Performance of the continuous glucose monitoring system (CGMS) during development of ketosis in patients on insulin pump therapy.

AIMS: Ketoacidosis is one of the most severe complications of Type 1 diabetes. Development of ketosis leads to substantial shifts in electrolyte and ion concentrations in the different fluid compartments of the body. This study was performed to investigate the performance of the continuous glucose monitoring device (CGMS) during ketoacidosis. METHODS: Twelve patients with Type 1 diabetes using continuous subcutaneous insulin infusion (CSII) participated in this trial [10 women, two men; age (mean +/- sd) 34 +/- 9 years; disease duration 17 +/- 10 years; HbA(1c) 7.1 +/- 1.0%]. In the morning, patients ate breakfast and the insulin pump was stopped at 11.00 h and restarted after 8 h. Observation parameters during this experiment were: blood glucose (laboratory reference and CGMS), 3-hydroxy-butyrate (3-OHB), pH, Na, pCO(2), pO(2), free fatty acids, osmolarity, standard bicarbonate, and lactate. RESULTS: Blood glucose increased and reached a plateau within 2 h after pump stop (from 6.2 +/- 2.56 to 16.7 +/- 4.44 mmol/l, P < 0.001). A constant increase in 3-OHB (from 0.0 to 0.8 +/- 0.5 mmol/l, P < 0.001) and decrease in pH (from 7.43 +/- 0.02 to 7.40 +/- 0.03, P < 0.05) indicated ketosis development. Na decreased from 141 +/- 1.4 to 138 +/- 2.8 mmol/l, P < 0.001). Free fatty acids increased from 0.577 +/- 0.330 to 1.330 +/- 0.462 mmol/l (P < 0.001). The CGMS values showed excellent agreement with the capillary blood laboratory method during the entire experiment, and a modified error grid analysis revealed that 99.5% of the values were in the clinically acceptable zones A and B. CONCLUSION: The CGMS device was confirmed to be reliable and accurate during the development of hyperglycaemia and ketotic conditions.

Camphor-Crataegus berry extract combination dose-dependently reduces tilt induced fall in blood pressure in orthostatic hypotension.

In order to test the efficacy of a combination of natural D-camphor and an extract of fresh crataegus berries (Korodin Herz-Kreislauf-Tropfen) on orthostatic hypotension, two similar, controlled, randomized studies were carried out in a balanced crossover design in 24 patients each with orthostatic dysregulation. The camphor-crataegus berry combination (CCC) was orally administered as a single regimen in 3 different dosages of 5 drops, 20 drops and 80 drops; a placebo with 20 drops of a 60% alcoholic solution served as control. Orthostatic hypotension was assessed with the tilt table test before and after medication. Source data of both studies were pooled and meta-analytically evaluated for all 48 patients. CCC drops decreased the orthostatic fall in blood pressure versus placebo, as almost uniformly established at all times by mean arterial pressure and diastolic blood pressure. Mean arterial pressure demonstrated the very fast onset of action by a clearly dose-dependent statistically significant effect even after 1-minute orthostasis. Increase of mean arterial pressure as compared to the orthostasis test before medication was on average 4.5 mmHg. CCC affected diastolic blood pressure after 1 minute of orthostasis in all dosages as compared to placebo. A statistically significant effect of the highest dose of 80 drops on diastolic blood pressure could be demonstrated after 1-, 3-, and 5-minute orthostasis. The hemodynamic findings of a stabilizing effect on arterial pressure in orthostasis corroborate the long-term medical experience with CCC and justify the indication orthostatic hypotension.

The pharmacological potency of various AT(1) antagonists assessed by Schild regression technique in man.

