Inhibition of 3,4-methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4-dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: implications for mechanisms of neurotoxicity.

3,4-Methylenedioxymethamphetamine (MDMA)'s O-demethylenated metabolite, 3,4-dihydroxymethamphetamine (HHMA), has been hypothesized to serve as a precursor for the formation of toxic catechol-thioether metabolites (e.g., 5-N-acetylcystein-S-yl-HHMA) that mediate MDMA neurotoxicity. To further test this hypothesis, HHMA formation was blocked with dextromethorphan (DXM), which competitively inhibits cytochrome P450 enzyme-mediated O-demethylenation of MDMA to HHMA. In particular, rats were randomly assigned to one of four treatment groups (n = 9-12 per group): (1) Saline/MDMA; (2) DXM/MDMA; (3) DXM/Saline; (4) Saline/Saline. During drug exposure, time-concentration profiles of MDMA and its metabolites were determined, along with body temperature. One week later, brain serotonin (5-HT) neuronal markers were measured in the same animals. DXM did not significantly alter core temperature in MDMA-treated animals. A large (greater than 70%) decrease in HHMA formation had no effect on the magnitude of MDMA neurotoxicity. These results cast doubt on the role of HHMA-derived catechol-thioether metabolites in the mechanism of MDMA neurotoxicity.

Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses.

At certain doses, the psychoactive drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") destroys brain serotonin axon terminals. By causing increases in plasma MDMA concentrations that exceed those predicted by the increase in dose, nonlinear pharmacokinetics has the potential to narrow the range between safe and neurotoxic doses of MDMA. The present study sought to determine whether the pharmacokinetics of MDMA in nonhuman primates are nonlinear and, if they are, to identify plasma concentrations of MDMA at which nonlinear accumulation of MDMA occurs. Four different oral doses of MDMA were tested in the same six squirrel monkeys in random order. At each dose, pharmacokinetic parameters for MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 3,4-methylenedioxyamphetamine were determined. Doses were selected to be equivalent to 0.4, 0.8, 1.6, and 2.8 mg/kg doses in humans. The maximal concentration (C(max)) and area under the curve (AUC) of MDMA increased nonlinearly with dose, whereas the C(max) and AUC of the metabolites HHMA and HMMA remained relatively constant. Nonlinear MDMA pharmacokinetics occurred at plasma MDMA concentrations of 100 to 300 ng/ml and above. The half-life (T(1/2)) of MDMA and its metabolites also increased with dose. These results firmly establish nonlinear pharmacokinetics for MDMA in squirrel monkeys and indicate that nonlinear MDMA accumulation occurs at plasma MDMA concentrations that develop in humans taking typical doses. By raising MDMA concentrations and prolonging its action, nonlinear pharmacokinetics and T(1/2) prolongation, respectively, may influence the likelihood and severity of MDMA toxicities (including brain serotonin neurotoxicity).

Stereochemical analysis of 3,4-methylenedioxymethamphetamine and its main metabolites in human samples including the catechol-type metabolite (3,4-dihydroxymethamphetamine).

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a designer drug commonly misused in large segments of young populations. MDMA is usually formulated in tablets of its racemate (1:1 mixture of its enantiomers) in doses ranging from 50 to 200 mg. MDMA has an enantioselective metabolism, the (S)-enantiomer being metabolized faster than the (R)-enantiomer. Different pharmacologic properties have been attributed to each enantiomer. The carbon responsible for MDMA chirality is preserved along its metabolic disposition. An analytical method has been developed to determine MDMA enantiomers and those from its major metabolites, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymeth-amphetamine (HHMA), and 4-hydroxy-3-methoxymethamphet-amine (HMMA). It has been applied to the analysis of plasma and urine samples from healthy recreational users of MDMA who participated voluntarily in a clinical trial and received 100 mg (R,S)-MDMA. HCl orally. (R)/(S) ratios both in plasma (0-48 h) and urine (0-72 h) for MDMA and MDA were >1 and <1, respectively. Ratios corresponding to HHMA and HMMA, close to unity, deviate from theoretical expectations and are most likely explained by the ability of MDMA to autoinhibit its own metabolism. The short elimination half-life of (S)-MDMA (4.8 h) is consistent with the subjective effects and psychomotor performance reported in subjects exposed to MDMA, whereas the much longer half-life of the (R)-enantiomer (14.8 h) correlates with mood and cognitive effects experienced on the next days after MDMA use.

