Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I.

BACKGROUND: Dabigatran etexilate (BIBR 1048) is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). OBJECTIVES: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. METHODS: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for 6-10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. RESULTS: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose-response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. CONCLUSIONS: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.

Safety and preliminary efficacy of one month glycoprotein IIb/IIIa inhibition with lefradafiban in patients with acute coronary syndromes without ST-elevation; a phase II study.

AIMS: Oral glycoprotein IIb/IIIa inhibitors might enhance the early benefit of an intravenous agent and prevent subsequent cardiac events in patients with acute coronary syndromes. We assessed the safety and preliminary efficacy of 1 month treatment with three dose levels of the oral GP IIb/IIIa blocker lefradafiban in patients with unstable angina or myocardial infarction without persistent ST elevation. METHODS: The Fibrinogen Receptor Occupancy STudy (FROST) was designed as a dose-escalation trial with 20, 30 and 45 mg lefradafiban t.i.d. or placebo. Five hundred and thirty-one patients were randomized in a 3:1 ratio to lefradafiban or placebo in a double-blind manner. Efficacy was assessed by the incidence of death, myocardial infarction, coronary revascularization and recurrent angina. Safety was evaluated by the occurrence of bleeding classified according to the TIMI criteria and by measuring clinical laboratory parameters. RESULTS: There was a trend towards a reduction in cardiac events with lefradafiban 30 mg when compared with placebo and lefradafiban 20 mg. The benefit was particularly apparent in patients with a positive (> or = O.1 ng. ml(-1)) troponin I test at baseline and less so in those with a negative test result. In patients receiving lefradafiban, the cardiac event rate decreased with increasing minimal levels of fibrinogen receptor occupancy. There was a dose-dependent increase in the incidence of bleeding: the composite of major or minor bleeding occurred in 1% of placebo patients, 5% of patients receiving lefradafiban 20 mg and in 7% of patients receiving 30 mg, with an excessive risk (15%) in the 45 mg group which resulted in early discontinuation of this dose level. Gingival and arterial or venous puncture site bleedings were most common and accounted for more than 60% of all haemorrhagic events. There was an increased incidence of neutropenia (neutrophils <1. 5 x 10(9)/l) in the lefradafiban groups (5.2% vs 1.5% in the placebo group), which did not result from bone marrow depression but rather from a reversible redistribution of neutrophils by margination or clustering. CONCLUSION: One month's treatment with the oral glycoprotein IIb/IIIa inhibitor lefradafiban in patients with unstable angina and myocardial infarction without persistent ST elevation resulted in a decrease in cardiac events with lefradafiban 30 mg and a dose-dependent increase in haemorrhagic events. The observed favourable trend towards a reduction in cardiac events in patients with elevated troponin levels requires confirmation in a large clinical trial.

Effect of hospitalisation on liver enzymes in healthy subjects.

OBJECTIVES: The aims of the present evaluation were to determine whether the elevations in liver enzymes observed in phase-I trials are more common in subjects being hospitalised than in ambulatory subjects and to assess the relevance of these elevations. We therefore investigated the effect of hospitalisation on liver enzyme levels in subjects of all phase-I trials of sufficient length performed at the two Human Pharmacology Centres of Boehringer Ingelheim, located in Biberach and Ingelheim, Germany, over a 10-year period. METHODS: The evaluation was based on 29 phase-I trials conducted between 1987 and 1996. These trials consisted of at least 4 days of observation of 220 subjects on placebo treatment in 273 trial participations. The mean changes (transformed into reference ranges) in the liver enzymes alkaline phosphatase, gamma glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase and the AST/ALT ratio of hospitalised subjects were compared with those of ambulatory subjects. RESULTS: A small but statistically significant increase in the mean of the parameters GGT, AST and ALT during phase-I trials was observed in hospitalised subjects compared with ambulatory subjects. The increases were: 8% of the reference range width for GGT, 8% for AST and 17% for the ALT, although the differences were small in absolute terms. A relevant increase (defined as an increase to above the reference range or by at least 50% of the reference range) was more common in hospitalised subjects. CONCLUSION: Hospitalisation, although it is believed to protect subjects from confounding environmental factors, can itself be associated with increases in liver enzyme levels. The definition of a relevant increase can be used to identify subjects who need further evaluation. The cause of the increase in liver enzyme levels remains unclear.

Precision of measurement of tissue concentrations by RLG.