RATIONALE: A quantitative technique was used to compare the pharmacological potency in healthy volunteers of angiotensin II receptor antagonists (AIIA): candesartan cilexetil, losartan, irbesartan, valsartan, and telmisartan. METHODS: In a randomised, double-blind, parallel-group (4x12 subjects) study, single oral doses of candesartan cilexetil 4, 8 and 16 mg, losartan potassium 25, 50 and 100 mg, valsartan 40, 80 and 160 mg, and irbesartan 75, 150 and 300 mg were administered on three consecutive days. Telmisartan 20, 40 and 80 mg was similarly evaluated in 12 volunteers in an open amendment. Angiotensin II (Ang II) antagonistic effects were determined in vivo from rightward shifts in Ang II dose-response curves for diastolic blood pressure (BP) and dose ratios were calculated. Apparent K(i)-doses, i.e. doses (in mg) required to induce a two-fold shift in Ang II dose-response curves (equivalent to approx. 50% blockade of receptors) were determined, using Schild regression analysis. RESULTS: All treatments dose-dependently attenuated increases in diastolic BP induced by infusion of exogenous Ang II. Candesartan cilexetil appeared to have a more pronounced increase in effect following cumulative dosing. At 24 hours, apparent K(i)-doses were: candesartan cilexetil 6 mg, irbesartan 123 mg, valsartan 93.5 mg, and telmisartan 54 mg. It was not possible to determine an apparent K(i)-dose for losartan at 24 hours. CONCLUSION: Consistent with results from experimental pharmacology, candesartan cilexetil displayed the highest pharmacological potency (i.e. antagonistic activity per mg substance) of the AIIAs tested. Apparent K(i)-doses at 24 hours were within the dose range recommended for clinical use in patients with hypertension.

Time course and extent of angiotensin II antagonism after irbesartan, losartan, and valsartan in humans assessed by angiotensin II dose response and radioligand receptor assay.

OBJECTIVES: To compare the angiotensin II antagonistic properties of the usual recommended oral starting doses of various angiotensin II receptor antagonists-150 mg irbesartan, 80 mg valsartan, and 50 mg losartan-in humans. SUBJECTS AND METHODS: Eighteen healthy men were enrolled in a double-blind, randomized crossover study. Angiotensin II dose-effect curves of diastolic blood pressure and radioreceptor assay were performed before and up to 47 hours after single and multiple doses of the antagonists. The rightward shift of the angiotensin II dose-effect curves (dose ratio-1) assessed the antagonistic effects in vivo. The degree of receptor occupancy in plasma was detected by a rat lung radioreceptor assay ex vivo in vitro. RESULTS: All of the drugs clearly showed antagonistic effects to angiotensin II in vivo (dose ratio-1) and in vitro (radioreceptor assay). Within the given doses the dose ratio-1 for irbesartan was greater than for valsartan and losartan after single and repetitive dosing, reaching statistical significance at various time points up to 36 hours versus valsartan and up to 47 hours versus losartan. The apparent half-lives of the decay of the effects were approximately 8 hours for valsartan and losartan, whereas 15 to 18 hours were obtained with irbesartan. These findings were supported by the radioreceptor assay data: the percentage of receptor occupancy for irbesartan was significantly greater than for valsartan and losartan up to 47 hours. CONCLUSION: Angiotensin II antagonistic effects of irbesartan, valsartan, and losartan were compared. Irbesartan showed the slowest decay and longest duration of its antagonistic effects. With the recommended initial doses used in this study, the following rank order of antagonistic intensity was obtained: irbesartan > valsartan > losartan. The findings of this study, specifically the longer-lasting effects of irbesartan, may have clinical implications.

Angiotensin II antagonism and plasma radioreceptor-kinetics of candesartan in man.

AIMS: The pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose-effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p.l.c. METHODS: Twelve healthy male volunteers received single oral doses of 4, 8 and 16 mg candesartan cilexetil and placebo. Plasma was obtained for h.p.l.c. and r.r.a. (receptors: rat lung; radioligand: [125I-Sar1Ile8]-angiotensin II). Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose-effect curves were fitted according to an Emax model and dose ratios (DR) calculated from the antagonist induced rightward shifts. RESULTS: Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6-9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4-7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent Ki-doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible. CONCLUSIONS: A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off-rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.

Pharmacodynamic and pharmacokinetic properties of an angiotensin II receptor antagonist--characterization by use of Schild regression technique in man.

