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.

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.

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.

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.

Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease.

Induction of hepatic monooxygenases reflected by 7-ethoxycoumarin O-deethylase has been proposed to be associated with the initiation of liver damage. This study investigated a possible correlation between 7-ethoxycoumarin O-deethylase, reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase and benzypyrene hydroxylase activity in liver biopsy specimens of 31 patients with liver disease and antipyrine elimination, an in vivo parameter of hepatic monooxygenase activity. No correlation was found between the enzyme activities and antipyrine clearance or half-life. When microsomal enzyme activities were compared with the formation rate of 4-hydroxyantipyrine, 3-methylhydroxyantipyrine, and norantipyrine, a correlation was found only between benzo[alpha]pyrene hydroxylase and 3-methylhydroxyantipyrine (r = 0.89; p less than 0.0005). There was also a correlation between 7-ethoxycoumarin O-deethylase and reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase (0.56; p less than 0.05). Our data suggest that antipyrine elimination is not related to 7-ethoxycoumarin O-deethylase activity in liver disease. However, the formation rate of antipyrine metabolites, rather than antipyrine half-life and clearance, may correlate with the activity of certain microsomal enzymes.

Effect of antipyrine and phenobarbital on renal gamma-glutamyltransferase excretion in human urine.

Serum gamma-glutamyltransferase is used as a marker of hepatic enzyme induction. The kidney contains high activities of gamma-glutamyltransferase in the brush border membrane of the proximal tubule, from which it is released into urine. This study investigated the effect of phenobarbital and antipyrine, two inducers of hepatic monoxygenases and gamma-glutamyltransferase, on the urinary excretion of renal gamma-glutamyltransferase. Three groups (n = 6) of healthy male volunteers received 100 mg phenobarbital for 7 and 14 days and 1200 mg antipyrine for 7 days, respectively. Antipyrine and phenobarbital increased antipyrine elimination, serum gamma-glutamyltransferase, and the urinary excretion of renal gamma-glutamyltransferase, whereas urinary beta-N-acetylglucosaminidase, beta-glucuronidase, and total protein and glucose excretion were unchanged. No correlation was found between serum and urinary gamma-glutamyltransferase or both enzymes and antipyrine elimination. Increases in antipyrine elimination were positively correlated to increases in serum, but not urinary gamma-glutamyltransferase. The findings suggest that antipyrine and phenobarbital increase urinary gamma-glutamyltransferase excretion. However, the increase in urinary gamma-glutamyltransferase does not reflect the magnitude of hepatic enzyme induction.

The effect of antipyrine and rifampicin on the excretion of renal enzymes in human urine.

Two well-known drugs that induce the liver microsomal enzyme system in man were administered to 3 different groups of healthy male volunteers. Antipyrine 1200 mg and rifampicin in two different doses of 600 mg or 1200 mg daily were given orally to each group over a period of seven days. The extent of liver microsomal enzyme induction was assessed by estimating antipyrine elimination, serum gamma-glutamyl-transferase (GGT) activity and the urinary excretion rate of 6-beta-hydroxycortisol. In addition, possible effects on renal enzymes were monitored by measuring gamma-glutamyltransferase (GGT) and beta-glucuronidase (GRS) urinary excretion rates before and after drug administration. The possibility of a direct toxic effect on the renal tubular epithelium following drug administration was assessed by the measurement of urinary beta-N-acetylglucosaminidase (AGS) activity, total protein and glucose. Antipyrine plasma clearance and 6-beta-OHF excretion rates increased significantly in the groups treated with antipyrine or rifampicin, while serum GGT activities were enhanced only following antipyrine. Antipyrine administration increased urinary GGT excretion both immediately and one week after cessation of drug administration, but no changes were found following the administration of rifampicin. GRS, AGS, total protein and glucose excretion in urine remained unchanged during and after the administration of each individual drug. Based on these findings, the increased urinary GGT excretion observed following antipyrine treatment may be due to an inducing effect on the renal tubular cells, as no evidence for a toxic renal damage was found.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.

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.

Phenobarbital influences the development of sodium retention in liver disease induced by bile duct ligation in the rat.

The onset of sodium retention in phenobarbital/carbon tetrachloride-induced cirrhosis in rats is preceded by a linear decrease in hepatic function as assessed by the aminopyrine rate constant of elimination. Sodium retention occurs when liver function decreases below a critical aminopyrine rate constant of elimination threshold of 1 min-1 x 10(-3). The objective of this study was to investigate this relationship in a different experimental model of cirrhosis in rats and to learn whether alteration of drug-metabolizing activity by hepatic enzyme induction changes the threshold for urinary sodium retention. Cirrhosis was induced in untreated and phenobarbital-treated rats by bile duct excision. Liver function, assessed by the aminopyrine breath test, and urinary sodium excretion on a constant salt diet were measured weekly for up to 4 wk. In untreated rats, the aminopyrine breath test rate constant of elimination was reduced by about 40% within 1 wk of surgery. Aminopyrine rate constant of elimination then decreased more slowly, but linearly. Urinary sodium excretion was initially unchanged, but sodium retention occurred after 2.5 wk and was maintained until the end of the experiment. Phenobarbital-treated rats had greater initial aminopyrine rate constant of elimination, but we saw a similar fall in aminopyrine rate constant of elimination of about 40% within 1 wk of bile duct excision to a value still above baseline aminopyrine rate constant of elimination of untreated controls. Aminopyrine rate constant of elimination remained at a plateau for 3.5 wk without changes in urinary sodium excretion. After 3.5 wk, a sudden decrease in aminopyrine rate constant of elimination was associated with the sudden onset of sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.