Efficacy and Safety of Ambroxol Lozenges in the Treatment of Acute Uncomplicated Sore Throat - a Pooled Analysis.

A pooled analysis is presented of 7 placebo-controlled RCT that investigated lozenges containing ambroxol for pain relief in acute sore throat.2 242 patients were treated with different ambroxol doses or control treatments, 2 183 were evaluable for efficacy. The present analysis is focused on the recommended dose of 20 mg (AXL20): 856 patients were treated with AXL20, 847 with matched placebo lozenges (PL).The average reduction in pain intensity over the first 3 h after the first AXL20 ranged from 38% to 52% of the maximum achievable effect (MAE). The overall treatment difference between AXL20 and PL was 11% (95% CI: 8-13%) of the MAE (post-hoc meta-analysis). The corresponding NNT was 6.0 (CI: 4.7-8.4) for an average pain reduction from baseline of 33% of the MAE over the first 3 h.71.9, 79.0, and 85.3% of the AXL20-patients scored the efficacy as "very good or good" at the end of the 1(st), 2(nd) and 3(rd) day, respectively, vs. 57.5, 64.4, and 70.4% of the PL-patients resulting in odds ratios of 1.9 (CI: 1.5-2.3) for the 1(st), 2.1 (CI: 1.7-2.6) for the 2(nd) and 2.43 (CI: 1.8-3.3) for the 3(rd) day.At the end of treatment 'no redness' or 'slightly red' was scored on pharyngeal inspection in 84.4% and 77.3% of AXL20- and PL-patients (OR: 1.6, CI: 1.3-1.9).AXL20-treatment was well tolerated and is safe and efficacious for acute uncomplicated sore throat of recent onset in adolescent and adult patients.

Postprandial haemodynamic changes: a source of bias in cardiovascular research affected by its own methodological bias.

The effects of heart rate and systolic and diastolic blood pressure of eating a 3100 kJ cold meal were assessed in eight young normal subjects studied in a randomised and balanced crossover study. Blood pressure was measured simultaneously and in the same arm by auscultation of the fossa cubitalis (Korotkoff I, IV, and V), by an automated device with a microphone over the brachial artery (equivalent to Korotkoff I and V), and by graphical analysis of these microphone signals (equivalent to Korotkoff I and IV). Eating caused a rise in mean heart rate, a small rise in systolic blood pressure, and a decrease in diastolic blood pressure, which was overestimated when Korotkoff V rather than Korotkoff IV endpoints were considered. Both the automated device and the graphical analysis yielded acceptable overall quantitative agreement with the auscultatory method. Both alternative methods allowed similar postprandial blood pressure trends to be detected, but the quantitative agreement in estimating the postprandial effects was far less optimal. Eating therefore was shown to cause changes that might distort and confuse the interpretation of cardiovascular data in studies in which subjects are allowed to eat. This source of bias itself appeared to be affected by its own methodological bias.

Efficacy and Safety of an Oral Ambroxol Spray in the Treatment of Acute Uncomplicated Sore Throat.

OBJECTIVE: Compare the efficacy and tolerability of oral spray formulations delivering 2.5, 5, and 10 mg ambroxol (AXS) per application (4 actuations/application) in relieving acute sore throat vs. spraying a matched placebo solution. DESIGN: Multi-centre, placebo-controlled, randomised, double-blind trial with up to 6 daily applications of the assigned medication for up to 3 days. PATIENTS: 511 outpatients with acute sore throat were enrolled, 494 were treated. TREATMENTS: Up to 6 spray applications per day as needed for up to 3 days. RESULTS: All treatments led to a reduction in pain intensity (PI); the mean cumulative PI-reductions over the first 2 h after the 1(st) dose (SPIDnorm(0-2)) were 24.7, 26.6, 26.0, and 32.2% (SEM: 0.023) of the predose PI for treatment with placebo, and the 2.5, 5, and 10 mg AXS, respectively. These mean reductions were 2 (CI: -3.6; 7.5), 1.3 (CI: -4.3; 6.8), and 7.5 (CI: 2.0;13.1) percent points larger than for placebo. The 2.5 and 5 mg AXS were not distinguishable from placebo, but the 10 mg AXS was evidently superior. The numbers needed to treat (NNT) when comparing 10 mg AXS with placebo, were 9.5 and 8.8 for an average pain relief of 33 and 50% of the maximum achievable effect over the first 2 h. CONCLUSIONS: 10 mg AXS showed a statistically significantly superior pain reduction relative to the placebo spray. Treatment with 10 mg AXS reaches an extent of pain relief that can be accepted to be clinically meaningful and was well tolerated.

