First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. RESULTS: In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l-1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. CONCLUSIONS: Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.

Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers.

BACKGROUND: The pharmacology of single doses of acetylsalicylic acid (ASA) administered intravenously (250 or 500 mg) or orally (100, 300, or 500 mg) was evaluated in a randomized, placebo-controlled, crossover study. METHODS: Blood and urine samples were collected before and up to 24 hours after administration of ASA in 22 healthy volunteers. Pharmacokinetic parameters and measurements of platelet aggregation were determined using validated techniques. RESULTS: A comparison between administration routes showed that the geometric mean dose-corrected peak concentrations (Cmax/D) and the geometric mean dose-corrected area under the curve (AUC0-∞/D) were higher following intravenous administration of ASA 500 mg compared with oral administration (estimated ratios were 11.23 and 2.03, respectively). Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous ASA doses, reflecting a rapid onset of inhibition that was not observed with oral dosing. At 5 minutes after administration, the mean reduction in arachidonic acid-induced thromboxane B2 synthesis ex vivo was 99.3% with ASA 250 mg intravenously and 99.7% with ASA 500 mg intravenously. In exploratory analyses, thromboxane B2 synthesis was significantly lower after intravenous versus oral ASA 500 mg (P<0.0001) at each observed time point up to the first hour after administration. Concentrations of 6-keto-prostaglandin1α at 5 and 20 minutes after dosing were also significantly lower with ASA 500 mg intravenously than with ASA 500 mg orally. CONCLUSION: This study demonstrates that intravenous ASA provides more rapid and consistent platelet inhibition than oral ASA within the first hour after dosing.

The safety of healthy volunteers in First-in-Man trials - an analysis of studies conducted at the Bayer in-house ward from 2000 to 2005.

OBJECTIVE: The Northwick Park incident has focused the attention on the risk of healthy volunteers participating in Phase I First-in-Man (FiM) studies irrespective of biologicals or small molecules being applied. However, only few data on the safety of healthy volunteers receiving small molecules in FiM trials are available. This study reports on the safety of healthy volunteers participating in single dose FiM studies performed with small molecules at the Bayer in-house study ward in Wuppertal from 2000 to 2005. METHODS: From 2000 to 2005, 24 FiM dose escalation studies with small molecules were performed. Twenty studies were performed with oral formulations and four studies with intravenous formulations. 1,094 young healthy male subjects were included into the studies. 77 subjects dropped out before receiving any study medication. The remaining 1,017 study participants (mean age 31.8 ± 6.5 years (range: 18 - 46 years)) received 1,160 treatments, 792 with active drug and 368 with placebo. RESULTS: In total, 586 adverse events (AE) occurred equaling 0.51 AE/treatment and 0.58 AE/ subject. 128 AEs occurred under placebo (0.35/treatment) and 458 under active drug (0.58/treatment). 98.3% of AEs were of mild or moderate intensity. Adverse events with a frequency > 2% were headache (17.1%), nasopharyngitis (7.3%), flushing (7.0%), feeling hot (5.5%), nausea (4.1%), nasal congestion (3.9%), dizziness (3.4%), diarrhea (3.24%), Alanine aminotransferase (ALT) increase (2.6%) and orthostatic hypotension (2.4%). In only 5 out of 1,160 treatments (0.4%) a serious adverse event occurred. Two cases of hypotension were related to the mode of action of CNS compounds and judged to be drug-related while the other three events (muscle enzyme elevation (2 ×), prolonged orthostatic reaction (1 ×) were not drug-related. None of the serious adverse events was medically worrying or required hospitalization. CONCLUSION: The incidence of adverse events in FiM trials with small molecules in our center between 2000 and 2005 and the severity of AEs is comparable to what has been reported previously for Phase I trials with small molecules [3, 4]. It reflects our experience with FiM trials of more than 25 years in which no medically worrying or hospitalization requiring serious adverse event occurred.

Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats.

