New model for simulation of fracture repair in full-grown beagle dogs: model characterization and results from a long-term study with ibandronate.

Introduction: Given that bisphosphonates reduce bone turnover, it is important to establish that their long-term administration does not impair bone quality. This paper describes a new model for simulation of fracture repair to evaluate several aspects of bone quality following long-term administration (34 or 36 weeks) of ibandronate in full-grown beagle dogs.

Methods: The treatment schedule consisted of continuous daily subcutaneous administration of a pharmacologically active dose (1 microg/kg/day) and two cyclical intermittent regimens providing a similar total dose per animal at the end of the experiment.

[Animal experiments in the context of quality control of pharmaceuticals. Review of the European Pharmacopoeia, 4th edition, 2002].

In the 4th edition of the European Pharmacopoeia, animal experiments are described, which are required for the quality control of pharmaceuticals. This refers to investigations regarding both biological activity and safety aspects of the medication. The latter include investigations to find contaminations with histamine and pyrogenic substances and tests for abnormal toxicity.

Prevention of cold-preservation injury of cultured endothelial cells by catecholamines and related compounds.

The present study was conducted to dissect the underlying mechanisms by which catecholamines protect cells against preservation injury. To this end, we firstly defined the cellular and molecular differences between protected and nonprotected cells and secondly defined the mediators that were involved in cold-induced damage. Cold storage of untreated human umbilical vein endothelial cells (HUVECs) resulted in profound cellular damage as assessed by lactate dehydrogenase (LDH) release and by morphological changes, e.

[The development and approval of alternative methods to bioassays used for quality assurance, a challenge for the pharmaceutical industry and the authorities].

Bioassays are performed to ensure a constant quality of medicines derived from biological sources. These tests are stipulated for some drugs in the German and European Pharmacopoeias. They are justified because physico-chemical or other analytical methods may not be appropriate to define exactly the potency of the drug in each individual batch and/or to detect any biologically relevant impurities.

Does intention-to-treat analysis answer all questions in long-term mortality trials? Considerations on the basis of the ANZ trial.

Aims: Intention-to-treat (ITT) analyses are the gold standard in endpoint analyses of randomized clinical trials. Valuable information, however, may be lost in this approach as the actual time on trial medication is not accounted for in patients who withdraw early. Since compliance per se can be a prognostic factor and the actual treatment time is a variable likely to influence clinical outcome, this information should be added to an ITT analysis concept.

Local drug delivery via transvascular injection.

Background: In this experimental series we tested drug distribution and systemic leakage using local drug delivery with a new transvascular injection system.

Methods: Porcine femoral and carotid arteries (n = 56) underwent local drug application with a new 5 French (Fr) over-the-wire needle-injection catheter system (NIC) using three needles. A radioactive indicator [C14-Carvedilol, 2.

[The effect of carvedilol on contrast echocardiography in comparison to metoprolol in conscious dogs].

This animal study was to demonstrate the effect of the betablockers carvedilol (CAS 72956-09-3) and metoprolol (CAS 37350-58-6), respectively, on myocardial perfusion which was quantified by the use of contrast echocardiography. Each of four experimental schemes were applied consecutively to each of six dogs. They were pretreated with oral administration of either carvedilol (2 mg/kg b.

Effects of naftopidil on some urodynamic parameters and arterial blood pressure in comparison with prazosin in conscious rats.

Naftopidil, an alpha 1-adrenergic antagonist, was orally tested in comparison with prazosin, in a rat cystomanometric model to evaluate the effect on the bladder volume capacity (BVC), the micturition pressure (MP) and the mean arterial blood pressure (MAP), contemporaneously recorded to evaluate the selectivity of action. Naftopidil induced a clearcut increase of BVC and a decrease of MP without lowering MAP at 6.25 mg kg-1 p.

Effect of 17beta-estradiol-bisphosphonate conjugates, potential bone-seeking estrogen pro-drugs, on 17beta-estradiol serum kinetics and bone mass in rats.

In order to target 17beta-estradiol directly at bone we synthesized three 17beta-estradiol-bisphosphonate conjugates (E2-BPs) with different esterase-sensitive linkers between both molecular moieties. The systemic administration of these compounds should result primarily in local estrogenic effects on bone with no or negligible systemic hormonal effects. Only if a considerable margin exists between the doses required for inhibition of bone loss and those for systemic hormonal effects can such a pro-drug be considered acceptable for patients refusing systemic estrogen replacement therapy for several reasons.

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.

Differential fibrinolytic properties of the recombinant plasminogen activator BM 06.022 in human plasma and blood clot systems in vitro.