Metabolism of 5-(glutathion-S-yl)-alpha-methyldopamine following intracerebroventricular administration to male Sprague-Dawley rats.

5-(Glutathion-S-yl)-alpha-methyldopamine [5-(GSyl)-alpha-MeDA] is a putative metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine and 3,4-(+/-)-(methylenedioxy)methamphetamine. Glutathione (GSH) conjugates of several polyphenols are biologically (re)active. Therefore, as part of our studies on the role of 5-(GSyl)-alpha-MeDA in MDA-mediated neurotoxicity, we determined the regional brain metabolism of 5-(GSyl)-alpha-MeDA (720 nmol) following intracerebroventricular administration to male Sprague-Dawley rats. 5-(GSyl)-alpha-MeDA was rapidly cleared from all brain regions examined, and regional differences in the distribution of gamma-glutamyl transpeptidase (gamma-GT) correlated with the formation of 5-(cystein-S-yl)-alpha-methyldopamine (5-[CYS]-alpha-MeDA). We also observed the formation of 5-(N-acetyl-L-cystein-S-yl)-alpha-MeDA (5-[NAC]-alpha-MeDA) in all brain regions, indicating that the brain has the ability to synthesize mercapturic acids. Peak concentrations of 5-(NAC)-alpha-MeDA were found in the order: hypothalamus > midbrain/diencephalon/telencephalon > pons/medulla > hippocampus > cortex > striatum. In contrast to 5-(GSyl)-alpha-MeDA and 5-(CYS)-alpha-MeDA, 5-(NAC)-alpha-MeDA was eliminated relatively slowly from the brain. Differences were also found in cystein conjugate N-acetyltransferase activity in microsomes prepared from the various brain regions, but little difference was observed in brain cytosolic N-acetyl-L-cysteine conjugate N-deacetylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Ibopamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in congestive heart failure.

Ibopamine is an orally administered dopamine agonist which is rapidly converted to its active metabolite epinine by esterase hydrolysis. Ibopamine acts predominantly as a vasodilator and inhibitor of neuroendocrine activation in congestive heart failure, but also has mild positive inotropic effects at higher doses. The beneficial effects on cardiac and systemic haemodynamic parameters seen in short term studies have been maintained in predominantly noncomparative trials for up to 1 year, and improvements in New York Heart Association (NYHA) functional class and clinical symptoms have been observed in patients with congestive heart failure of varying severity. In double-blind studies conducted in small numbers of patients, the efficacy of ibopamine was comparable to that of digoxin, captopril, enalapril and hydrochlorothiazide. Ibopamine can successfully replace treatment with intravenous dopamine in patients with severe heart failure, and is effective and well tolerated when administered in combination with digoxin, diuretics and/or angiotensin converting enzyme (ACE) inhibitors. Ibopamine has shown no detrimental effects on renal function, few adverse effects on neurohormonal parameters and has demonstrated no significant proarrhythmic properties at therapeutic doses in patients with congestive heart failure. No adverse metabolic effects were observed during ibopamine therapy in patients with diabetes mellitus, nor did ibopamine have detrimental effects in patients with chronic obstructive pulmonary disease. While reliable evidence is required concerning effects on mortality before the role of ibopamine can be clearly defined, the drug appears to be a useful agent for combination with conventional therapies in treating patients with mild to severe congestive heart failure.

Kinetics and pharmacodynamic effects of a novel prodrug of N-methyldopamine at single dose in healthy volunteers.