Effect of age and spontaneous hypertension on the tachyphylaxis to 5-hydroxytryptamine and angiotensin II in the isolated rat kidney.

The isolated and perfused kidney of the mature spontaneously hypertensive rat (SHR) exhibits an increased vascular reactivity and a delayed tachyphylaxis to 5-hydroxytryptamine, when compared to weight-matched normotensive animals. To evaluate the influence of the duration of the hypertensive state on these differences, the vascular reactivity to 5-hydroxytryptamine was determined in isolated kidneys from age-matched normotensive and spontaneously hypertensive rats of 3.5, 6 and 12 months of age. Responses to increasing doses of 5-hydroxytryptamine were compared. At all ages the responses to the agonist were greater in the SHR than in the control rats. In the normotensive rats, the sensitivity to the monoamine decreased, while the maximal response increased with aging. The vascular reactivity to increasing doses of 5-hydroxytryptamine was not altered by aging in the SHR. There was a significant correlation between the maximal vasoconstrictor response to 5-hydroxytryptamine in the isolated kidneys and the systolic arterial blood pressure (SBP) of the donor rats. Maximal constrictor responses to 5-hydroxytryptamine were repeated at given intervals. The degree of tachyphylaxis was decreased in hypertensive rats compared with normotensive rats at 3.5, and 6 months age. Tachyphylaxis to 5-hydroxytryptamine was depressed by aging in both normotensive and hypertensive rats. By contrast, tachyphylaxis to angiotensin II (AII) was not effected by either age or hypertension. There was no cross-tachyphylaxis between 5-hydroxytryptamine and AII. Lowering the Ca2+-concentration of the perfusate did not affect tachyphylaxis to either 5-hydroxytryptamine or AII. The present experiments indicate that the delayed tachyphylaxis to 5-hydroxytryptamine in the kidneys of SHR is due to a specific alteration of th vascular smooth muscle cells, which may be the consequence of premature aging.

Erythromycin increases plasma concentrations of alpha-dihydroergocryptine in humans.

OBJECTIVE: Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)-inhibiting agents such as erythromycin and the dopamine agonist alpha-dihydroergocryptine (DHEC). METHODS: The study was carried out as a single-center, controlled, nonblinded, 2-way crossover clinical trial with randomly allocated period-balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4-day treatment (days -2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2-25.1 kg x m(-2)) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol. RESULTS: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24-hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay). CONCLUSIONS: The concomitant use of erythromycin or similarly CYP3A4-inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.

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.

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.

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.

Usefulness, usability, and quality criteria for noninvasive methods in cardiovascular clinical pharmacology.

Validation of study methods is a prerequisite for their usability. Empirical quality criteria based on test-theoretical principles are useful for this purpose. These criteria are discussed for several noninvasive methods used in cardiovascular clinical pharmacology: electrocardiography, systolic time intervals, blood pressure, and estimates of stroke volume. Several of these methods are highly reliable and sensitive to drug effects. However, they are inherently low in validity because they are based on oversimplified algorithms and yield estimates rather than measurements of function and changes therein. These estimates are method-specific and are likely to be subject to method*subject*effect interaction. Highlighting these constraints and the limitations of these methods need not preclude their useful contribution to the early evaluation of drug action in humans.