Existing investigations about the precision of radioluminography (RLG) are restricted to descriptive analysis of the tissue samples. The aim of the present experiments was to obtain a general prospective statement about the precision that the RLG method can achieve. Several pharmaceutical companies in Europe participated in the experiments. Albino rats of various strains were dosed with various (14)C-labeled compounds. Whole-body sections were produced, and blood calibration scales were set up with standard radioactivity sources of dog or rat blood. Photostimulated luminescence was detected using Fuji imaging plate BAS-III. For each organ separately, variability was investigated on each of the levels: rat, section of rat, region within section, and residual, with the help of variance components. The producing company was seen as a fixed factor and adjusted for. A mixed linear model was fitted to the log-transformed data. The variance component (SD estimate) for the residual term gave the desired prospective statement about the achievable precision of the RLG method. Exponential back transformation from the logarithmic to the natural scale transformed the SD estimates to multiplication factors. In total, 29 organs were investigated. The RLG method was comparable in precision to the dissection/combustion method.

Meloxicam pharmacokinetics in renal impairment.

AIMS: The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment. METHODS: Meloxicam was administered to subjects with mild (creatinine clearance 41-60 ml min-1) to moderate (20-40 ml min-1) renal impairment compared with normal renal function (> 60 ml min-1). Thirty-eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods. RESULTS: Subjects with no or mild renal impairment showed similar pharmacokinetic profiles (geometric mean AUCSS (%gCV) 55 (33%) vs 55 (38%) micrograms ml-1 h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUCSS 35 (50%) micrograms ml-1 h, with corresponding higher plasma clearance (P = 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups. CONCLUSIONS: On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.

Pharmacokinetics and tolerability of meloxicam after i.m. administration.

1. The pharmacokinetics and tolerability of a new nonsteroidal anti-inflammatory drug (NSAID), meloxicam, administered i.m., were investigated in two studies conducted in healthy male volunteers. Study 1 was an open, placebo-controlled design in which 32 volunteers were randomized to a single ascending i.m. dose of meloxicam (5, 10, 20, and 30 mg) or placebo. Study 2 had an open, randomized two way crossover design in which 12 volunteers received single i.m. and i.v. doses of meloxicam (15 mg). 2. Meloxicam showed an excellent tolerability in both studies. No effect was seen on serum creatinphosphokinase (CK, the isoenzyme of the skeletal muscle enzyme, CK-MM, was determined). 3. Following i.m. administration meloxicam was rapidly and completely absorbed (mean absolute bioavailability 102%). Dose-proportionality was demonstrated with respect to Cmax (maximum plasma concentration) and AUC (extrapolated area under the plasma concentration-time curve from zero time to infinity) over a range of 5-30 mg. 4. Intravenous administration of meloxicam (15 mg) resulted in higher initial plasma concentrations (C3min, i.e. concentration in plasma 3 min after start of injection = 2.99 +/- 0.75 microgram.ml-1) than after i.m. injection (Cmax: 1.62 +/- 0.20 mg ml-1). All other pharmacokinetic parameters were similar for both routes of administration (apparent elimination half-life = 15-22 h; plasma clearance = 7-9 ml min-1). 5. In conclusion, the excellent tolerability of i.m. meloxicam together with its rapid and complete absorption may provide an alternative to oral administration of this drug.

Interaction of meloxicam with cimetidine, Maalox, or aspirin.

Meloxicam is a new enol carboxamide nonsteroidal antiinflammatory drug (NSAID). Preclinical studies have indicated that it possesses a high antiinflammatory potency and a low ulcerogenic potency. This open, randomized, crossover study was conducted to examine the effects of aspirin, the antacid Maalox (Rhone-Poulenc Rorer, Cologne, Germany), and cimetidine on the pharmacokinetics and bioavailability of a single oral dose of meloxicam 30 mg in healthy male volunteers. Plasma concentrations of meloxicam were determined and subjected to noncompartmental pharmacokinetic analysis. Meloxicam was well tolerated, and concomitant treatment with cimetidine or Maalox had little or no effect on the plasma concentration-time curves, maximum plasma concentration (Cmax), or the area under the plasma concentration-time curve (AUC0-infinity) of meloxicam. Concurrent treatment with aspirin increased plasma concentrations of meloxicam, increasing Cmax by approximately 25% and AUC0-infinity by 10%. These differences were not considered to be clinically relevant, and no adjustments of meloxicam dose should be required with coadministration of aspirin, Maalox, or cimetidine.

Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers.

OBJECTIVE: The pharmacokinetics of meloxicam have been studied following administration of a single 15-mg capsule to 12 patients with end-stage renal failure. Pharmacokinetic parameters were determined after haemodialysis. The pharmacokinetic profile obtained in these patients is compared to data obtained from age- and gender-matched healthy volunteers. RESULTS: Total plasma meloxicam concentrations were lower in patients with end-stage renal failure (AUC0-infinity 12.6 micrograms.h.ml-1) in comparison with healthy volunteers (AUC0-infinity 39.3 micrograms.h.ml-1). This was reflected by an increase in total clearance (+211%). However, there was an enhanced free meloxicam fraction (unbound drug) in the end-stage renal failure patients (0.9% vs. 0.3% in healthy volunteers). This was observed in association with raised free Cmax (5.0 vs. 2.6 ng/ml) but similar free AUC0-infinity (0.13 vs. 0.11 microgram.h.ml-1) in both groups. Therefore, the raised free fraction is compensated for by the increased total clearance such that no accumulation of meloxicam occurs. Meloxicam plasma concentrations were similar before and after haemodialysis. CONCLUSION: Meloxicam has displayed a pharmacokinetic profile in end-stage renal failure which is similar to that observed for other highly protein bound nonsteroidal anti-inflammatory drugs (NSAIDs). However, in view of the higher free Cmax value, and despite no evidence of accumulation, it may be prudent to treat this group of patients with a 7.5-mg dose of meloxicam. This is the lower dose normally recommended for adults. Meloxicam is not dialysable.

Effect of zatebradine, a novel 'sinus node inhibitor', on pulmonary function compared to placebo.

Zatebradine, a member of a novel class of drugs called 'sinus node inhibitors', is a specific heart rate lowering drug suitable for the treatment of stable angina pectoris. Animal studies showed that relatively high intravenous doses of zatebradine contracted guinea-pig airways by a histamine-like mechanism. Therefore, the objective of the present study was to assess the bronchopulmonary effects in asthmatic patients who showed a moderate to severe bronchial hyperreactivity towards histamine (PC20 FEV1 < or = 1 mg/ml). Moreover, it had to be established to what extent the bronchial responsiveness to inhaled salbutamol was retained and whether pulmonary effects were related to the severity of bronchial hyperreactivity. By means of a double-blind cross-over design, single oral doses of zatebradine (10 mg) or placebo were administered on two occasions with a washout phase of at least 3 days. Sixteen patients, four female and 12 male, with stable mild to moderate bronchial asthma (FEV1 less than 80% predicted) were selected. Their mean age was 54 years and the mean FEV1 was 1.831 (59% predicted). They showed a mean improvement in FEV1 of 27% 15 min after inhaling 200 micrograms salbutamol; the mean PC20 was 0.35 mg/ml. Following test drug intake, the respiratory and cardiac effects were assessed at regular time intervals up to 6 h after administration. In comparison to placebo, zatebradine induced small, but significant (P < 0.05), mean falls of 128 ml and 168 ml in FEV1 at 3 h and 6 h after drug intake. A large inter-individual variation in response was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term efficacy and safety of pimobendan in moderate heart failure. A double-blind parallel 6-month comparison with enalapril. The Pimobendan-Enalapril Study Group.

In view of growing scepticism as to the efficacy and safety of agents with predominant phosphodiesterase inhibiting properties in heart failure, the clinical efficacy and safety of pimobendan, a calcium-sensitizing and partially phosphodiesterase-inhibiting compound, was compared with enalapril in 242 patients with mild to moderate heart failure (NYHA classification II-III) despite diuretics and digitalis, and abnormal haemodynamics at baseline. Patients were randomly assigned to either pimobendan (average 10.3 mg.day-1, n = 119), or enalapril (average 10.7 mg.day-1, n = 123) in a double-blind fashion for 6 months. Forty-two pimobendan and 37 enalapril patients stopped the treatment, five pimobendan and six enalapril due to worsening of failure without death, whereas 13 and eight patients, respectively, died from cardiac disorders (ns). Other reasons for discontinuation and adverse events not leading to discontinuation were also comparable. Although Holter analysis at 14 days, but not at 6 months, indicated increased ventricular extrasystoles in pimobendan patients, these did not lead to serious clinical events. NYHA classification improved similarly in both groups, from 2.51 to 2.16 (pimobendan) and from 2.40 to 2.06 (enalapril). The number of patients needing a change in background therapy or hospitalization did not differ between the two groups. Haemodynamic variables at rest were improved by both compounds after 6 months. In contrast, only enalapril improved haemodynamics during exercise, and reduced the cardiothoracic ratio. The primary endpoint, exercise capacity, increased significantly during the first 3 months by 45 and 53 s, under pimobendan and enalapril, respectively, but, although unchanged thereafter, the improvement was no longer statistically significant at 6 months in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute and long-term effects of pimobendan (UD-CG 115) in NYHA II and III heart failure. Results of a randomized multicenter double-blind study]. / Akut- und Langzeiteffekte von Pimobendan (UD-CG 115) bei Herzinsuffizienz NYHA II und III. Ergebnisse einer randomisierten multizentrischen Doppelblindstudie.