Kinetics and cardiovascular effects of SIM2055 (CAS 103878-96-2), the 4-O-phosphate of N-methyldopamine (epinine), at single dose by the oral route were studied in 9 healthy adult volunteers (6 women and 3 men) ranging in age from 22 to 39 years. SIM2055 was administered at increasing doses (from 100 to 300 mg). Plasma concentrations of free epinine were not detectable after the 100 mg dose, but were measurable after the 200 mg and 300 mg doses. Pharmacokinetic data suggest that in man SIM2055 is promptly absorbed, quickly hydrolysed to epinine, metabolized to homovanillic acid and 3,4-dihydroxy-phenylacetic acid, conjugated with sulphuric acid and excreted in large amounts into urine. The 24-h urinary recovery of the 3 metabolites considered together, expressed as a percentage of the dose of SIM2055 administered, was 78 +/- 6 with the 100 mg dose, 66 +/- 11 with the 200 mg dose and 55 +/- 6 with the 300 mg dose (mean +/- S. D.). SIM2055 was well tolerated by all subjects. After its administration, the heart rate and the systolic and diastolic blood pressure presented no systemic or clinically significant variations. No substantial changes were observed with the ECG parameters. No subject reported gastric or systemic effects during the period of observation.

Ocular pharmacokinetics and pharmacodynamics in rabbits of ibopamine, a new mydriatic agent.

Ibopamine is an original dopamine analogue. The drug, instilled in the conjunctival sac, induces mydriasis and is well-tolerated. In the present study, we have investigated the pharmacokinetic and pharmacodynamic characteristics of ibopamine after ocular application. Ibopamine produces a dose-dependent mydriasis endowed with very interesting characteristics: rapid onset, marked pupil dilation and rapid return to normal pupillary diameter. Ibopamine is well absorbed through the cornea, it is rapidly hydrolysed by esterases to epinine and the mydriatic effect is correlated with the concentration of epinine in the aqueous humor. The results of the experiments with the alpha 1-antagonists bunazosin and thymoxamine, and with reserpine, suggest that the mydriatic effect of ibopamine is obtained by direct stimulation of the alpha 1-adrenergic receptors; pretreatment with bunazosin almost completely inhibits the mydriatic activity of ibopamine; the mydriasis is also antagonized by thymoxamine. Pretreatment with reserpine has no effect on the extent of the mydriasis induced by ibopamine.

Investigation of a possible pharmacokinetic interaction between ibopamine and isosorbide-5-mononitrate.

The possibility of a pharmacokinetic interaction between isosorbide-5-mononitrate (5-ISMN) and epinine, the active metabolite of ibopamine, has been investigated in 8 healthy male subjects given single doses of 200 mg ibopamine and 20 mg 5-ISMN, separately and together. The plasma 5-ISMN concentration-time profile was the same whether 5-ISMN was administered concomitantly with ibopamine or alone [AUC(o-t): 2.24 micrograms.ml-1.h after 5-ISMN alone, 2.16 micrograms.ml-1.h after 5-ISMN+ibopamine]. The plasma concentrations of total and free epinine and the urinary recovery of total epinine, homovanillic acid and dihydroxyphenylacetic acid, too, were not different when ibopamine was administered alone or concomitantly with 5-ISMN. The intake of ibopamine did not change the blood pressure and heart rate. The decrease in diastolic blood pressure induced by 5-ISMN was not influenced by concomitant intake of ibopamine. The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between 5-ISMN and ibopamine.

Hemodynamic effects and pharmacokinetics of long-term therapy with ibopamine in patients with chronic heart failure.

To evaluate the attenuation of the effectiveness of long-term ibopamine therapy, ibopamine was administered in single doses of 100 and 200 mg to 10 patients with chronic heart disease. The hemodynamic studies using Swan-Ganz catheter and pharmacokinetic studies were carried out. Ibopamine was found to increase cardiac output and stroke index and to decrease systemic vascular resistance in this acute study. Six patients underwent long-term therapy with the drug and were evaluated for the development of tolerance. Three out of 5 patients experienced an improvement in NYHA functional class after 12-23 weeks of treatment. There was no attenuation in the effects of ibopamine on hemodynamics, pharmacokinetic parameters remained almost unchanged, and tolerance was not observed. These results suggest that ibopamine is useful as an orally administered anti-heart failure drug.

Dopaminergic drugs in the management of chronic heart failure.

