Gisbert Sponer

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.

Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis

The thrombolytic and systemic effects of BM 06.022 were evaluated and compared with those of alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle-2 and protease domains of human tissue plasminogen activator (t-PA) and is unglycosylated because of its expression in Escherichia coli cells. Thrombus formation in anesthetized open chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery at a high level site of obstruction. In heparinized dogs, none of six vehicle-treated animals exhibited reperfusion. Reperfusion was achieved in four of six dogs at 18.3 +/- 6 min after intravenous bolus injection of 140 kU/kg (0.24 mg/kg) of BM 06.022, whereas four of six dogs exhibited reperfusion later (p less than 0.05) at 76.5 +/- 16.1 min during infusion of 1.33 mg/kg of alteplase (0.13 mg/kg as initial bolus injection, followed by 0.66 mg/kg over 1 h and 0.53 mg/kg over 2 h). Significantly later (p less than 0.05) reperfusion than that achieved with BM 06.022 was achieved in five of six dogs at 57.8 +/- 12.1 min after intravenous injection of 0.4 U/kg of anistreplase. Streptokinase (21,000 IU/kg over 60 min) and urokinase (20,000 IU/kg as an intravenous bolus injection, followed by 20,000 IU/kg over 89 min) each induced reperfusion in three of six dogs but at 67 +/- 12 and 84.3 +/- 17.1 min (p less than 0.05 vs. BM 06.022), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

A method for evaluating postural hypotension in conscious rabbits as a model to predict effects of drugs in man

Because of the importance of postural hypotension as a side effect of antihypertensive drugs in man, an experimental model has been developed that permits the investigation of blood pressure response to tilting. Conscious rabbits were placed on a tilting table and tilted rapidly from horizontal to vertical position. Blood pressure was recorded continuously throughout the whole period. The individual orthostatic reaction was expressed as an orthostatic index. The experimental data obtained with guancydine, clonidine, guanethidine, prazosin, and dihydralazine were compared with clinical observations with regard to the impairment of orthostatic reaction; dihydralazine did not agree, but there was a good agreement for guancydine, clonidine, guanethidine, and prazosin. Although complete agreement between the experimental data and clinical observations does not exist, the model seems to be sufficient to differentiate between drugs with low or high potential for postural hypotension.

Pharmacokinetic properties of an Escherichia-coli-produced recombinant plasminogen activator (BM 06.022) in rabbits

The recombinant plasminogen activator BM 06.022 consists of the kringle 2 and the protease domains of human t-PA and is unglycosylated because of its expression in Escherichia coli. The pharmacokinetic properties of BM 06.022 following intravenous injection over 1 min were characterized in anesthetized male New Zealand white rabbits. BM 06.022 was injected at doses of 50, 100, 200, and 400 kU/kg bw (n = 5-6/dose). Activity concentrations in plasma were determined using an indirect spectrophotometric assay. The maximum plasma concentration and the area under the plasma concentration vs. time curve (AUC0-00) of BM 06.022 increased linearly with dose. The systemic clearance ranged from 2.5 to 3.0 ml.min-1.kg-1 and did not show dose-dependency, in contrast to alteplase which was studied at doses of 200, 400, 800, and 1600 kU/kg. A direct comparison of clearance rates of BM 06.022 and alteplase at doses of 200 and 400 kU/kg each revealed a 8.5-fold slower clearance rate of BM 06.022. The majority (18/23) of rabbits with BM 06.022 injection showed a pharmacokinetic profile which was best characterized by a one-compartment model in contrast to alteplase (10/23). The dose-groups of BM 06.022 showed an average dominant half-life ranging from 11.6 to 15.4 min, which was about five-times longer than the dominant half-life values of alteplase (2.3 to 4.5 min). Assuming a two-compartment model in the remaining animals, the initial alpha-phase of BM 06.022 accounted for 40.1 +/- 13.2% (n = 5) of the total AUC, whereas the alpha-phase of alteplase accounted for 82.7 +/- 3% (n = 13) of the total AUC.