OBJECTIVE: The pharmacodynamic properties of a new angiotensin II receptor antagonist (BAY 10-6734) in humans were to be quantitatively characterized from the rightward shifts of the agonist dose-response curves after administration of different doses of the antagonist. METHODS: 24 healthy male volunteers received single oral doses of 20-300 mg BAY 10-6734. Before and up to 23 h post dosing (p.d.) plasma was obtained for HPLC measurement of parent compound and active metabolite BAY 10-6735. Exogenous angiotensin II was infused in increasing dose steps until blood pressure had increased by +25 mmHg. Angiotensin II dose-response curves were fitted individually using the sigmoidal Emax model. From the antagonist-induced rightward shifts, as compared to a premedication curve, dose ratios (DR) were determined and DR-1 plotted versus applied dosages and measured plasma concentrations. From these Schild regression plots the fictive doses and concentration (Ki) inducing a DR-1 = 1, i.e. a 2-fold shift in agonist dose-response curves, were derived. The "doubling (t2.0) time" of the apparent Ki doses was calculated. RESULTS: BAY 10-6734 dose-dependently induced rightward shifts of the angiotensin II blood pressure response curves, mean maximum DR at 2 h p.d. ranged from 42 (80 mg) to 216 (300 mg), and at 23 h p.d. decreased to about 2 (80 mg) to 4 (300 mg). Pharmacodynamic (3.4-4.6 h) and pharmacokinetic half-lives (3.4-4.3 h) were nearly identical. Apparent Ki doses increased from about 1-2 mg at 2 h p.d. to about 80-100 mg at 23 h p.d., their time course revealed a doubling (t2.0) time of 3.5-3.8 h. A Ki concentration of about 10 micrograms/l was obtained for the active metabolite BAY 10-6735. CONCLUSIONS: Oral administration of BAY 10-6734 in man antagonized angiotensin II dose blood pressure response curves in a dose-dependent manner. The time kinetics of the pharmacodynamic effect, derived from the decay of DR-1 values, as well as the doubling time of the apparent Ki values well agreed with the pharmacokinetic half-life. Schild regression revealed competitive angiotensin II antagonistic properties within the dose/concentration range tested. This technique was shown to be an adequate means to evaluate pharmacodynamic potency and kinetic behavior of an angiotensin II receptor antagonist in vivo.

Beta-adrenergic stimulation enhances left ventricular diastolic performance in normal subjects.

To determine the effects of beta-adrenergic stimulation on transmitral Doppler echocardiography flow characteristics of left ventricular diastolic filling, we studied 10 healthy volunteers aged 23-31 years (mean age, 26.6 years) during intravenous infusion of isoprenaline in consecutive steps of 0.1, 0.2, 0.4, 0.75, and 1.5 micrograms/min (each for 15 min). Saline control infusion was given in the same manner in a crossover and blinded protocol. Compared with the infusion of placebo, stepwise increasing doses of isoprenaline caused a dose-related increase in early and late diastolic filling velocities and velocity-time integrals, a lengthening of the acceleration time, and a shortening of the deceleration and filling time. The chosen method proved highly sensitive, as statistically significant changes were detectable at the lowest dose of 0.1 microgram/min for all variables except velocity-time integral of late filling and deceleration time (> or = 0.2 microgram/min). The effects related to dose in a log-linear fashion except for the lengthening of the acceleration time (early ceiling), the increase of peak early filling velocity (increased steepness at higher doses), and the shortening of the filling time. Inclusion of the associated increases in heart rate and systolic blood pressure and the decrease in diastolic blood pressure blunted all treatment contrasts except for the increase of peak early filling velocity. In addition, the hemodynamics with respect to heart rate and loading conditions were not altered at low dosages of drug (< 0.4 microgram/min). Effects of at least the peak early filling velocity must be interpreted as an active adrenergically mediated myocardial relaxation process. These findings have potentially important clinical implications for this noninvasive, readily available, and convenient technique in clinical pharmacology, stress testing, and possibly therapeutic interventions in diastolic dysfunction in humans.

Influence of antihypertensive therapy with cilazapril and hydrochlorothiazide on the stiffness of the aorta.