BACKGROUND: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT(1A)-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT(1A)-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown. In this study, we sought to establish (a) the effects of repinotan on spontaneous breathing and nociception, and (b) the interaction with the standard opiate morphine. METHODS: The dose-dependent effects of repinotan, given alone or in combination with morphine, on spontaneous minute ventilation (MV) and nociceptive tail-flick reflex latencies (TFLs) were measured simultaneously in spontaneously breathing anesthetized rats. An additional series with NaCl 0.9% and the 5-HT(1A)-R-antagonist WAY 100 135 served as controls. RESULTS: (a) Repinotan dose-dependently activated spontaneous breathing (MV, mean [95% confidence interval]; 53% [29%-77%]) of pretreatment level) and suppressed nociception (TLF, 91% maximum possible effect [68%-114%]) with higher doses of repinotan (2-200 µg/kg). On the contrary, nociception was enhanced with a small dose of repinotan (0.2 µg/kg; TFL, -47% maximum possible effect [-95% to 2%]). Effects were prevented by 5-HT(1A)-antagonist WAY 100 135. (B) Morphine-induced depression of ventilation (MV, -72% [-100% to -44%]) was reversed by repinotan (20 µg/kg), which returned spontaneous ventilation to pretreatment levels (MV, 18% [-40% to 77%]). The morphine-induced complete depression of nociception was sustained throughout repinotan and NaCl 0.9% administration. Despite a mild decrease in mean arterial blood pressure, there were no serious cardiovascular side effects from repinotan. CONCLUSIONS: The 5-HT(1A)-R-agonist repinotan activates spontaneous breathing in anesthetized rats even in morphine-induced ventilatory depression. The potency of 5-HT(1A)-R-agonists to stimulate spontaneous breathing and their antinociceptive effects should be researched further.

First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.

Pulmonary hypertension (PH) is associated with impaired production of the vasodilator nitric oxide (NO). Riociguat (BAY 63-2521; Bayer Healthcare AG, Wuppertal, Germany) acts directly on soluble guanylate cyclase, stimulating the enzyme and increasing sensitivity to low NO levels. The present study evaluates riociguat safety, tolerability and efficacy in patients with moderate-to-severe PH (pulmonary arterial hypertension, distal chronic thromboembolic PH or PH with mild to moderate interstitial lung disease). The optimal tolerated dose was identified by incremental dosing in four patients with PH; pharmacodynamic and pharmacokinetic parameters were assessed following single-dose administration (2.5 mg or 1 mg) in 10 and five patients with PH, respectively. All subjects (n = 19) were analysed for safety and tolerability. Riociguat had a favourable safety profile at single doses < or =2.5 mg. It significantly improved pulmonary haemodynamic parameters and cardiac index in patients with PH in a dose-dependent manner, to a greater extent than inhaled NO. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110 mmHg. The present report is the first to describe the use of riociguat in patients with pulmonary hypertension. The drug was well-tolerated and superior to nitric oxide in efficacy and duration. Riociguat, therefore, has potential as a novel therapy for pulmonary hypertension and warrants further investigation.

Simultaneous administration of vardenafil and alcohol does not result in a pharmacodynamic or pharmacokinetic interaction in healthy male subjects.

OBJECTIVES: To investigate the pharmacodynamic effects of the combined administration of vardenafil and ethanol on blood pressure and heart rate and to study the mutual pharmacokinetic interaction, safety and tolerability of the combination. METHODS: 12 healthy male subjects aged 18 - 45 years received 3 different single-dose treatments in a randomized, double-blind, placebo-controlled crossover design: 20 mg vardenafil plus 0.5 g/kg ethanol, vardenafil plus placebo and ethanol plus placebo. Heart rate (HR) as well as systolic (SBP) and diastolic blood pressure (DBP) were measured in supine position after 15 min of rest at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15 and 24 h post dosing using a validated oscillometric sphygmomanometer. Vardenafil, vardenafil metabolite M-1 and ethanol pharmacokinetics were assessed. RESULTS: There were no statistically significant differences between treatments in DBP and SBP. Significantly higher increases in HR were seen when the combination vardenafil/ethanol and ethanol/placebo treatment, respectively, was compared with vardenafil/placebo treatment. The difference between the 2 treatments including ethanol, however, was not significant. All hemodynamic changes were not clinically relevant. The pharmacokinetics of vardenafil and ethanol were not changed in the treatment "vardenafil + ethanol" compared to the respective treatment with vardenafil and ethanol alone. The most frequently reported adverse events were vasodilation and nasal congestion, well-known side effects of PDE-5 inhibitors such as vardenafil. CONCLUSION: Concomitant administration of vardenafil and alcohol was well-tolerated. No clinically relevant pharmacodynamic or pharmacokinetic interactions were detected.