The importance of the dopaminergic system in heart failure is unknown and the therapeutic potential of orally active compounds stimulating dopaminergic receptors has yet to be established. Despite similar acute haemodynamic changes in heart failure and despite a comparable profile of receptor stimulation, oral levodopa (the prodrug of dopamine) and oral ibopamine (the prodrug of epinine) produce opposite effects on plasma norepinephrine and have different pharmacokinetics. Placebo-controlled studies indicate a beneficial effect of ibopamine on exercise tolerance in patients with heart failure, whereas invasive evaluation of left ventricular function indicate that at the doses used in these trials, ibopamine does not act as a positive inotropic drug but rather as a vasodilator. This suggests that DA1 and DA2 receptor stimulation may be beneficial in heart failure. Further studies are, however, needed to specify the exact role of this therapeutic approach in comparison with other agents, such as ACE inhibitors, also able to modulate neuro-humoral activation in heart failure.

[Ibopamine--pharmacologic principles]. / Ibopamin--Pharmakologische Grundlagen.

Ibopamine is the 3,4-diisobutyrylester of N-methyl-dopamine (epinine). Oral ibopamine is transferred during and after resorption (first-pass effect) to the active metabolite epinine by blood and tissue esterases. 200 mg ibopamine lead to maximal plasma concentrations of 60 to 100 nmol/l. The ratio of total epinine to free epinine is about 10:1. Epinine is intensively metabolized so that less than 1% of the oral dosage is eliminated via the kidneys. The plasma half-life of epinine amounts to about 45 min. Epinine activates dopamine (DA1, DA2)-, beta 1- and beta 2- as well as alpha-receptors. The affinity is of the other: DA1, DA2 greater than beta 1, beta 2 greater than alpha. Stimulation of postsynaptic DA1-receptors predominantly induces renal vasodilation and increase in diuresis. Stimulation of presynaptic DA2-receptors leads to a reduced liberation of noradrenaline (NA) from its presynaptic storage vesicles. This effects a decrease in NA-plasma concentration, peripheral resistance, and it is partly responsible for diuresis and natriuresis. Investigations in isolated organs have shown that the action on DA1, DA2-receptors occurs in the range of 100-700 nmol/l), whereas stimulation of beta 1- and beta 2-receptors affords significantly higher levels (affinity to human cardiac beta 1- and beta 2-receptors 5-10 mumol/l). alpha-receptors are only stimulated at still higher concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic and pharmacodynamic interactions between single oral doses of ibopamine and food in normal man.

The pharmacokinetic and pharmacodynamic interactions between single oral doses of 200 mg ibopamine and a standard cold 3100 kJ meal were assessed in 12 normal male subjects, who were studied on 4 occasions, receiving either ibopamine or matched placebo (double-blind) in fasting condition or at the end of a meal. Treatments were randomly allocated in a period-balanced within-subject cross-over study design. The plasma concentrations of epinine (N-methyldopamine) were extensively profiled up to 4 h after dosing. Food caused a profound reduction of both Cmax and AUC of unconjugated epinine with a prolongation of Tmax. The subjects were furthermore profiled in detail up to 4 h after dosing by transthoracic impedance cardiography. Food caused substantial and protracted effects that affected virtually all parameters profiled. Ibopamine had clear cardiac performance enhancing effects only over the first hour after dosing. These effects were furthermore subject to significant food interaction. It therefore appeared that food resulted in a profound blunting of both ibopamine's pharmacokinetic and pharmacodynamic characteristics.

Ibopamine kinetics after single and multiple dosing in patients with congestive heart failure.

The pharmacokinetics of ibopamine after single and multiple dosing was studied in 20 patients with congestive heart failure (CHF) of NYHA functional class II. Ibopamine 100 mg was given 3 times a day for 7 days in 6 patients and for 30 days in the other 14 patients. Plasma pharmacokinetics of total (mainly conjugated) and free epinine was studied after the first dose and on the 3rd, 7th and 30th days of treatment. The urinary recoveries of total epinine, HVA and DOPAC were measured in 5 patients for 24 h after ibopamine ingestion on the 1st and 30th days. Plasma pharmacokinetics of ibopamine did not vary during the repeated administration of the drug. In the course of the treatment, total epinine elimination t1/2 showed no significant variations. The build-up of Cmax, Cmin and AUC of total epinine observed after multiple dosing was as expected on the basis of the interval adopted between the doses of ibopamine and of the elimination t1/2 of total epinine. Pharmacokinetic parameters of free epinine did not show significant variations during the course of the treatment. The amounts of HVA and DOPAC recovered in urine on the 1st and 30th days of treatment were similar while the amount of total epinine was greater on the 30th day, the increment mainly reflecting a partial carry over of the less rapidly excreted conjugated epinine from the last previous doses. The results obtained for free epinine plasma levels and for the urinary recoveries of ibopamine metabolites thus indicated that no saturation of the enzymes involved in ibopamine metabolism occurred.