The purpose of this study was to examine the effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on the elastic properties of the aorta. A standard diuretic antihypertensive drug, hydrochlorothiazide, served for comparisons. Increased aortic stiffness leads to a reduction of the buffering windkessel function and is a major component in the pathophysiology of systolic hypertension, inducing an increase in left ventricular afterload and arterial pulsatile stress as well as a decrease in the subendocardial blood supply. Stiffness of arteries increases with age and blood pressure, and depends on the functional elastic structures of the aortic wall. ACE inhibitors have been shown to directly influence elastic properties of peripheral arteries. Seventeen patients with mild to moderate essential hypertension (age 45-67 years) were treated for 3 months double-blind randomized with either cilazapril (C) 5 mg daily (n = 9) or hydrochlorothiazide (HCTZ) 25 mg daily (n = 8). Aortic elastic properties were noninvasively assessed by measurement of pulse wave velocity along the aorta at rest and during isometric handgrip stress. Accelerated pulse wave velocity indicates elevated arterial stiffness and vice versa. A pressure standardized index of aortic cross-sectional distensibility (2 m) was calculated from arterial mean pressure and pulse wave velocity. Compared with pretreatment values, both therapies significantly reduced blood pressure and pulse wave velocity at rest (C: 9.4 +/- 0.9 vs. 7.7 +/- 0.7 m/sec; HcTZ: 8.9 +/- 0.3 vs. 7.8 +/- 0.4 m/sec; means +/- SEM p < 0.05). During isometric stress only C showed a significant decrease in pulse wave velocity (C: 11.3 +/- 0.8 vs. 9.1 +/- 0.8 m/sec; HCTZ: 9.9 +/- 0.5 vs. 9.0 +/- 0.5 m/sec; means +/- SEM p < 0.05). The index 2m at rest and during handgrip increased significantly (p < 0.05) after C but not after HCTZ. With cilazapril we obtained steeper slopes for the treatment-induced reductions in blood pressure and pulse wave velocity for both rest and handgrip stress values. Correlation of the data at rest and during stress revealed a direct relationship between blood pressure and pulse wave velocity. HCTZ linearly extended the relation observed before treatment toward lower values of blood pressure and corresponding pulse wave velocity without changing the relation per se. Cilazapril, in contrast, moved the relation between these variables and decelerated the pulse wave velocities to a greater extent than would have been expected from the corresponding blood pressure reduction (delta approximately 1 m/sec). These results in patients with mild to moderate essential hypertension support the idea that ACE inhibitors, in addition to reducing blood pressure, may exert an additional hemodynamic effect in improving the elastic properties of the aorta.

Dose-effect and kinetic-dynamic relationships of the beta-adrenoceptor blocking properties of various doses of talinolol in healthy humans.

Twelve healthy subjects were investigated on six separate occasions at least 1 week apart when they either received a single oral dose of 80 mg propranolol; 25, 50, 100, or 400 mg talinolol; or placebo (double-blinded, period-balanced six-way cross-over design). The subjects were investigated during supine rest and performed supine bicycle ergometry 0200, 0500, 0730, 1000, and 2400 h after dosing. Isoprenaline (ISO) and epinephrine (EPI) were infused intravenously (i.v.) at a constant infusion rate of 1 microgram/min for 10 min, at 0315 and 0400 h after dosing, respectively. At various timepoints, blood was drawn for the high-performance liquid chromatography (HPLC) determination of the plasma concentrations of talinolol's enantiomers and for the ex vivo in vitro determination of beta 1- and beta 2-adrenoceptor binding and related concentrations by radioreceptor assay (RRA). Talinolol was confirmed to bind to beta-adrenoceptors with moderate affinity but to act as a highly selective and efficient beta 1-adrenoceptor antagonist in terms of the relative degree and duration of its ergometric effects. At doses < or = 100 mg talinolol hardly altered the reduction of estimated vascular total peripheral resistance (TPR) in response to the intravenous infusion of ISO and EPI. Only at doses of 400 mg did talinolol more closely approximate the effects of propranolol, which lead to a loss of the vasodilatory actions of EPI ("EPI reversal"). On the average, there was a smoothly linear relationship between the ergometric treatment effects and log-transformed dose, the logtransformed concentrations of the S(-)-enantiomer measured by HPLC, and the RRA-derived estimated occupancies beta 1-adrenoceptors.

Method specificity of non-invasive blood pressure measurement: oscillometry and finger pulse pressure vs acoustic methods.