Continuous measurement of hemodynamic alterations during pharmacologic cardiovascular stress using automated impedance cardiography.

The contribution of computerized impedance cardiography in monitoring and differentiating cardiovascular responses to pharmacologic stress after the administration of dipyridamole (group 1, n = 24) or dobutamine (group 2, n = 26) was investigated during stress echocardiography. Heart rate, stroke volume index, cardiac index and systemic vascular resistance index were evaluated continuously with an automated, computerized, signal-averaged impedance cardiography system. Dipyridamole had little average effect on heart rate, stroke volume index, and cardiac index. The responses were similar in patients with positive (n = 9) or negative (n = 15) stress echocardiography test results (as characterized by echocardiographic wall-motion abnormalities). Dobutamine induced a similar mean increase in heart rate in patients with negative (n = 13) or positive (n = 13) results on stress echocardiography. The mean increase in stroke volume index induced by dobutamine was greater in patients with negative stress echocardiography test results than in patients with stress-induced wall-motion abnormalities. This distinction was also seen in the cardiac index; the mean change in patients with negative stress echocardiography test results was larger than in patients with positive results. It is concluded that automated computerized impedance cardiography not only allows surveying and monitoring hemodynamic changes during pharmacologic stress echocardiography but also contributes to differentiation of pathologic stress responses.

Opportunities for the treatment of erectile dysfunction by modulation of the NO axis--alternatives to sildenafil citrate.

Erectile function in man depends upon a complex interaction of psychogenic, neurologic, hormonal and vascular factors, and therefore the management of erectile dysfunction (ED) reflects this complexity of control. Therapeutic options include psychological and non-pharmacological approaches as well as drug treatments. The effectiveness of the type-5 cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra) confirms the pivotal role of the NO-cGMP axis in promoting and maintaining erection. Although widely acclaimed, sildenafil leaves many questions unanswered, especially regarding its susceptibility to pharmacokinetic drug interactions, and its safety in patients with ischaemic heart disease and those taking nitrates. In view of the epidemiological link between erectile dysfunction and cardiovascular disease in the elderly, this limitation might have much broader implications. The presently available scientific documentation, although less extensive, indicates that NO donors, such as topically applied nitroglycerin (GTN; for example, 1-2 puffs of an ordinary GTN spray applied to the shaft of the penis), might be a reasonable alternative. Further larger-scale research on the efficacy and tolerability of topical GTN is needed to establish its full therapeutic potential in the treatment of erectile dysfunction.

Influence of the dopamine agonist alpha-dihydroergocryptine on the pharmacokinetics of levodopa in patients with Parkinson's disease.

This study investigated whether chronic coadministration of alpha-dihydroergocryptine (DHEC) altered the plasma pharmacokinetics of individualized treatments with levodopa in 12 patients with Parkinson's disease. Steady-state pharmacokinetics of plasma levodopa (L-Dopa) under combined treatment were compared with those under treatment with L-Dopa alone. There was no evidence of increased exposure to L-Dopa caused by concomitant treatment with DHEC. In contrast, additional treatment with DHEC reduced the overall exposure to L-Dopa (17.5% reduction in area under the curve; 95% CI: 23%-6%). This effect was small but statistically significant for the area under the plasma concentration-time curve, whereas tmax (time of maximum plasma concentration) and peak-to-trough fluctuation were not affected. Cmax (maximum plasma concentration), on average, was reduced to a similar extent (-14.5%; 95% CI: 38% to -17%), albeit not significantly. The magnitude of the interaction does not suggest changing the current clinical practice of up-titrating DHEC and subsequently adapting L-Dopa to the individual needs of patients.

Analysis of pharmacokinetic-dynamic interrelations with special reference to applications in cardiovascular clinical pharmacology.