The effects of pimobendan (UD-CG 115) on hemodynamics and exercise capacity after acute (single dose) and chronic (6 month) oral treatment, as well as acute treatment after 6 months were investigated in 67 patients with chronic heart failure of NYHA classes II or III, which had persisted in spite of treatment with diuretics and digitalis. They were treated with pimobendan (2.5 mg bid or 5 mg) or placebo in a randomized, double-blind multicenter trial. With a single administration before and after 6 months' treatment there was-compared to placebo-a significant fall in pulmonary capillary pressure (PCP) at rest (R) and during exercise (E) of 7% to 24%. Right atrial pressure (R) and pulmonary arterial pressure (PAP) (R, E) decreased after pimobendan on day 1; cardiac index (E) increased significantly. All other parameters were not influenced. After chronic therapy, PCP (E), PAP (E), LV stroke work index (E), and pulmonary resistance (R and E) values were significantly lowered by pimobendan when compared to day 1. Exercise duration was prolonged after 6 months by 83 s and 47 s after 5 and 10 mg/day, resp., compared to the placebo group (group difference not significant). Subjective wellbeing was improved in all three groups (no group difference). Clinical symptoms were not altered; six patients (two in each group) died suddenly. Another nine patients discontinued the trial prematurely because of poor efficacy or adverse events (no group difference). Overall, pimobendan was well-tolerated and had favorable effects on both acute and chronic hemodynamics and on exercise capacity. There was no evidence of any tolerance development.

Dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo.

1. In a randomized, double-blind trial we compared the inhibition of the platelet-vessel wall interactions in whole blood ex vivo. There were four groups of 24 healthy volunteers each of whom were treated orally for 3.5 days with either 200 mg dipyridamole (sustained release preparation), 25 mg acetylsalicylic acid, both drugs combined or placebo twice daily. 2. The mean area of all platelets/aggregates was reduced by 6.2% +/- 4.2% (+/- s.e. mean) by placebo (n = 23), 19.8% +/- 6.7% by dipyridamole (n = 22), 53.7% +/- 4.9% by acetylsalicylic acid (n = 23) and 71.4% +/- 3.7% by the combination of both drugs (n = 24), when compared with total inhibition of aggregation by EGTA. Thus, low-dose acetylsalicylic acid inhibited aggregation (P less than 0.001). 3. Dipyridamole reduced the size of platelet aggregates (P less than 0.01, two-fold analysis of variance). The reduction was correlated with the individual dipyridamole plasma levels (P less than 0.05, analysis of covariance). The subgroup of large and very large thrombi being formed was also reduced by dipyridamole (P less than 0.05). 4. This ex vivo study demonstrates that dipyridamole alone inhibits formation of thrombi on subendothelial matrix and enhances the inhibitory effect of low dose acetylsalicylic acid in this model of thrombosis.

Lactate and pyruvate kinetics after treadmill exercise in patients with intermittent claudication.

Lactate and pyruvate movements in arterial and venous blood during recovery following treadmill exercise in 8 patients with arterial occlusive disease were studied by means of a two-compartment model. Blood lactate and pyruvate concentration curves over the recovery period were found to fit a two-exponential time function including a rapidly increasing and a slowly decreasing component. The velocity constants gamma 2 were dependent on the exercise load. The time of lactate disappearance during recovery decreased with the work load in patients with intermittent claudication. The velocity constant of the arterial blood pyruvate decrease was similar to that of the simultaneously measured lactate indicating that the rate of lactate removal is closely related to that of pyruvate. In conclusion, the use of the model allows to study factors likely to modify the coefficients, such as physical training, therapeutic effects and active recovery.