Study of the bioequivalence of three oral formulations of ibopamine in healthy volunteers.

Ibopamine (SK & F 100168-A), a new chemical entity, is capable of eliciting positive inotropic effects accompanied by vasodilating, diuretic and saliuretic activity after oral administration. The relative bioavailability and bioequivalence of 3 oral presentations of Ibopamine was examined after a single oral dose. Thirty healthy subjects (15 males and 15 females) received the 3 formulations at one-week intervals according to "single-blind assayer" latin-square crossover design. Two tablets of 100 mg ibopamine (SIMES formulations), 2 tablets of 100 mg ibopamine (UK formulation) and 1 tablet of 200 mg ibopamine (US-Tiltab formulation) were used. In a 4th occasion, all volunteers received again the 200 mg-tablet of the US-Tiltab formulation in order to assess the intra-individual variability of its oral bioavailability. Free epinine plasma levels were measured before and 10, 20, 30, 45, 60, 90, 105 min and 2, 2.5, 3, 4, 6, 8 and 24 h after each oral administration. Free epinine was assayed by HPLC/electrochemical detection method. The amount of drug absorbed as measured by the area under the curve, AUC0-8 h, and the rate of absorption, as measured by Cmax and tmax, were compared by examining the symmetric 95% confidence intervals. If the symmetric 95% confidence interval with respect to AUC is between 80% and 120%, two formulations are considered bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacokinetics of ibopamine on different diseases and conditions.

The pharmacokinetics of ibopamine was studied after single dose and after single and multiple dosing. The studies after single dose were conducted in normal subjects (NS) and in patients with congestive heart failure (CHF) of NYHA functional classes II, III and IV, in patients with chronic renal impairment (CRI), with hepatic cirrhosis (HC) and in elderly patients. Furthermore, ibopamine-quinidine pharmacokinetic interaction and the effects of food on plasma kinetics were evaluated in NS. The studies after single and multiple dosing were conducted in CHF patients. The effects were also studied of chronic oral ibopamine treatment on the pharmacokinetics of digoxin after chronic oral dosing and of treatment with digoxin on ibopamine pharmacokinetics. Ibopamine appears to be rapidly and extensively absorbed, quickly hydrolyzed to epinine and then excreted mainly through the kidneys either after being sulpho-conjugated or oxidized to homovanillic acid and 3,4-dihydroxyphenylacetic acid. Epinine is thought to be the therapeutically active moiety of the drug. In patients with CHF epinine pharmacokinetics does not depend on the NYHA functional class, and it falls within the same area as that in NS; the pharmacokinetics of epinine does not vary during the repeated administration of the drug for one month. In patients with CHF the pharmacokinetic data do not suggest the need to adjust the dose according to the NYHA functional class. In patients with CRI the pharmacokinetics of epinine does not vary with the degree of renal impairment. In HC patients AUC and Cmax of epinine seem to be higher than in NS; in these patients a higher amount of epinine is excreted into urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Ibopamine. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy.

Ibopamine is an orally active derivative of dopamine which undergoes hydrolysis to the active moiety epinine. In single-dose and short term studies ibopamine demonstrated inotropic and vasodilating properties. It improved cardiac and systemic haemodynamics by increasing cardiac output and reducing afterload, both at rest and during exercise. In non-comparative clinical studies ibopamine produced benefits in functional class and clinical symptoms for up to 1 year in patients with moderate to severe congestive heart failure. Similarly, short term comparative studies with placebo have indicated ibopamine as a useful adjunct in the treatment of patients maintained on conventional therapy with digoxin, diuretics and vasodilators. Preliminary evidence also suggests that ibopamine is as effective as digoxin in the treatment of patients with moderate congestive heart failure. Should the results of long term comparative studies confirm these encouraging findings, ibopamine will be a useful addition to the drugs available or as an alternative to digoxin for the treatment of congestive heart failure.