Adverse events in volunteers participating in phase I clinical trials: a single-center five-year survey in 1,559 subjects.

OBJECTIVE: This report analyzes all adverse events (AEs) which occurred in healthy volunteers in a phase I center over a five-year period. It included 142 phase I studies with a total of 1,559 participants receiving 2,955 treatments with 32 different active drugs and placebo (ratio 6.5 : 1 in terms of follow-up days). The observation period covered a total of 29,664 follow-up days. METHODS: All adverse events (AEs) as well as clinically relevant laboratory findings were counted. The incidence of AEs was defined as the ratio between the number of AEs and the number of follow-up days. Severity of AEs was classified as mild, moderate and severe; serious AEs were analyzed separately. A chi2-test was used to compare incidence rates of the AEs. Statistical tests based on the normal distribution were used for comparison of demographic data and relative frequencies; p < 0.05 was defined as the minimum level of significance. RESULTS: There were 2,604 AEs and 291 different types of AEs with headache (2.23%), diarrhea (1.37%) and common cold (0.72%) being the most frequent. The overall incidence of AEs was 8.8% with no significant difference between those occurring with active drug and those on placebo when the studies were taken as a whole (8.5% vs. 9.1%), but the incidence of AEs in the active treatment groups was higher than under placebo (14.1% vs. 9.1%; p < 0.001) in placebo-controlled studies. The overall rate of AEs was 1.7 per subject and 0.9 per treatment. The vast majority of AEs were of mild or moderate intensity (99.2%). Only six AEs were serious as defined by GCP but two, a pseudoallergic reaction and a prolonged orthostatic dysregulation were rated as possibly or probably drug-related and these resolved completely. The incidence of AEs was three-fold (all AEs) and six-fold (AEs with probable relationship to study medication) higher (p < 0.001) in multiple-dose studies than in single-dose trials, and within multiple-dose trials the difference between AEs on active drug and on placebo was also significant (22.9% vs. 12.5%; p < 0.001). Irrespective of whether on active drug or placebo, AEs occurred with a significantly higher incidence on the first day of the study drug administration, in the first study period, with respect to the overall population in elderly subjects and in volunteers with a high body weight. CONCLUSION: AEs in phase I studies are common, but usually of mild or moderate intensity. Placebo effects and study conditions contribute significantly to the rate of their occurrence. Multiple-dose placebo-controlled studies are of particular importance in determining the substance-specific AE profile.

Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype.

The metabolism of acetaminophen (paracetamol) is thought to be altered in patients with Gilbert's syndrome (GS), a chronic unconjugated hyperbilirubinemia. The underlying cause of GS is a polymorphism in the promotor region of the uridine diphosphate glucuronosyltransferase isoform 1A1 gene (UGT1A1*28), its encoded enzyme being responsible for the glucuronidation of bilirubin and presumably acetaminophen. Decreased enzyme activity results in elevated bilirubin levels and may activate various metabolic pathways leading to higher amounts of potentially hepatotoxic acetaminophen metabolites. Patients with GS might be more susceptible to unexpected side effects while taking acetaminophen and other drugs which are substrates of UGT1A1. The possibility of a correlation between glucuronidation capacity with respect to acetaminophen, UGT1A1 promotor polymorphism and the bilirubin serum level were investigated in 23 healthy male volunteers selected for UGT1A1 genotype (6 wildtypes, 9 mutants and 8 heterozygotes). One gram acetaminophen was administered p.o. and urine was collected over 2 4-hour periods. Unchanged acetaminophen and its glucuronide metabolite were determined using HPLC. The metabolic ratios unchanged acetaminophen/acetaminophen glucuronide in UGT1A1-wildtypes, heterozygotes and mutants showed no statistically significant differences. An association between metabolic ratio and serum bilirubin level could not be detected in any of the urine collection periods. These data confirm that there is no correlation between the capacity to glucuronidate acetaminophen, the UGT1A1 genotype and the bilirubin serum level. Acetaminophen is likely to be substrate of a UGT isoform other than the UGT1A1.

Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose.

