Klaus Prof. Strein

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.

Pharmacokinetics of the novel recombinant plasminogen activator BM 06.022 in rats, dogs, and non-human primates

Abstract The recombinant plasminogen activator BM 06.022 consists of the kringle 2 and protease domains of human t-PA. BM 06.022 is unglycosylated due to its expression in E. coli cells. The pharmacokinetic properties for activity of BM 06.022 in comparison with alteplase were evaluated in rats, dogs, and non-human primates following i.v. bolus injection of 200 kU/kg over 1 min to four-seven animals per agent. The dominant half-life of BM 06.022 was in the range of 4.3–12.7 min, depending on the species compared, and with half-life values between 1.0 and 2.6 min for alteplase. The systemic plasma clearance of BM 06.022 ranged from 7.6-5 ml·min −1 ·kg −1 , in contrast to that of alteplase which ranged from 43-17 ml·min −1 ·kg −1 in three animal species. These results in rats, dogs, and primates consistently show a modified pharmacokinetic profile of BM 06.022 compared with alteplase.

Differences in the nitrite ion formation and the toxicological findings between isosorbide dinitrate and isosorbide-5-mononitrate.

In the metabolism of isosorbide dinitrate (ISDN), fast denitration with the formation of nitrite ions and a mononitrate plays an important role. In contrast, the denitration of isosorbide-5-mononitrate (IS-5-MN) to isosorbide is very slow. Accordingly po administration of high doses of ISDN (92.5 and 236 mg/kg) in conscious dogs led to maximum nitrite concentrations in the blood of 0.9 and 3.3 mg/liter, respectively. In contrast, with equimolar doses of IS-5-MN (75 and 191 mg/kg) we were able to detect nitrite ions reliably only at the higher dose and this gave a maximum blood concentration of 0.4 mg/liter. The rise in nitrite ion concentration is followed by the formation of methemoglobin. As is known from the literature, there is a rise in the activity of alkaline phosphatase in the serum of rabbits in addition to methemoglobin formation following repeated administration of sodium nitrite. So we have specifically investigated whether this is also the case following ISDN and IS-5-MN administration. On po administration of 236 mg/kg ISDN/day to dogs, there was a continuous rise in alkaline phosphatase from about the 20th day onward which we did not observe after the equimolar dose of IS-5-MN (191 mg/kg). NaNO2, 35 mg/kg po, led to a comparable maximal rise in methemoglobin to that obtained with 236 mg/kg ISDN. Repeated po administration of 35 mg/kg NaNO2/day also caused a rise in alkaline phosphatase. It is concluded that the formation of nitrite ions from ISDN is the reason for the rise in methemoglobin and alkaline phosphatase. The lower formation of nitrite ions from IS-5-MN can also be of clinical importance, at least in certain cases.

Pharmakologisches Spektrum des Metipranolol und Erfahrungen der klinischen Anwendung

In den letzten Jahren haben sich β-Rezeptorenblocker in der Therapie des Glaukoms einen zwar nicht unumstrittenen, jedoch festen Platz erworben. Diese Indikation hat sich ganz unerwartet ergeben. Messungen des Augendruckes bei Glaukompatienten, die wegen anderer Erkrankungen, z. B. Angina pectoris oder Hypertonie mit β-Rezeptorenblockern oral behandelt wurden, liesen einen augeninnendrucksenkenden, d. h. therapeutischen Effekt erkennen [1, 2].

Effects of the novel recombinant plasminogen activator BM 06.022 on human platelet aggregation in vitro

The present study was performed to evaluate effects of the novel recombinant plasminogen activator BM 06.022 on human platelet aggregation. BM 06.022 is an unglycosylated deletion variant of human tissue-type plasminogen activator. Aggregation was measured in platelet-rich plasma (PRP) from healthy human volunteers in response to adenosine diphosphate (ADP). Exposure of PRP to BM 06.022 induced a concentration-and time-dependent reduction of platelet aggregation compared with vehicle-control experiments. Incubation of high (3200 U/ml) concentrations of BM 06.022 for 0 to 15 min did not increase platelet aggregation. The platelet inhibitory effect of BM 06.022 could be reduced or abolished by aprotinin or chloromethylketone (PPACK), respectively, which is indicative of a plasmin-dependent mechanism. Concomitant incubation of BM 06.022, acetylsalicylic acid (ASA), and heparin decreased platelet aggregation less than BM 06.022 plus ASA alone, because heparin alone increased platelet aggregation. These findings demonstrate an inhibitory effect of BM 06.022 on platelet aggregation in citrated plasma, probably at least in part due to a plasmin-dependent mechanism.

Pharmacological Spectrum of Metipranolol and Experience in Clinical Use

In the past few years β-receptor blockers have assumed a firm although not entirely undisputed position in the treatment of glaucomas. This indication came quite unexpectedly. When the ocular pressure of glaucoma patients who were receiving oral treatment with β-receptor blocking agents for other diseases, e. g. angina pectoris or hypertension, was measured a pressure reducing, i. e. therapeutic effect, was revealed [1, 2].