Inhibition of angiotensin-I response by cilazapril and its time course in normal volunteers.

Cilazapril is a new angiotensin-converting enzyme (ACE) inhibitor. In a double-blind crossover study six normal male volunteers received single oral doses of cilazapril, 4 mg, captopril, 25 mg, enalapril, 10 mg, and placebo. The response of diastolic blood pressure to an intravenous infusion with increasing doses of angiotensin I (AT-I) (0.1 to 18 micrograms/min) was determined at control and up to 36 hours after oral drug intake. Additionally the response to AT-I was established before, during, and after cessation of a 15-day 2.5 mg/day cilazapril administration. The ACE inhibitors antagonized the AT-I effects and shifted the AT-I dose-effect curves rightward, whereas placebo was not effective. After single doses the effects of cilazapril and enalapril declined with a similar elimination half-life of approximately 4 hours; with captopril approximately 2 hours was observed. After multiple administration of cilazapril there was no evidence of cumulative effects. Cilazapril is an orally active ACE inhibitor that does not show pharmacodynamically relevant accumulation.

Digoxin and bepridil: pharmacokinetic and pharmacodynamic interactions.

The influence of bepridil on steady-state serum digoxin concentrations (SDCs) and the pharmacodynamic actions of both drugs were tested in 48 healthy subjects in a randomized, double-blind study. Subjects were assigned to one of two groups of 24 subjects each: One group received placebo 1, while the other received digoxin, 0.375 mg/day, loaded with doubled doses on days 1 and 2, for 14 days. After 7 days the groups were subdivided into four groups of 12 subjects each and received concurrent dosing of digoxin with either placebo 2 or bepridil, 300 mg/day, loaded with 900 mg on day 8. Mean (+/- SD) SDCs rose during concurrent bepridil dosing from 0.93 +/- 0.22 to 1.25 +/- 0.25 ng/ml (P less than 0.001). Noninvasive cardiovascular parameters from ECG, systolic time intervals, and electrical impedance cardiography were not influenced by the placebos. Digoxin and bepridil reduced heart rate and prolonged the PQ interval because of negative chronotropic and dromotropic properties. Positive inotropism from digoxin shortened the corrected electromechanical systole (QS2c) and the preejection period and increased impedance cardiography [(dZ/dt)/RZ index]; the opposite effects occurred after bepridil, indicating negative inotropism. The QT interval corrected for heart rate (QTc) showed a similar pattern of changes, as did QS2c for each drug. Concurrent dosing of both drugs resulted in an addition of their chronotropic effects, whereas the dromotropic effects of each drug alone was not intensified. The strengthened digoxin effect from the increased SDC diminished the negative inotropic effect of bepridil. Overall, drug coadministration resulted in a nearly unchanged digoxin-induced positive inotropism.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Interaction between digoxin and calcium antagonists and antiarrhythmic drugs.

The influence of several calcium antagonists and antiarrhythmic drugs on digoxin kinetics and actions were investigated in 36 healthy men during digoxin steady state (0.375 mg/day). The subjects were randomly assigned to three subgroups and each group received placebo (control) and two of the following regimens (doses three times a day) in a randomized sequence for 2 wk each: verapamil (80 mg) and nifedipine (10 mg), verapamil (120 mg) and gallopamil (50 mg), or propafenone (150 mg) and quinidine (250 mg). Plasma digoxin concentration (PDC) rose during the cotreatments in the sequence: gallopamil (+16%) less than propafenone (+37%) less than nifedipine (+45%) less than verapamil (almost independent of dose, +69%) less than quinidine (+118%). These increases in PDC correlated closely to decreases in renal digoxin clearances. Renal creatinine clearance was virtually unaffected. The rise of PDC resulted in increased glycoside effects, as measured by the shortening of systolic time intervals and flattening of T wave. There was a linear correlation between PDC and changes in mean corrected electromechanical systole and T wave flattening. We conclude that, in addition to quinidine, other antiarrhythmic drugs and various calcium antagonists interact kinetically with digoxin and that the increasing PDCs are cardioactive.

Differential effects of two dihydropyridine calcium antagonists in humans.

We studied the effects after single doses of niguldipine (0.3, 0.6, and 0.9 mg intravenously; 8 and 16 mg orally) and nifedipine (2 mg intravenously; 20 mg orally) in healthy male volunteers in randomized placebo-controlled experiments. Total peripheral resistance (TPR), heart rate-corrected electromechanical systole (QS2c), and preejection period (PEPc) were assessed noninvasively. Both drugs induced a similar pronounced decreased in TRP, indicating peripheral vasodilation, followed by increasing heart rate and cardiac output, a decrease in diastolic blood pressure, and a shortening of the PEPc. QS2c was unchanged after niguldipine. The prolongation of QS2c after oral nifedipine is suggestive of a negative inotropic effect. We conclude that the vasodilatory effects of dihydropyridines may (as for nifedipine) or may not (as for niguldipine) be associated with changes that are suggestive of negative inotropic effects, and that this difference is detectable by noninvasive methods in healthy subjects.