OBJECTIVES: To evaluate the effect of two doses of vardenafil hydrochloride on penile rigidity and tumescence while determining the pharmacokinetics. METHODS: Twenty-one patients with erectile dysfunction completed three oral single-dose regimens (placebo, 20 and 40 mg vardenafil) in a randomized, placebo-controlled, 3-way cross-over study. Penile rigidity and tumescence were measured at the base and tip with a Rigiscan for up to 2 h after dosing. The period included three 20-min repeated episodes of visual sexual stimulation. Blood samples were taken periodically up to 24 h after dosing. RESULTS: After 20 and 40 mg vardenafil, the mean duration of >60% rigidity of the base of the penis was greater than after placebo by 42.9 min (95% Cl 29.3-56.4) and by 49.3 min (95% Cl 35.7-62.9), respectively (p<0.001), and greater than after placebo by 34.6 min (95% Cl 22.1-47.1) for both doses at the tip. Additionally, significantly greater rigidity activity units and tumescence activity units were found for both doses compared with placebo (p<0.001). The plasma concentrations of vardenafil increased rapidly, with a median t(max) of about 40 min and a mean t1/2 of 4.4-4.8 h. Relative bioavailability was slightly higher for the 40-mg dose than for the 20-mg dose. The treatments were well tolerated, although slightly more adverse events, primarily headache, flushing and nasal congestion, were seen with the 40-mg dose compared with placebo. CONCLUSION: The findings confirm that vardenafil was able to generate stronger erections of longer duration than placebo under conditions of visual sexual stimulation in patients with erectile dysfunction. The pharmacokinetic, pharmacodynamic and tolerability profiles support vardenafil hydrochloride as a strong candidate for further testing as a treatment for erectile dysfunction.

Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study.

The pharmacodynamic effect on penile rigidity and tumescence and the pharmacokinetic properties of single oral doses of 10 and 20 mg vardenafil, a new PDE5-inhibitor, were investigated in 21 erectile dysfunction patients. Patients were evaluated with RigiScan on three occasions in a randomized, placebo-controlled, double-blind crossover fashion, while receiving visual sexual stimulation. Relative to placebo, a single dose of 10 mg vardenafil led to a mean increase in the duration of >60% penile rigidity of 24.4 min (95% CI: 7.4 to 41.3) at the base and of 24.8 min (8.5 to 41.1) at the tip. For the 20-mg dose, the increase in duration of > 60% penile rigidity relative to placebo was 37.2 min (20.2 to 54.1) at the base and 28.7 min (12.7 to 44.7) at the tip. Single doses of 10 and 20 mg vardenafil led to a rapid rise in the plasma concentrations of vardenafil, with a median tmax of 0.9 h and 0.7 h and a geometric mean Cmax of 9.1 microg/l (geometric SD = 1.63) and 20.9 microg/l (geometric SD = 1.83), respectively. In the post-absorptive phase, the concentrations declined with an average terminal t 1/2 of 4.2 h (geometric SD = 1.27) and 3.9 h (geometric SD = 1.31). The systemic exposure of vardenafil expressed as AUC normalized for dose and body weight was dose-proportional (associated 90% CI: -4 to 30%) as well as Cmax (associated 90% CI: -12 to 33%). The treatments were well tolerated. There was a small, clinically irrelevant reduction in blood pressure with a small compensatory rise in heart rate. There were no electrocardiographic effects or relevant changes of the safety laboratory screens. The observed pro-erectile properties, pharmacokinetic characteristics and safety profile make vardenafil a suitable candidate for further evaluation in the treatment of erectile dysfunction.

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.

Urinary sodium balance in patients with cirrhosis: relationship to quantitative parameters of liver function.

