Mika Scheinin

Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.

The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine—a novel α2‐adrenergic receptor agonist under development for preanesthetic use—were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5,1.0, and 1.5 µg/kg) and placebo were administered to six subjects in a single‐blind, multiple crossover study. Dexmedetomidine induced dose‐related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose‐dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose‐related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half‐life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6‐hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic‐pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this α2‐agonist.

Disposition of single oral doses of E‐10‐hydroxynortriptyline in healthy subjects, with some observations on pharmacodynamic effects

The active and major metabolite of nortriptyline (NT), E‐10‐hydroxynortriptyline (E‐10‐OH‐NT), was taken orally as the hydrogen maleate in single doses by nine healthy subjects. The doses (10 to 100 mg) were completely absorbed, as shown by the high urinary recovery of 86.1% ± 9.9%. Of the given dose, 51.2% ± 8.7% was recovered as conjugated E‐10‐OH‐NT and 23.9% ± 4.3% was recovered as unchanged compound. The plasma t1/2 of E‐10‐OH‐NT was 8.0 ± 1.2 hours and total plasma clearance was 47.5 ± 10.3 L/hr. The rate of elimination varied little between individuals. There was no indication of dose‐dependent elimination. The mean apparent volume of distribution was 7.7 ± 2.1 L/kg. Single oral doses of 50 mg E‐10‐OH‐NT significantly increased the plasma levels of norepinephrine in both the supine and standing positions (P < 0.01). Pulse rate increased in the standing but not the supine position. These effects might result from inhibition of neuronal uptake of norepinephrine by E‐10‐OH‐NT. Coupled with its low affinity for muscarinic receptors, these kinetic and pharmacodynamic features of E‐10‐OH‐NT call for further phase I studies.

Simultaneous inhibition of catechol‐O‐methyltransferase and monoamine oxidase A: Effects on hemodynamics and catecholamine metabolism in healthy volunteers

To evaluate the effects of simultaneous pharmacologic inhibition of catechol‐O‐methyltransferase (COMT) and monoamine oxidase type A (MAO‐A) on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during exercise.

Exercise hemodynamics and catecholamine metabolism after catechol‐O‐methyltransferase inhibition with nitecapone

The effect of catechol‐O‐methyltransferase inhibition with nitecapone (OR‐462) on the hemodynamic responses to exercise and catecholamine metabolism was studied in 10 healthy male volunteers (aged 19 to 26 years). Nitecapone, a new specific and selective catechol‐O‐methyltransferase inhibitor, was given at increasing single oral doses up to 100 mg. Nitecapone did not influence resting or exercise heart rate, blood pressure, systolic time intervals, or plasma catecholamine levels. It altered the metabolic profile of catecholamines as shown by (1) an increase of 140% in the plasma concentration of the monoamine oxidase–dependent metabolite 3,4‐dihydroxyphenylethyleneglycol (p < 0.001), (2) a decrease of 27% in the plasma concentration of its methylation product 3‐methoxy‐4‐hydroxyphenylethyleneglycol (p < 0.05), and (3) a 25% reduction in the urinary excretion of the methylated metabolites 3‐methoxy‐4‐hydroxymandelic acid and homovanillic acid (p < 0.05). Nitecapone was well tolerated and seemed to be hemodynamically safe in humans.

Comparison of free MHPG in rat cerebrospinal fluid with free and conjugated MHPG in brain tissue: effects of drugs modifying noradrenergic transmission

The changes of free 3-methoxy-4-hydroxyphenylglycol (MHPG) in cerebrospinal fluid (CSF) were compared with the corresponding alterations of free and conjugated MHPG in rat brain tissue after various pharmacological treatments modifying noradrenergic neurotransmission. In addition, the effects of the drug treatments on the concentration of noradrenaline (NA) in brain were determined. alpha-Methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase) induced decreases in free and conjugated MHPG in CSF and brain; the free species appeared to decline more rapidly. Reserpine caused similar biphasic changes in free MHPG in CSF and brain but the rapid and transient initial increase in MHPG-SO4 was very weak. Pargyline (monoamine oxidase inhibitor) induced a sharp decline in the concentration of free MHPG in brain and CSF while MHPG-SO4 in brain definitely decreased more slowly. Relatively similar time courses were seen for all three MHPG parameters after administration of MPV-1248 (alpha 2-antagonist) and clonidine (alpha 2-agonist) i.e., increases and decreases, respectively. The present results support the validity of monitoring drug-induced acute changes in central turnover of NA by repeated measurements of free MHPG levels in rat cisternal CSF.