1. The agreement of blood pressure measurements by stethoscope auscultation (SBPa, DBPa-IV and DBPa-V), oscillometry (Dinamap; SBPo, and DBPo) and digital photoplethysmography (Finapres; SBPf, and DBPf) with the graphical analysis of the analogue microphone signals of vascular wall motion sound (SBPg and DBPg) was evaluated in eight healthy subjects in the presence of responses to the intravenous infusion of 1 microgram min-1 isoprenaline. 2. In general, there was good agreement between the SBP/DBP-measurements based on auscultatory Korotkoff-I- and IV-criteria and the reference method; the average method difference in estimating the isoprenaline responses for SBPa-SBPg was: -1.1, 95% CI: -5.4 to 3.1 mm Hg with a within-subject between-method repeatability coefficient (REP) of 11.6 mm Hg and for DBPa-IV-DBPg: 3.5, 95% CI: -0.5 to 6.5 mm Hg, REP: 11.5 mm Hg. The ausculatation of Korotkoff-V substantially overestimated the isoprenaline induced reduction of DBP: method difference DBPa-V-DBPg: -11.3, 95% CI: -17.8 to -4.7 mm Hg, REP: 31.8 mm Hg. 3. Oscillometry yielded good approximations for the SBP response to isoprenaline (average method difference SBPo-SBPg: -2.9, 95% CI: -9.0 to 3.3 mm Hg, REP: 17.6 mm Hg) but was poorly sensitive with regard to the DBP responses: method difference DBPo-DBPg: 6.5, 95% CI: -1.3 to 14.3 mm Hg, REP: 25.7 mm Hg. 4. Whilst the finger pulse pressure agreed well with regard to DBP (method difference for the DBP responses to isoprenaline: DBPf-DBPg: 1.8, 95% CI: -5.1 to 8.6 mm Hg, REP: 18.5 mm Hg) it was rather unsatisfactory with regard to SBP (method difference SBPf-SBPg: -14.1, 95% CI: -28.2 to -0.1 mm Hg, REP: 49.9 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Relative sensitivity of four noninvasive methods in assessing systolic cardiovascular effects of isoproterenol in healthy volunteers.

STUDY OBJECTIVE: The study was performed to evaluate the relative sensitivity of various noninvasive methods to detect and describe the systolic cardiovascular effects of stepwise increasing doses of isoproterenol: two-dimensional left ventricular echocardiography (main variable, ejection fraction), ACVF (attenuation compensated volume flow)--dual-beam Doppler echoaortography (time-averaged mean velocity), electrical impedance cardiography [(dZ/dtmax)/RZ index], and systolic time intervals from mechanocardiography (PEP and QS2c). METHODS: Isoproterenol was administered by constant rate intravenous infusion in consecutive steps of 0.1, 0.2, 0.4, 0.75, and 1.5 micrograms/min (each for 15 minutes). Saline control infusions were given in analog fashion. The treatments (isoproterenol and saline solution) were administered in a period-balanced two-way crossover design with randomly allocated sequences. The subjects, observers, and analysts were blinded to the treatment protocol. Study subjects were 10 healthy male volunteers (age range, 23 to 31 years; mean age, 26.6 years). RESULTS: Compared with saline solution, isoproterenol caused a dose-related increase in ejection fraction, (dz/dt)/RZ index, and time-averaged mean velocity and a dose-related shortening of PEP and QS2c. The responses are congruent with an enhancement of cardiac systolic performance caused by a positive inotropic stimulation and an afterload reduction ("inodilatory" response). The effects on systolic time intervals reached statistical significance (alpha = 0.05) at the first isoproterenol dose step, the effects on the impedance cardiography and the Doppler echoaortography variables reached statistical significance at the second dose step, and the effects on the two-dimensional echocardiography reached statistical significance at the third dose step. CONCLUSIONS: All methods allowed to detect isoproterenol-related changes. Systolic time intervals were the most sensitive, followed by impedance cardiography, ACVF--dual-beam Doppler echoaortography, and two-dimensional echocardiography. The practical convenience and high sensitivity of the systolic time intervals makes them suitable to evaluate investigational systolic inodilatory changes in humans.