The relationship between the impairment in hepatic and renal function in cirrhosis has not been well established. This study investigated urinary sodium excretion in comparison with quantitative parameters of liver function in 75 patients with various degrees of cirrhosis kept on a constant salt diet of 120 mmol/d for 5 days before the start of the study. The aminopyrine breath test (ABT), indocyanine green (ICG) elimination, galactose elimination capacity (GEC), and hepatic sorbitol elimination (HSE) served as quantitative parameters of liver function. Results for the quantitative tests were compared with those for the Child-Pugh score. Urinary sodium excretion showed a significant nonlinear relationship to ABT (r = .70; P < .0001). Less-significant correlations were observed for ICG (r = .60), the Child-Pugh score (r = -.57), GEC (r = .44), and HSE (r = .34). Because a number of significant correlations were observed between the different liver function tests, multivariate analysis was used to further elucidate the relationship between hepatic function and sodium excretion. Only one independent predictor of urinary sodium excretion could be identified, and that was the ABT (P < .02). More than half of the nonascitic patients showed a urinary sodium excretion of less than 80% of dietary sodium intake, indicating impaired renal sodium handling in preascitic cirrhosis. Based on the 95% confidence interval (CI) for ABT of nonascitic patients with normal (mean ABT 0.56% dose x kg/mmol CO2; 95% CI: 0.44 to 0.69) and reduced urinary sodium excretion (mean ABT 0.26% dose x kg/mmol CO2; 95% CI: 0.18 to 0.35), a threshold level of ABT of about 0.4 (% dose x kg/mmol CO2) for conservation of normal urinary sodium excretion in cirrhosis can be defined. This ABT value reflects an approximate 50% reduction in function compared with the mean of cirrhotic patients with normal liver and kidney function (0.81% dose x kg/mmol CO2). The presence of ascites was also associated with a reduction in ABT to below 0.4 (% dose x kg/mmol CO2), while, for all other parameters, either the cut-off point was close to the lower limit of normal or no cut-off level could be detected. In conclusion, the results of the present study provide further evidence that the impairment in urinary sodium excretion in cirrhosis is related to hepatic function. The data suggest a nonlinear relationship. Because ABT has been shown to reflect functional hepatocellular mass, the occurrence of sodium retention and ascites appears to be related to a threshold of an approximate 50% reduction in functional liver cell mass.

Pharmacodynamics and pharmacokinetics of BAY x 7195 aerosol, a new and selective receptor antagonist of cysteinyl-leukotrienes, in normal volunteers.

1. The safety, tolerability and pharmacokinetics of BAY x 7195 aerosol, a new selective receptor antagonist of cysteinyl-leukotrienes, were investigated in healthy male volunteers in two observational studies (1 and 2 mg; n = 5 each) and two double blind, placebo-controlled two way crossover studies (4 and 8 mg; n = 6 each) using the commercially available Inhaler Ingelheim M. 2. The pharmacodynamic effect was assessed by testing the ability of BAY x 7195 aerosol to inhibit leukotriene-D4 (LTD4) induced bronchoconstriction in healthy volunteers. Using a double-blind, placebo-controlled three way crossover design, volunteers received 2 and 4 mg of BAY x 7195 by means of a newly developed metered dose dry powder inhaler. Bronchoprovocation with nebulized LTD4 was performed 20 min and 8 h (n = 6 each) after drug administration. Specific airways of conductance (SGaw) served to assess the airway's response. 3. BAY x 7195 aerosol was safe and well tolerated. Inhalation of the aerosol had no effect on baseline lung function. Only one volunteer reported cough following the inhalation of the 8 mg dose. 4. The pharmacokinetics of unchanged drug following the administration of BAY x 7195 aerosol were linear in the investigated range of doses and in general very similar to a previously investigated tablet formulation. Plasma-concentration vs time courses followed a two-compartment body model. Compared with oral administration of the tablet formulation absorption tended to be more rapid with the aerosol formulation. 5. Compared with placebo, 2 and 4 mg BAY x 7195 increased the concentration of LTD4 needed to produce a 35% decrease in SGaw 20 min after drug administration by a mean (geometric) of 14.2 and 29.7 fold, respectively. For both doses only three volunteers showed a protective effect against LTD4 induced bronchoconstriction 8 h after drug administration. Individual shifts in the concentration-response curve ranged between 0.4 and 7.2 fold. 6. In conclusion, the present results suggest that BAY x 7195 aerosol is a safe and potent but short acting receptor antagonist of cysteinyl leukotrienes in man.

Pharmacokinetics, safety and tolerability of the orally administered receptor antagonist of cysteinyl-leukotrienes BAY x 7195 in single-dose escalation studies.

