Erwin Böhm

Pharmacological characteristics of the stereoisomers of carvedilol

SummaryThe racemic compound carvedilol possesses two complementary pharmacological effects, vasodilation and β-blockade. TheR- andS-enantiomers of carvedilol and the racemate were investigated with respect to the β-blocking, vasodilating, and hypotensive actions. In agreement with results obtained with other β-blockers, only theS-enantiomer of carvedilol exerts β-blocking effects. In contrast, no substantial difference between the enantiomers could be seen with respect to α-blockade. The greater hypotensive activity ofS-carvedilol may be attributed to β-blockade, which inhibits counter-regulatory mechanisms provoked by vasodilation. From these results it is concluded that there is a rationale for using carvedilol as the racemate. Using theS-enantiomer would lead to relatively strong β-blockade with only a weak vasodilating effect. TheR-enantiomer alone would act only as a hypotensive agent without β-blockade.

Therapeutic Use of the Natriuretic Peptide Ularitide in Acute Renal Failure

BACKGROUND Ularitide is a member of the natriuretic peptide family. This hormone exhibits an N-terminal extension by four amino acids compared with atrial natriuretic peptide. Ularitide was shown to exert strong diuretic and natriuretic effects when infused intravenously. Its main action sites are the glomerulum, inducing preglomerular vasodilation and postglomerular vasoconstriction and thereby elevating the glomerular filtration rate, and the tubular system inhibiting Na(+)-reabsorption. In initial uncontrolled clinical trials, this peptide was shown to have beneficial effects in patients suffering from oliguric acute renal failure. METHODS We conducted a double-blind, placebo-controlled, multicenter, dose-finding trial recruiting 176 patients randomized into 4 different Ularitide doses groups (U5, U20, U40, and U80 ng/kg/min) and a placebo group (U0). Ularitide/placebo infusion was performed for 5 days with half the originally infused dose on day 5. The primary objective of the study was to test various doses of Ularitide in patients suffering from oliguric acute renal failure to avoid mechanical renal replacement therapy during the first 12 hours. FINDINGS The results indicate that Ularitide does not reduce the incidence of mechanical renal replacement therapy compared with placebo-treated patients during the first 12 h of treatment (U0: 36 (20), U5: 35 (11), U20: 36 (9), U40: 28 (8), U80: 41 (12), (% (n) (p = 0.87)). Diuresis increased in the Ularitide-treated groups and the placebo group after onset of infusion and did not show any significant difference in the first 12 h collection period (U0: 576, U5: 514, U20: 500, U40: 360, U80: 158 ML/12h (Median), (p = 0.16)). INTERPRETATION In summary, the incidence of mechanical renal replacement therapy in critically ill patients suffering from oliguric acute renal failure could not be altered positively by Ularitide administration according to our protocol. Further prospective clinical trials are needed to answer the question whether a different patient collective or a prophylactic administration of Ularitide are more promising approaches in the clinical setting of oliguric acute renal failure.

Pharmacokinetics of the thioether phospholipid analogue BM 41.440 in rats.

BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a cytotoxic thioether phospholipid analogue that recently has entered phase I trials in cancer patients. The objective of this study was to evaluate the pharmacokinetics of this compound in female rats after administration of a single oral dose (15 mg/kg body weight [bw]). Furthermore, BM 41.440 serum concentrations were determined under a daily oral treatment of up to 13 weeks. Blood samples were obtained via permanent catheters from the femoral arteries before and after drug administration for a total of 120 hr. Urine was collected in 24 hr-intervals for 120 hr; the volume was measured, and aliquots were stored at −20 C until analytical determination of the thioether derivative. BM 41.440 was assayed in serum and urine by means of a specific, newly developed reverse-phase high pressure liquid chromatography technique. Mean maximum serum concentrations (1.7 μg/ml, n=4 animals) were attained after seven hr. A terminal half-life of ca. 27 hr was calculated from the rate constant for the terminal elimination phase (λz ∼ 0.026/hr). The mean serum BM 41.440 concentration-time-area-under-the-curve was 52.9 mg × hr/l. The ratio of total body clearance to absorption fraction was 4.7 ml/min × kg bw. Only a small amount of the drug was found in the urine. The quantity excreted in the urine during a 24 hr-interval never exceeded 1.5% of the administered dose. Under a daily oral schedule (15 mg/kg bw × day) up to 13 weeks, mean BM 41.440 serum concentrations of 3.3±0.5 μg/ml and 5.2±1.2 μg/ml (mean ±S.D., n=10 animals) were found after five and 13 weeks, respectively. Taken together, the data indicate that BM 41.440 was absorbed from the gastrointestinal tract after oral administration and that accumulation of BM 41.440 can occur in rats.