adrenoceptor antagonists (yohimbine and idazoxan). 6. Although not orally active, atipamezole may prove to be a useful agent in studies of alpha 2‐adrenoceptor function in man.

Rapid reversal of alpha 2‐adrenoceptor agonist effects by atipamezole in human volunteers.

“…By this time point the effects of dexmedetomidine had subsided also in the placebo session of this study, as in a previous volunteer study with dexmedetomidine . The elimination half-life of atipamezole is quite short, 1.5-2 h (Karhuvaara et al, 1990), and it is near the elimination half-life of approximately 2.5 h calculated for dexmedetomidine (Kallio, unpublished results). Both drugs are relatively short-acting as judged from the previous phase I studies Karhuvaara et al, 1990), and the termination of the actions of each drug seems to be related to their elimination and not to redistribution.…”

“…In human subjects atipamezole, administered as intravenous infusions, causes an increase in venous plasma noradrenaline concentrations indicating an increased sympathetic activity, blood pressure elevation and an increase in salivary flow. Subjective effects have included anxiety, sweating and coldness of hands and feet, and tremor (Karhuvaara et al, 1989(Karhuvaara et al, , 1990.…”

Potentiation of the anti‐obesity effect of the selective β3‐adrenoceptor agonist BRL 35135 in obese Zucker rats by exercise

“…Theoretically, at least two possible mechanisms of action of atipamezole could be implemented. First, since the activity of noradrenaline release from the nerve terminals is partly controlled by presynaptic a2-receptors, atipamezole may increase noradrenaline release as shown in humans (Karhuvaara et al, 1990). Since the activity of sympathetic tone is low in obese Zucker rats, as well as in human obesity, C2-receptor antagonists might thus be able to improve low sympathetic activity.…”

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

“…In human subjects, blockade of á 2 -receptors is generally mildly anxiogenic (62,64). Animal studies with yohimbine have discovered a rather subtle spectrum of behavioral alterations, not all of which are shared by more selective antagonists.…”

“…This effect appears to be spinally mediated as it is not seen in spinalized animals (i.e., the pressor effect is not due to leakage of drug into the circulation, 81), and presumably arises from disinhibition of sympathetic preganglionic neurons. In man, intravenous atipamezole and RX 811059 cause increases in arterial blood pressure when given alone, but this effect is likely to have a peripheral component (25,62).…”