Digoxin concentrations in serum and cantharides blister fluid: correlations with cardiac response.

The relationship between the pharmacokinetics and dynamics of digoxin was investigated using a skin blistering technique that allows experimental access to tissue fluid concentrations. Eight healthy volunteers received digoxin, 1.0 mg, and placebo intravenously according to a double-blind crossover design. Drug concentrations were determined during a 72-hour period in serum, urine, and cantharides blister fluid (CBF). Digoxin levels in the hypothetic peripheral compartments were calculated from serum concentrations. Digoxin effects (total electromechanical systole [QS2c], left ventricular ejection time [LVETc], preejection period [PEPc], QTc time, heart rate, and T wave amplitude) were measured simultaneously. Peak levels in the shallow and deep compartments occurred at 12 1/2 to 20 minutes and 3 hours and the maximum concentration in CBF (2.75 +/- 0.48 ng/ml) occurred at 1 hour. Digoxin effects on QS2c, PEPc, and the ratio PEP/LVET were not related to serum concentrations but were closely related to CBF concentrations (r = 0.90). CBF concentrations were then within the range of serum digoxin concentrations usually associated with the treatment of heart failure. Thus, CBF allows experimental access to active drug concentrations after a single intravenous dose.

Quinidine-digoxin interaction: cardiac efficacy of elevated serum digoxin concentration.

Cardioactivity due to elevated serum digoxin concentration (SDC) after quinidine (Q) and digoxin (D) was evaluated in six healthy subjects by means of measurement of systolic time intervals (STIs). Each subject randomly received basic treatments with 0.2 mg D and placebo (PL1). Randomized coadministrations with Q (1 gm/day), sparteine (SP) (0.8 gm/day), and placebo (PL2) were given for 7-day periods. A steady-state dose of 0.4 mg D was added. Mean SDC increased from 0.48 ng/ml during 0.2 mg D + PL2 to 1.13 ng/ml on 0.2 mg D + Q (P less than 0.05); it was unchanged by SP. On 0.4 mg D there were further shortenings of STIs compared to those on 0.2 mg D + PL2. Q markedly prolonged STIs; the SP effects were similar but less pronounced. When given with Q or SP, the effect of D was obscured by opposing inotropic properties; consequently, despite increasing SDC, measureable STIs were unchanged. The true glycoside effect was determined by comparing the effects of the pure antiarrhythmic to those of the antiarrhythmic with D. These calculations showed that the glycoside effect of the elevated SDC during Q + D dosing was much the same as the effect of 0.4 mg D.

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.

Kinetics of fenoximone, a new cardiotonic, in healthy subjects.

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (+/- SD) elimination t1/2 (t1/2 beta) of 60 +/- 14 min after intravenous injection and 78 +/- 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 +/- 846 ml/min, renal clearance (ClR) was 5.3 +/- 2.4 ml/min, and extrapolated volume of distribution was 0.37 +/- 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t1/2 beta s were calculated as 132 +/- 15 min after intravenous injection and 140 +/- 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 +/- 106 ml/min after intravenous injection; 24-hr urinary recovery of the sulfoxide was 75.7% +/- 5.7% after intravenous injection and 64.3% +/- 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).

Differential effects of oral losartan and enalapril on local venous and systemic pressor responses to angiotensin I and II in healthy men.

This double-blind, placebo-controlled crossover study was designed to differentiate the pharmacodynamic effects of the angiotensin II receptor antagonist losartan from the angiotensin converting enzyme inhibitor enalapril. Effects of placebo, enalapril (10 mg), and losartan (20 and 100 mg) on local venous and systemic pressor responses to angiotensin I and II were compared in eight healthy male subjects. Treatments were administered orally approximately 4 hours before agonist infusions into a dorsal hand vein. Local changes in hand vein diameter and systemic blood pressure were monitored during the infusions. The 100 mg dose of losartan attenuated local venoconstrictor and systemic pressor responses to angiotensin I and II. In contrast, enalapril blocked only responses to angiotensin I. Both losartan and enalapril increased plasma renin concentration compared with placebo. These results are consistent with direct antagonism of angiotensin II receptors by losartan and with indirect effects of enalapril through inhibition of angiotensin converting enzyme.