Influence of heparin and systemic lysis on coronary blood flow after reperfusion induced by the novel recombinant plasminogen activator BM 06.022 in a canine model of coronary thrombosis

OBJECTIVES We sought to evaluate whether anticoagulation by an intravenous heparin infusion prevents deterioration of coronary blood flow restored by the novel recombinant plasminogen activator BM 06.022, and to compare the effects of profound fibrinogenolysis with those of an intravenous bolus injection of heparin. BACKGROUND Recent clinical studies indicate that heparin appears to be effective in reducing reocclusion when combined with recombinant tissue-type plasminogen activator (rt-PA), but that heparin is associated with an increased bleeding incidence. Therefore, the need for heparin has to be critically evaluated in the development of BM 06.022. METHODS BM 06.022 is an unglycosylated variant of human tissue-type plasminogen activator. Thrombus formation in anesthetized open chest dogs was induced by electrical injury. Left circumflex coronary artery blood flow was monitored for 4 h using an electromagnetic flow probe. Twenty dogs were randomized to receive intravenous heparin (100 IU/kg bolus plus 100 IU/kg per h) in group B or saline solution in group A before an intravenous bolus injection of 200 kU/kg (= 0.34 mg/kg) BM 06.022 1 h after thrombus formation. Another 14 dogs were randomized to receive a single intravenous bolus injection of 200 IU/kg heparin plus 200 kU/kg BM 06.022 in group D or saline solution plus 1,000 kU/kg BM 06.022 in group C. RESULTS In the absence of a systemic lytic state, heparin infusion prolonged (p < 0.05) the cumulative patency time (sum of time intervals during which the coronary artery was patent) to 204.3 +/- 7.4 min (group B) compared with 34.6 +/- 10.8 min with saline solution (group A), and increased (p < 0.05) the area under the curve for coronary blood flow versus time (AUCFlow) to 34.0 +/- 3.4 ml.h.min-1 compared with 7.7 +/- 4.6 ml.h.min-1. Profound fibrinogenolysis after administration of 1,000 kU/kg BM 06.022 (group C) and a single intravenous heparin injection (group D) did not differ in their effects on the cumulative patency time (182 +/- 30.3 vs. 177.5 +/- 25.4 min) and AUCFlow (36.0 +/- 10.3 vs. 30.5 +/- 4.8 ml.h.min-1), but these values were improved (p < 0.05) compared with those obtained after administration of saline solution plus 200 kU/kg BM 06.022 (group A). CONCLUSIONS In the absence of a systemic lytic state, intravenous heparin is required as an adjunct to BM 06.022 to maintain coronary blood flow in dogs.

Haemodynamic profile of an inhibitor of phosphodiesterase III, adibendan (BM 14.478): comparison with nitroprusside and dobutamine in conscious dogs

1 This study was performed to investigate whether cardiac positive inotropic as well as peripheral vasodilator properties of adibendan contribute to its overall haemodynamic profile in conscious dogs. 2 Haemodynamic measurements were carried out in conscious chronically instrumented dogs after administration of adibendan, sodium nitroprusside or dobutamine. 3 The cardiovascular changes induced by adibendan (0.01 and 0.03 mg kg−1) resembled those of dobutamine (1.0–4.0 μg kg−1 min−1): left ventricular dP/dt60 (LV dP/dt60), stroke volume (SV) and cardiac output (CO) increased to a similar extent, but mean arterial pressure (MAP) and heart rate (HR) remained unchanged. 4 In contrast to dobutamine, higher doses of adibendan (0.1–1.0 mg kg−1) decreased MAP and LVEDP. These effects were of a similar magnitude to those observed following nitroprusside administration (0.5–12.5 μg kg−1 min−1). In contrast to nitroprusside, adibendan still showed additional effects on LV dP/dt60 and CO. 5 From these results, it is concluded that both the peripheral vasodilator and the cardiac positive inotropic action of adibendan contribute to its overall haemodynamic profile.

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].

The influence of epsilon-aminocaproic acid on the mineralocorticoid hypertension of the rat.

The development of hypertension induced by DOCA/salt in rats can be reduced by epsilon-aminocaproic acid. Analogously to the clinical finding, glomerulopathy is also less marked. Recognising on the one hand the interaction between the coagulation system and the vessel wall and on the other hand the fibrinolysis-blocking properties of EACA, it can be assumed that derangements of the coagulation system are aetiologically involved i hypertension induced by salt/DOCA. As a secondary finding, it was observed that the course of an existing lung infection is deleteriously affected by fibrinolysis-blockade with EACA.