Agreement and reproducibility of the estimates of cardiovascular function by impedance cardiography and M-mode echocardiography in healthy subjects.

The reproducibility and agreement of the estimates of stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) by transthoracic impedance cardiography (ZCG) and M-mode echocardiography (ECHO) were analyzed before and after the placebo-controlled administration of ascending doses of isosorbide dinitrate and nicorandil in 12 healthy subjects. There was no biostatistical agreement between the two methods in estimating cardiovascular function either before or after dosing (ZCG estimated substantially larger SV, CO and lower TPR). But, ZCG and ECHO estimated about similar overall treatment related changes (across treatments and periods) and reached substantially better agreement when the values were expressed as ratio of the baseline before dosing. Such improvement did not occur when the data were expressed as arithmetic difference from baseline. In spite of the improvement of agreement by expressing the data as ratio of baseline, the coefficients of reproducibility between the two methods (circa 25% of baseline) remained too large to judge the methods interchangeable.

Captopril does not interact with the pharmacodynamics and pharmacokinetics of digitoxin in healthy man.

The chronic oral administration of 0.07 mg digitoxin o.d. for up to 58 days to 12 healthy volunteers caused a small drop in mean heart rate HR (95% CI: -7.9 to -1.6 beats.min-1), in mean diastolic blood pressure (95% CI: -8.3 to -0.4 mmHg), shortening of the QTc-interval (95% CI: -42 to -19 ms), shortening of the HR-corrected pre-ejection period PEPc (95% CI: -16 to -1 ms) and electromechanical systole QS2c (95% CI: -25 to -1 ms), and an increase in the impedance cardiographic Heather index (dZ/dtmax/RZ, 95% CI: 0.3 to 4.3) relative to the baseline measurements before digitalisation. The concomitant administration of 25 mg oral captopril b.d. did not significantly alter these responses relative to the concomitant double-blind administration of placebo, nor did it alter the pharmacokinetic characteristics of plasma digitoxin at steady state. Thus, no relevant change in the pharmacokinetic and pharmacodynamic characteristics of chronically administered digitoxin were induced by concomitant treatment with captopril.

Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy.

In a double blind, placebo controlled study, propranolol (240 mg), atenolol (200 mg) or bisoprolol (100 mg) were administered as a single oral dose to groups of 6 healthy male volunteers. Exercise tachycardia was monitored for 84 hours after administration of the drugs to monitor beta blockade in vivo. Plasma samples drawn in parallel with these effects were used to detect beta 1- or beta 2-adrenoceptor occupancy in two subtype selective in vitro receptor binding assays. Reduction of exercise tachycardia parallels beta 1-adrenoceptor occupancy. Furthermore, at comparable beta 1-adrenoceptor occupancy, less beta 2-adrenoceptor occupancy was observed after bisoprolol than after atenolol. The latter finding is in agreement with the two-fold higher beta 1/beta 2-selectivity ratio of bisoprolol (75-fold) versus atenolol (35-fold). It is concluded, that beta blockade observed via the reduction of exercise tachycardia can be delineated from the in vitro occupancy of beta 1-adrenoceptors by an antagonist present in plasma samples.

Dose-response following single administrations of a new cardiac performance enhancer RO 13-6438 in normal volunteers.

We assessed the changes in cardiovascular function in humans caused by RO 13-6438, a new drug that enhances cardiac performance, by means of noninvasive methods which included measurement of systolic time intervals and electrical impedance cardiography. Twelve healthy male volunteers received RO 13-6438 doses of 10 and 20 mg intravenously and 20, 40, and 60 mg orally according to a double blind, randomized, crossover, placebo-controlled design. A dose-dependent distinct enhancement in cardiac performance was seen. This was attributed to positive inotropism (shortening of heart rate-corrected electromechanical systole) and to a vasodilating action (decline of diastolic blood pressure and total peripheral resistance). In addition, the drug increased heart rate slightly. The cardiac effects were detectable for 6 h. To reach the average equivalent inotropic response over 6 h, the oral dose was approximately 1.8-fold of the i.v.; this indicated a high bioavailability of RO 13-6438. Transient color vision disturbances were reported mainly following the intravenous administration. The properties of RO 13-6438 suggests that it may be useful for treatment of heart failure.