Hemodynamics, biochemical effects, and pharmacokinetics of the renin inhibitor remikiren in healthy human subjects.

INTRODUCTION: Remikiren (Ro 42-5892) is a potent and specific inhibitor of human renin in vitro. Its in vivo action on plasma renin activity (PRA), immunoreactive renin, and blood pressure has been shown in pilot studies in humans. OBJECTIVE: To investigate tolerability, hemodynamic effects, and biochemical effects of remikiren in relation to its pharmacokinetics after single ascending intravenous and oral doses in healthy humans. METHODS: In this double-blind, placebo-controlled, two-way crossover (intravenous and oral) study, single ascending doses of 10, 20, 40, 80, 160, and 320 mg (intravenous) and 100, 200, 400, 800, and 1600 mg (oral) were given; six subjects received active drug and three received placebo at each dose level. At regular intervals, blood pressure, heart rate, cardiac output, PRA, immunoreactive renin, and drug plasma levels were determined. RESULTS: The compound was well tolerated except at the 1600 mg oral dose level at which diarrhea occurred in two subjects. At neither dose were there effects on blood pressure, heart rate, or cardiac output relative to placebo. PRA and angiotensin I production rate decreased and immunoreactive renin increased dose dependently after both intravenous and oral administration. The duration of these effects was also dose dependent and was longer than 12 hours with higher doses. Systemic plasma clearance, volume of distribution, and absolute bioavailability of remikiren were in the magnitude of 900 ml/min, 70 L, and below 1%, respectively. The angiotensin I production rate correlated in a sigmoidal way with plasma drug concentrations independent of the route of administration. CONCLUSION: Remikiren is a potent inhibitor of renin in humans with long-lasting effects after both intravenous and oral administration.

Dose-effect and pharmacokinetic-pharmacodynamic relationships of the beta 1-adrenergic receptor blocking properties of various doses of carvedilol in healthy humans.

OBJECTIVE: To evaluate the pharmacodynamic properties of carvedilol across a broad range of doses in relation to its enantiospecific kinetics and adrenergic receptor occupancies, relative to placebo and propranolol. METHODS: Twelve healthy male subjects were investigated on six separate occasions at least 1 week apart when they received either a single peroral dose of 40 mg propranolol, 12.5, 25, 50, or 100 mg carvedilol, or placebo. The subjects were extensively profiled at supine rest, and they underwent supine bicycle ergometry before and at 2, 4, 6, 9, 12, and 22 hours after dosing. At these time points blood was drawn for the high performance liquid chromatographic determination of the enantiomers of carvedilol and for the radioreceptor assay determination of alpha 1- and beta 1-adrenergic receptor binding and related concentrations. RESULTS: Carvedilol was confirmed to bind to beta 1-adrenergic receptors and (albeit to a lesser extent) to alpha 1-adrenergic receptors. Carvedilol furthermore attenuated the ergometric increase in heart rate in a closely dose-related fashion, which exemplified its beta 1-adrenergic receptor blocking effects. However, the basal efferent adrenergic drive might have been too low to show consistent alpha 1-blocking properties. The radioreceptor and enantiomer kinetics were proportional with dose. There was no indication that the overall kinetic behavior of contributing active metabolites would differ from that of the S(-)-enantiomer. On average, there was a smooth linear relationship between the ergometric treatment responses and log-transformed dose, log-transformed concentrations of the S(-)-enantiomer, and the radioreceptor assay derived beta 1-adrenergic receptor occupancies. CONCLUSION: The relative complexity of the kinetics of carvedilol (enantiospecific kinetics and dynamics, protein binding, and involvement of active metabolites) does not preclude relatively simple and straight-forward dose-effect and kinetic-dynamic relationships.

Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40-5967 were investigated in 64 patients with hypertension. In a double-blind, placebo-controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose-dependently reduced over the full 24-hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, -34/-25 mm Hg, p less than 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose-dependently increased and concentration-effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40-5967 has a long-lasting antihypertensive effect after once-daily administration.

Dynamic responses to intravenous urapidil and dihydralazine in normal subjects.

Hemodynamic responses after urapidil were compared with those after dihydralazine in placebo-controlled, double-blind studies after cumulative intravenous doses. We recorded heart rate, blood pressure, systolic time intervals corrected for heart rate (electromechanical systole and preejection period), electrical impedance cardiography [(dZ/dt)/RZ index and mean electrical thorax impedance], and M-mode echocardiogram (end-systolic and -diastolic diameters, end-systolic wall stress, fractional shortening, and cardiac output). Both drugs induced dose-dependent reductions in total peripheral resistance, which resulted in reduction in left ventricular end-systolic wall stress and increases in heart rate (limited at +10 bpm with urapidil), fractional shortening, cardiac output, and the (dZ/dt)/RZ index. With each drug, diastolic blood pressure fell by 5 mm Hg, the corrected preejection period shortened (dihydralazine greater than urapidil), the corrected electromechanical systole did not change, and mean electrical thorax impedance rose with urapidil. The spectrum of effects indicates that both drugs reduce left ventricular afterload, thereby increasing left ventricular pump performance. Urapidil also exerts some preload reduction.