BAY x 7195 is a novel receptor antagonist of cysteinyl-leukotrienes currently under development for the treatment of asthma. It is effective in antagonizing the leukotriene-D4 induced bronchoconstriction in healthy volunteers following oral administration. The pharmacokinetics, safety and tolerability of the drug were investigated in six partially placebo-controlled studies in healthy volunteers with single oral administration of a 50, 100, 250, 500 and 1000 mg dose as a tablet. The drug was well tolerated. The only remarkable adverse event was diarrhea in one volunteer receiving the highest dose of 1000 mg. There were no additional clinically relevant changes in any safety parameter including laboratory values. Concentrations of BAY x 7195 were determined in plasma and urine by high performance liquid chromatography with fluorescence detection and plasma-concentrations were further evaluated by compartmental and non-compartmental methods. The concentration vs time profiles of the drug were biphasic with a dominant t1/2 of 0.5-2 h and a terminal t1/2 of 5-10 h. Pharmacokinetics were linear in the investigated range of doses. In spite of substantial inter-subject variability intra-individual variability in AUC and Cmax was reasonable. In general, the concentration vs time profiles could be described with a 2-compartment body model. However, in some cases the occurrence of second and third concentration maxima necessitated the use of a multiple segment absorption model to accomplish a good fit to the data. Enterohepatic recirculation following glucuronidation of the drug is the likely reason for the multiple peaks. Urinary excretion of BAY x 7195 and its glucuronide metabolite was negligible the amount excreted into urine from 0 to 48 h being < 0.1% of the dose. The low renal clearance of BAY x 7195 (< or = 0.07 ml/min) is suggestive of significant reabsorption in the renal tubuli taking into account that the expected renal clearance for a drug with 99.5% protein binding is about 0.6 ml/min.

Relationship of the aminopyrine breath test and the Child-Pugh score to urinary sodium retention in patients with liver cirrhosis.

This study investigated the relationship between urinary sodium excretion and liver function, as assessed by the aminopyrine breath test (ABT) and conventional parameters, in 62 patients with cirrhosis kept on a constant salt diet. Urinary sodium excretion was related non-linearly to the ABT (r = 0.76). Less significant correlations were observed to the Child-Pugh score (r = -0.65), cholinesterase (r = 0.58), bilirubin (r = -0.56), albumin (r = 0.51) and prothrombin time (r = 0.49). When patients were arbitrarily divided into 6 groups according to the ABT, sodium excretion balanced the sodium intake up to a 50% reduction in ABT. In groups with more than a 50% reduction sodium retention occurred. When patients were grouped according to the Child-Pugh score, urinary salt output was balanced in patients with scores of 5 and 6 and decreased in patients with scores greater six. However, the change in sodium output from normal salt excretion to sodium retention was less pronounced in patients grouped according to the Child-Pugh score than in patients grouped according to the ABT. The results suggest a non-linear relationship between the impairment in hepatic and renal function in cirrhosis. They are compatible with the concept of a threshold of hepatic function necessary to maintain normal renal function.

Relationship between oxidative hepatic metabolism, urinary sodium excretion and sympathetic nerve activity in experimental cirrhosis in the rat.

This study investigated the relationship between changes in renal sympathetic activity as assessed by renal norepinephrine spill-over and the onset of renal sodium retention in the phenobarbital/carbon tetrachloride model of experimental cirrhosis in rats. In this model, sodium retention occurs when hepatic function, assessed by the aminopyrine breath test (ABT), falls below a critical threshold. Three groups of rats, studied on a constant salt diet, included a group with cirrhosis and sodium retention, a group with cirrhosis of similar duration and no sodium retention and a time-control phenobarbitaltreated group. ABT, renal plasma flow (RPF), glomerular filtration rate (GFR) and mean arterial pressure (MAP) were measured at the time of catecholamine sampling in anesthetized rats. Cirrhosis was associated with reductions in MAP, no change in RPF and GFR, and an ABT below the threshold in rats with sodium retention. In contrast, rats without sodium retention had liver function above the threshold. Renal norepinephrine spill-over increased continuously from controls to non-sodium retaining and sodium retaining animals. The difference between sodium retaining animals and controls was significant. Norepinephrine spill-over correlated to ABT and MAP but not urinary salt excretion. The data suggest that, under these experimental conditions, increased sympathetic activity may contribute to the onset of sodium retention. A plausible explanation for the continuous increase is that catecholamines are released as a compensatory mechanism in response to a primary yet undefined vasodilator.

Dynamics of cognitive brain dysfunction in patients with cirrhotic liver disease: an event-related P300 potential perspective.