The relationship between a (detectable) cardiovascular response and plasma concentrations is affected by 1. the temporal delay of the equilibrium between sampling site and effector site(s), 2. the intrinsic relationship between the primary effect(s) and concentration at the effector site(s) and 3. inter-pharmacodynamic processes that link the primary effects to a net response and that might attenuate or amplify the primary effects. Confounding factors (active metabolites, time-variant protein-binding, enantiospecific pharmacological behavior, physiological counter-regulation, etc.) might confuse the issue even more. Models that address kinetic-dynamic interrelations are usually confined to the first two processes listed above and hardly account for the third factor (and often are inadequate if more than one confounding factor is involved). They yield model-driven assimilative solutions that are characterized by a high level of indetermination. The "fit" of the experimental data with an analytical model (in itself usually quite appealing by its mathematical elegance and inductive creativity) should not be mistaken as a "match" between the model and physio-pharmacological "reality". In consequence, these models are cognitive constructions that provide important insight in the complexity of these physio-pharmacological processes without necessarily solving it. Their actual "proof" and ultimate value thus lies in their practical applicability (i.e. their effective instrumental use) to predict, correct and optimize (pharmacotherapeutic) response. Unfortunately most models have failed to be successfully tested in this regard.

Hemodynamic surrogate end-points in phase I studies?

Clinical pharmacology studies in healthy volunteers ("human pharmacology studies") characterize the pharmacokinetic and pharmacodynamic hallmarks of pharmacological action and their interrelation in the intact effector system unconfounded by disease and comedication. They constitute a valuable basis for the subsequent explicit investigation of the clinical efficacy, safety, efficiency, and therapeutic benefit in patients, but are not a valid surrogate for them.

Inverse PK/PD: estimation and differentiation of bioavailability from effect kinetics--observations with beta-adrenoceptor antagonists.

The time course of pharmacodynamic effects allow to resolve bioavailability relevant pharmacokinetic information, provided simple assumptions can be made about their interrelation. This approach furthermore allows to differentiate ancillary properties of chemically distinct pharmacological agents on the basis of their mutual pharmacodynamic actions. The advantages and pitfalls of this strategy are discussed here for beta-adrenoceptor antagonists on the basis of their pharmacodynamic characterization by the extent of their binding ability to ex vivo in vitro beta-adrenoceptors (RRA assay) and their blunting effects on the ergometric rise in heart rate.

Evaluation of the noninvasive estimates of cardiac output by Doppler aortoechography according to test-theoretical principles.

The usability of noninvasive methods can be quantified by a formal assessment of empirical quality criteria based on test-theoretical principles. The ACVF Doppler aortoechography is a pulsed dual-beam ultrasound technique with online estimates of cardiac output (CO) based upon the measurement of the mean Doppler shift frequency across the ascending aorta, its estimated cross-sectional area and the cycle's heart rate. The method has a relatively high reliability, sensitivity, and pharmacosensitivity (for inodilatory changes in particular), but tends to underestimate cardiac output. Furthermore, the method lacks objectivity because it is highly observer-dependent. Precise method description and stringent standardization thus are required. Because of the method specificity of its estimates, data should not be combined with those of other methods. The inherently poor validity of its CO estimates, using this method, call for caution in the mechanistic interpretation of its observations.

Differentiation of inodilatory responses by non-invasive measures of cardiovascular performance in healthy man.