Influence of the angiotensin converting enzyme inhibitor cilazapril, the beta-blocker propranolol and their combination on haemodynamics in hypertension.

This study compared the antihypertensive effects and the haemodynamic mechanisms of action of an angiotensin converting enzyme (ACE) inhibitor, a beta-blocker and the combination of both in patients with mild to severe hypertension. After a placebo run-in period of 2 weeks, patients were treated for 3 weeks with each of the following: cilazapril (2.5 mg daily) and propranolol (120 mg daily), in a randomized sequence, and thereafter a combination of the two drugs. Blood pressure, cardiac output (measured by Doppler ultrasound) and total peripheral resistance (TPR) in a sitting position at rest were determined. One patient out of 18 was withdrawn in the cilazapril phase. Both monotherapies yielded significant and similar reductions of diastolic blood pressure (average -10 mmHg). Cardiac output and TPR showed opposite effects. Cardiac output was lower with the beta-blocker than with the ACE inhibitor (3.4 versus 4.5 l.min-1), while TPR behaved conversely (2646 versus 2005 dyne.s.cm-5). The combination of both drugs lowered diastolic blood pressure significantly more than the monotherapies (average -20 mmHg); the haemodynamic effects of the monotherapies were attenuated by the combination (cardiac output = 3.7 l.min-1; TPR = 2170 dyne.s.cm-5). A sitting diastolic blood pressure of less than or equal to 90 mmHg could be achieved in six out of 17 patients with propranolol alone, in eight out of 18 with cilazapril alone, and in 14 out of 17 with the coadministration of both drugs. The combination was better tolerated subjectively than the beta-blocker alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme inhibitors. Relationship between pharmacodynamics and pharmacokinetics.

The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.

Clinical pharmacodynamic studies with cilazapril and a combination of cilazapril and propranolol.

We evaluated the degree of inhibition of angiotensin converting enzyme (ACE), principally by cilazapril, by assessing the blood pressure response to a continuous infusion of increasing doses of angiotensin I, and assessed the possible pharmacokinetic and pharmacodynamic interactions between cilazapril and propranolol in healthy volunteers and patients with mild to severe essential hypertension. The specificity of the angiotensin I infusion method was verified when a single dose of cilazapril 30mg antagonised the increase in diastolic blood pressure induced by angiotensin I but did not influence the response to angiotensin II. Using this method, we showed that single oral doses of cilazapril 4 mg, captopril 25 mg and enalapril 10mg shifted the angiotensin I dose-effect curve to the right and determined a pharmacological half-life of about 4 hours for cilazapril. Increasing single oral doses (1.25, 3.75, 10 and 30mg) of cilazapril reduced diastolic blood pressure dose-dependently and shifted the angiotensin I dose-response curves to the right. The dose representing 50% inhibition of ACE activity (apparent Ki-dose) was about 0.6mg, 3 hours after cilazapril administration. Cilazapril and propranolol did not exhibit any clinically significant pharmacokinetic interaction in healthy volunteers; each drug reduced diastolic and systolic blood pressure by about 7 mm Hg, and this was doubled by the combination. Cilazapril had no significant effect on heart rate, in patients with essential hypertension whereas both propranolol and the combination of cilazapril and propranolol reduced it. Monotherapy with each drug reduced blood pressure, and combined administration enhanced the antihypertensive effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy.

The development of angiotensin-converting enzyme inhibitors and selective angiotensin type 1 (AT1)-receptor antagonists has provided new insights into understanding the mechanism of the renin-angiotensin system (RAS) in the pathophysiology of cardiovascular disease. There is good evidence from meta-analyses that shows that inhibition of the RAS achieves organ protection features that go beyond blood pressure control. Candesartan cilexetil, a new angiotensin II receptor antagonist, is characterised by its tight binding to and slow dissociation from the AT1 receptor, and high antagonistic potency, resulting in long-lasting antagonistic effects. It is anticipated that these pharmacological characteristics may bring additional benefits to patients, not only for the management of essential hypertension but also for the management of end-organ damage.

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.

Dose-proportionality of oral thioctic acid--coincidence of assessments via pooled plasma and individual data.

Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.