Ibopamine kinetics after a single oral dose in patients with congestive heart failure.

The kinetics of ibopamine, the 3,4-diisobutyryl ester of N-methyldopamine (epinine), was assessed in 27 patients with congestive heart failure (CHF) and 8 healthy normal subjects (NS). Nine patients were in functional class IV according to the NYHA definition, 9 in class III and 9 in class II. Ibopamine was administered at a single oral dose of 100 mg. Epinine, both free and total (mainly conjugated), plasma concentrations and urinary recoveries of total epinine, HVA and DOPAC were studied. The results showed that ibopamine kinetics is not substantially different in CHF patients and in NS. In both groups the absorption of the drug was equally prompt and elevated. Mean Cmax, tmax and AUC infinity values of total epinine in CHF patients did not differ significantly from those in NS. In CHF patients t 1/2 of total epinine was significantly higher than in NS (4.1 +/- 0.2 h vs 3.1 +/- 0.2 h, mean +/- SE). Mean Cmax, tmax, AUCt and MRT values of free epinine in CHF patients were not significantly different from those in NS. The urinary recovery of the 3 metabolites considered together was comparable in CHF patients and in NS. The mean +/- SE total urinary recoveries in the 24 h after dosing, expressed as percentages of the administered dose, were 60 +/- 3 in CHF patients and 69 +/- 4 in NS. Conjugated epinine in urine was found to be constituted by 3-O-sulfate (84%) and 4-O-sulfate (16%).

Pharmacokinetics of ibopamine in patients with renal impairment.

The pharmacokinetics of a single oral dose of ibopamine 100 mg were studied in 15 patients with various degrees of chronic renal impairment (CRI) and in 8 subjects with normal renal function and of comparable age, taken as a control group. Plasma total (mainly conjugated) and free epinine and urinary metabolites (total epinine, HVA and DOPAC) were measured. Both total and free epinine were detectable at the earliest sampling time (15 min) in CRI patients and in normal subjects, thus confirming the promptness of ibopamine absorption. Free epinine pharmacokinetic parameters did not show any appreciable differences among the groups with different degrees of renal impairment, and no statistically significant differences were observed between normal subjects and CRI patients. Progressive renal impairment was associated with higher Cmax, longer t1/2 and larger AUC infinity of total epinine, and with reduced urinary elimination of total epinine and metabolites. Statistically significant differences (p less than 0.01) in Cmax/70 kg, t1/2, and AUC infinity/70 kg of total epinine were found between normal subjects and patients with mild renal impairment. No statistically significant differences were observed in 24-h urinary recoveries of both total epinine and metabolites between normal subjects and patients with mild renal impairment. No adverse effects were experienced during the course of the study. As the kinetics of ibopamine's active moiety, free epinine, were not apparently altered by chronic renal failure, adjustment of its dosage should not be necessary in renal diseases.

Pharmacokinetics and pharmacodynamics of single oral doses of ibopamine, quinidine and their combination in normal man.

The pharmacokinetics and haemodynamics (phono- and impedance cardiography) of single oral doses of 200 mg ibopamine (SK&F 100168), 400 mg quinidine sulphate, and their combination, have been assessed in 6 healthy male volunteers. No significant differences in the mean pharmacokinetic parameters of either drug were seen between the single and combined doses. Ibopamine caused an increase in mean estimated stroke volume (SV +29% for the maximum change from baseline and +15% cumulatively over the first h) with no change in mean heart rate (HR) or QTc. Quinidine administered concomitantly blunted the response of SV. A tendency to a lower mean concentration of epinine early after administration of the combination may have contributed to the difference. Quinidine alone hardly affected SV (-3% from baseline over the first h), but it did increase mean HR (+6 beats.min-1) and mean QTc (+30 ms). These changes were sustained up to 8 h after dosing, and were not affected by concurrent ibopamine.