The effects of the unglycosylated recombinant plasminogen activator BM 06.022, consisting of the kringle 2 and protease domains of tissue-type plasminogen activator (t-PA), on clot lysis were evaluated in an in vitro system. Fresh and aged 125I-labelled human platelet-poor (PPP) and platelet-rich plasma (PRP) and whole blood clots were immersed in human plasma.

Norepinephrine-induced changes in rat heart function, metabolism, and weight are antagonized by carvedilol.

One aim of our study was to characterize in intact rats the pharmacologic effects of carvedilol. After 3 days of continuous intravenous (i.v.

Influence of hepatic and renal failure on pharmacokinetic properties of the novel recombinant plasminogen activator BM 06.022 in rats.

BM 06.022 is a novel recombinant, unglycosylated plasminogen activator comprising only the kringle 2 and protease domains of human tissue-type plasminogen activator (t-PA), and it has a longer half-life than t-PA. Because t-PA is mainly cleared by the liver, rat models of hepatic and renal insufficiency were used to identify the main catabolic organ of BM 06.

Rapid reversal of canine thromboembolic pulmonary hypertension by bolus injection of the novel recombinant plasminogen activator BM 06.022.

We used a canine model of embolic pulmonary hypertension induced by intravenous (i.v.) injection of autologous thrombi to evaluate whether the novel recombinant plasminogen activator (r-PA) BM 06.

Naftopidil, a new adrenoceptor blocking agent with Ca(2+)-antagonistic properties: interaction with adrenoceptors.

The interaction of naftopidil with adrenoceptors was studied in comparison to standard drugs. Naftopidil binds specifically to alpha 1-adrenoceptors. The Ki values are 58.

Hirudin and sulotroban improve coronary blood flow after reperfusion induced by the novel recombinant plasminogen activator BM 06.022 in a canine model of coronary artery thrombosis.

Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery. One-hour postocclusion, administration of vehicle to heparinized dogs (n = 12) did not induce reperfusion despite concomitant treatment with acetylsalicylic acid (ASA), sulotroban, or saline. Intravenous bolus injection of 140 kU/kg (= 0.

Pharmacokinetic and thrombolytic properties of unglycosylated recombinant tissue-type plasminogen activator (BM 06.021) produced in Escherichia coli.

Recombinant tissue-type plasminogen activator (rt-PA) was produced in Escherichia coli cells in order to obtain an unglycosylated rt-PA (BM 06.021) with increased thrombolytic potency due to altered pharmacokinetic properties. The pharmacokinetics were studied in rabbits upon intravenous infusion of 200 kU/kg over 30 min.

Double bolus administration of the novel recombinant plasminogen activator BM 06.022 improves coronary blood flow after reperfusion in a canine model of coronary thrombosis.

Reocclusion of coronary arteries is a major problem after successful thrombolysis in patients with acute myocardial infarction. We evaluated in a canine model of coronary thrombosis which is known to elicit reocclusion, whether an increased single i.v.

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.

Vasodilatory action of carvedilol.

Carvedilol is a dual-acting drug designed to produce two complementary effects: beta-blockade and vasodilation. These effects are induced in the same dose range, a prerequisite for utilizing both properties in an appropriate manner. The vasodilation is mediated predominantly by specific alpha 1-adrenoceptor blockade.

Pharmacological profile of beta-adrenoceptor blockers with vasodilating properties, especially carvedilol--rationale for clinical use.

The rationale for the combined use of beta-adrenoceptor antagonists and vasodilators is to improve the efficacy of the antihypertensive therapy and to reduce the incidence of side effects. If suitable coagents are selected and used at appropriate doses, the disadvantages of each separate component (compromised blood flow to individual organs, increase in total peripheral resistance, unfavorable lipid profile for beta-blockers; stimulation of counter-regulatory mechanisms, retention of water and electrolytes for vasodilators) can be balanced. In addition, the favorable effects of each (reduction in cardiovascular morbidity and mortality for beta-blockers, and favorable hemodynamic profile for vasodilators) may be used to advantage.

Coronary thrombolytic properties of a novel recombinant plasminogen activator (BM 06.022) in a canine model.

We studied the thrombolytic dose-response relationship of a recombinant plasminogen activator (rPA) (BM 06.022) compared with alteplase in a canine model of coronary artery thrombosis. BM 06.

Thrombolysis with an Escherichia coli-produced recombinant plasminogen activator (BM 06.022) in the rabbit model of jugular vein thrombosis.

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 the expression in Escherichia coli. The thrombolytic and pharmacokinetic properties as well as the hemostasis effects of BM 06.

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.

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.