The dynamics of cognitive brain functions of 104 patients with both chronic non-cirrhotic (NC) and cirrhotic liver disease (C: C1, non-encephalopathic; C2, encephalopathic) were investigated by means of visual P300 potentials elicited in both the paradigms of transient (PI) and selective attention (PII). Conventional PVEPs, psychometric tests and quantitative liver function tests were also performed. As compared to both an age-matched control group (N) and the non-cirrhotic patients (NC), the N250 and P300 latencies of the cirrhotics (C) were equally prolonged in both P300 paradigms (P = 0.0001). By contrast, the P300 amplitudes were not different between the patient groups in either P300 paradigm. In the cirrhotics, however, the P300 amplitude differences between PII and PI (+ 3.7 +/- 2.8 muV, mean +/- 1 S.D.) were significantly (P < 0.01) smaller than in the non-cirrhotics (+ 7.5 +/- 5.2 muV) reflecting disturbances in the dynamics of visual attention. Interestingly, these P300 amplitude differences between both paradigms were positively correlated (r = 0.35; P = 0.005) with hepatic metabolic capacity, but not with liver blood flow (r = 0.23; P > 0.05). The diagnostic efficacy of the visual P300 in PI (sensitivity, 48%; specificity, 100%) was lower than that of the visual P300 in PII (79%; 100%) and that of the psychometric tests (63%; 94%), but it remained superior to that of the PVEPs (29%; 97%). It is concluded that in patients with cirrhotic liver disease visual P300 potentials can even reveal the dynamics of minor cognitive brain dysfunction and may also provide interesting pathophysiological information.

Effect of BAY x 7195, an oral receptor antagonist of cysteinyl-leukotrienes, on leukotriene D4-induced bronchoconstriction in normal volunteers.

Leukotrienes (LT) have been proposed to play an important role in the pathogenesis of asthma. This paper reports the results of two studies investigating the effect of BAY x 7195, a new oral receptor antagonist of cysteinyl-leukotrienes, on LTD4-induced bronchoconstriction in healthy male volunteers. Using a double-blind, placebo-controlled, crossover design, volunteers received 250 mg (n = 6; study 1) and 100 and 500 mg (n = 6; study 2) of BAY x 7195. Bronchoprovocation with nebulized LTD4 was performed 2 (250 mg) and 2 and 8 (100 and 500 mg) h p.a. The specific airway's conductance (SGaw) was used to assess the airway's response. Blood samples to determine plasma concentrations of BAY x 7195 were taken at the end of bronchoprovocation. BAY x 7195 showed no effect on baseline lung function. Compared to placebo, the different doses of BAY x 7195 increased the concentration of LTD4 needed to produce a 35% decrease in SGaw 2 h p.a. between 1- and 23-fold. Eight hours p.a., 100 and 500 mg caused shifts in the concentration-response curve of between 1- and 13-fold. There was no predictive relationship between plasma concentrations of BAY x 7195 and the response to LTD4 challenge. However, there was a relationship between dose and effect. No relevant adverse effects were reported. In conclusion, the present results suggest that BAY x 7195 is an effective LTD4-receptor antagonist in man.

Antipyrine elimination in patients with alcoholic and non-alcoholic cirrhosis.

The metabolism of antipyrine to each of its three major metabolites 4-hydroxy-, 3-methylhydroxy- and norantipyrine has previously been demonstrated to be differentially affected in alcoholic cirrhosis. This study compared the metabolism of antipyrine to its metabolites in 30 patients with alcoholic cirrhosis to 15 patients with non-alcoholic cirrhosis and 20 healthy controls. Both groups of cirrhotic patients were comparable with respect to their disease stage, as assessed by the Child-Pugh classification. Compared to controls, patients with alcoholic and non-alcoholic cirrhosis showed a comparable significant reduction in antipyrine clearance and increase in antipyrine half-life. The reduction in antipyrine clearance was due to a reduction in the formation rate of all three antipyrine metabolites in both alcoholic and non-alcoholic cirrhotics. In both groups, the formation rate of norantipyrine was reduced to a greater extent than of 3-methylhydroxy- and 4-hydroxyantipyrine. No significant differences in the parameters of antipyrine elimination, however, were observed between patients with alcoholic and non-alcoholic cirrhosis. Parameters of antipyrine elimination correlated significantly to the Child-Pugh score and single laboratory parameters, however, the correlation coefficients were generally low (< 0.56). The present results suggest that the P450 enzymes involved in antipyrine metabolism are differentially affected in cirrhosis, but there appear to be no differences in the activity of the enzymes between alcoholic and non-alcoholic cirrhosis. Antipyrine metabolism, therefore, depends on the severity rather than the etiology of liver disease and may serve as a measure of hepatic function irrespective of the cause of liver disease.