The cardiovascular responses to various inodilatory interventions were investigated noninvasively in healthy man by monitoring heart rate (HR), blood pressure (SBP/DBP, according to Korotkoff I and IV criteria), systolic time intervals (PEP, VET and QS2) and impedance cardiographic estimates of stroke volume (SV) and cardiac output (CO). The following inodilatory interventions were evaluated and compared: the i.v. infusion of adrenaline (1 microgram/min), the i.v. infusion of isoprenaline (1 microgram/min) with and without pretreatment with 100 mg talinolol (a beta 1-selective beta-adrenoceptor antagonist), the p.o. administration of 1200 mg celiprolol (a beta 1-adrenoceptor antagonist with ancillary beta-adrenergic agonistic properties at the chosen dose level), the p.o. administration of 0.4 mg bimakalim (a K+ channel activator without direct cardiac effect) with and without pretreatment with 5 mg bisoprolol and the p.o. administration of the PDE-III inhibitors meribendan and isomazole. The extent of the inodilatory rise of HR, shortening of PEP, rise of SV and CO relative to the associated reduction of the calculated total peripheral resistance (TPR) proved a powerful tool to differentiate inodilatory properties: adrenaline, isoprenaline after beta 1-selective beta-adrenoceptor blockade and celiprolol led to similar ancillary adrenaline-like cardiovascular changes relative to the vasodilatation; bimakalim led to similar associated changes except for a relatively larger rise in HR, which could be blocked by bisoprolol; isoprenaline induced clearly larger associated changes, for which HR, VET, and QS2c were particularly sensitive; meribendan and isomazole resulted in the largest ancillary changes, characterized by a critical shortening of the ejection time VET, so that the rise of CO was almost exclusively defined by the rise of HR. These differences could be detected and differentiated sufficiently and adequately by HR, SV, CO, TPR, PEP, and VET. There seems little value in using more assumptive variables such as HR-corrected VETc and QS2c, the Weissler index and the impedance cardiographic Heather index.

Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction.

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC- and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study.(ABSTRACT TRUNCATED AT 250 WORDS)

Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction.

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC-and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study. The corresponding 90%-confidence intervals were all within the equivalence range of 0.8-1.25 so that lack of interaction either by inhibition or induction can be concluded.

Plasma and urine pharmacokinetics of the dopamine agonist alpha-dihydroergocryptine in patients with hepatic dysfunction.

OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic behavior of unchanged alpha-dihydroergocryptine (DHEC, Almirid, Desitin Arzneimittel GmbH, Hamburg, Germany, under licence of Polichem S.A., Luxembourg) and total DHEC (unchanged DHEC and pooled metabolites) in plasma and urine in patients with impaired hepatic function, following administration of single oral doses. METHODS: The study was carried out according to an open, uncontrolled, parallel-group design, investigating two study groups: patients with hepatic dysfunction, i.e. with evidence of stable cirrhosis (n = 10) and age- and sex-matched healthy subjects (n = 8). Each subject received a single dose of 20 mg DHEC. Blood samples were taken at specified intervals up to 72 h after dosing and urine was collected fractionally for 24 h. Concentrations of unchanged DHEC were determined by RIA and concentrations of total DHEC (unchanged and pooled metabolites) by EIA. RESULTS: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by large variability. In patients with impaired hepatic function, the geometric mean Cmax and AUC(0-infinity) values for unchanged DHEC were 571.3 pg/ml (CV: 0.87) and 4038 pg x h/ml (CV: 1.04) and were approximately 2 times (2.04, 95% CI: 0.93 to 4.46 and 2.11, 95% CI: 0.58 to 7.73 for Cmax and AUC(0-infinity), respectively) larger than those measured in age-matched healthy controls. The 24-hour urinary excretion was approximately 3 times (3.41, 95% CI: 0.95 to 12.21) higher in patients with hepatic dysfunction. Similar results were obtained for total DHEC. CONCLUSIONS: The results reflect an increased systemic exposure in patients with impaired hepatic function which is not due to a reduced urinary excretion/elimination or reduced renal clearance. The most likely mechanism involved is a reduction in pre-systemic biotransformation. The observed range of effects on the pharmacokinetics of DHEC in patients with compromized hepatic function does not suggest the need to revise the dosage recommendations, since treatment with DHEC is generally started with low doses and is slowly up-titrated according to the individual response and the occurrence of adverse effects. Nevertheless, lower maintenance doses are likely to be achieved.