Biological correlates of mental stress related to anticipated caesarean section

The relationships between self‐reported assessments of acute anxiety and several biochemical and physiological indicators of stress reaction were investigated in pregnant women at term in connection with spinal analgesia for caesarean section. Fear and apprehension were statistically significantly associated only with blood pressure and with an increase in heart rate from the previous daty. The subjective estimate of the quality of the preoperative nights sleep was negatively associated with biochemical plasma and cerebrospinal fluid (CSF) measures of sympatho‐adrenal activity. The previously reported negative correlation between body height and 5‐hydroxyindoleacetic acid (5‐HIAA, an indicator of serotonin metabolism) in lumbar CSF was confirmed. The concentration of 5‐HIAA in CSF was positively correlated with the levels of other acidic monoamine metabolites and cortisol in CSF. It is concluded that hormone and monoamine metabolite measurements in CSF and plasma have only limited usefulness as quantitative indicators of the intensity of preoperative fear and anxiety.

Effect of low-dose propofol infusion on total-body oxygen consumption after coronary artery surgery.

OBJECTIVEnTo investigate the effect of low-dose propofol infusion on total-body oxygen consumption (VO2) after coronary artery bypass grafting (CABG) surgery.nnnDESIGNnA prospective, randomized, placebo-controlled, double-blind study.nnnSETTINGnCardiovascular intensive care unit in a university hospital.nnnPARTICIPANTSnThirty patients after elective, uncomplicated CABG surgery.nnnINTERVENTIONnPatients were administered a continuous infusion of propofol with a fixed rate of 1 mg/kg/h (n = 15) or placebo (n = 15) during the spontaneous rewarming period of approximately 5 hours after surgery. A light level of sedation (Ramsay sedation score > or =2) was maintained by administering small doses of diazepam, 0.1 mg/kg, as required. Morphine, 0.05 mg/kg, was administered for analgesia as required.nnnMEASUREMENTS AND MAIN RESULTSnTotal-body VO2 was measured by indirect calorimetry. In addition, shivering (on a five-grade scale), hemodynamics, and plasma catecholamine and serum cortisol concentrations were measured. Diazepam, 5.6+/-7.4 mg (mean +/- standard deviation), was administered to the patients receiving propofol, and 16.1+/-12.2 mg was administered to the patients receiving placebo (p < 0.05). There was no difference in the dose of morphine between the groups (3.2+/-3.9 v 4.2+/-5.5 mg in the propofol and placebo groups, respectively). At any time during the study, VO2 was not different between the groups. VO2 increased from 130+/-29 to 172+/-29 mL/min/m2 in the propofol group and from 118+/-24 to 167+/-27 mL/min/m2 in the placebo group. Mean arterial pressure and heart rate were lower in the propofol group (p < 0.05). Stress hormone levels did not differ between the groups.nnnCONCLUSIONnLow-dose propofol infusion and additional diazepam as required does not decrease total-body VO2 compared with a pure diazepam bolus-dose technique when administered for light sedation during the immediate recovery period after CABG surgery.

Noradrenergic and dopaminergic effects of nomifensine in healthy volunteers.

Intravenous doses (100 mg in 20 minutes) of the antidepressant drug nomifensine, administered to male volunteers, increased heart rate and blood pressure, elevated the plasma levels of norepinephrine and its metabolite 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), and powerfully stimulated growth hormone release and inhibited the secretion of prolactin. Oral nomifensine, either as a single 100 mg dose or as a similar dose after 2 weeks treatment with the drug (150 mg/day), caused none of the above effects. This was in line with the limited (less than 30%) oral bioavailability of the active, unconjugated form of the drug, estimated in the same subjects. MHPG in plasma was slightly but consistently reduced by the 2 weeks treatment, suggesting reduced turnover of norepinephrine. The observed clinical effects of nomifensine are compatible with uptake inhibition and augmented release of norepinephrine and dopamine and possibly direct agonistic effects on dopamine receptors. Although nomifensine was withdrawn from the market because of immunologic complications, it serves as a model compound of a new pharmacologic class of antidepressants, devoid of many of the disturbing side effects of the tricyclic drugs.