Pharmacokinetics and pharmacodynamics of the dual FII/FX inhibitor BIBT 986 in endotoxin-induced coagulation.

BIBT986 is a dual inhibitor of factors Xa and IIa. The aim of this study was to compare with placebo the effect of three doses of BIBT986 on coagulation, platelet activation, and inflammation. This was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants received one of three doses of BIBT986 or placebo intravenously together with a bolus infusion of 2 ng/kg lipopolysaccharide (LPS). BIBT986 dose-dependently changed global coagulation parameters and in vivo markers of thrombin generation and action: BIBT986 doses, which prolonged activated partial thromboplastin time by 100%, completely suppressed the LPS-induced increases in prothrombin fragment, thrombin-antithrombin complexes, and D-dimer, which were 6.1-, 14.5, and 3.5-fold in the placebo group, respectively. BIBT986 did not influence inflammation, fibrinolysis, or platelet activation. Therefore, BIBT986 is a potent anticoagulant in the human endotoxemia model.

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa.

BACKGROUND: Current anticoagulant development focuses on agents with predictable pharmacokinetic and pharmacodynamic (PD) properties. BIBT 986 is a novel potent anticoagulant with a dual mechanism of action: it competitively inhibits factor (F) Xa and FIIa. AIMS: To determine the safety, tolerability, pharmacokinetics (PK) and PD of BIBT 986 following intravenous infusion in healthy male volunteers. METHODS: In three randomized, double-blind, placebo-controlled trials, subjects were administered by intravenous infusion escalating doses of BIBT 986 for up to 32 h. BIBT 986 concentrations were determined in plasma and urine samples by high pressure liquid chromatography tandem mass spectrometry. Pharmacodynamic response was assessed by measuring the changes in blood coagulation times. Activated partial thromboplastin time, International Normalized Ratio, thrombin time and ecarin clotting time were determined and compared with baseline results. RESULTS: In all three studies, intravenous infusion of BIBT 986 was safe and well tolerated. BIBT 986 exhibited linear PK over the dose range tested. Clearance was about 8 L h(-1) and V(ss) about 50 L. Apparent steady state concentrations were reached within 24 h, indicating a dominant half-life of about 6 h. The terminal half-life of BIBT 986 was approximately 12 h. Renal excretion contributes approximately 50% to total elimination. Overall interindividual variability in pharmacokinetic and PD parameters was < 40%. There was a linear correlation between plasma concentrations and PD responses, suggesting excellent predictability. CONCLUSION: BIBT 986 is the first small molecule of a novel class of anticoagulants that potently and directly inhibits both coagulation FXa and thrombin. It has predictable pharmacokinetic and PD characteristics.

Long QT syndrome associated with inflammatory degeneration of the stellate ganglia.

A well-studied case of intermittent long QT syndrome in a 21-year-old female is presented. Electrophysiologic investigation repeated three times revealed changing sinoatrial and atrioventricular dysfunction and nonsustained ventricular tachycardia. The patient died 29 months after first hospitalization in a stage of electromechanical dissociation after runs of torsade de pointes although she had been treated with repeated anti-inflammatory therapy as well as high doses of propranolol. Postmortem examination demonstrated active inflammation of stellate ganglia. Myocardium appeared normal.

[Arrhythmogenic effects of anti-arrhythmia agents]. / Arrhythmogene Effekte von Antiarrhythmika.

Arrhythmogenic effects appear in 5-22% of all patients. On the basis of a literary investigation on 11,547 patients with 1,114 proarrhythmic effects and of 21 own observations mechanisms, risks and diagnostics of this dangerous side effect are demonstrated. In most cases patients with severe functional disturbances of the heart and known ventricular tachyarrhythmias are affected. Not infrequently a prolonged QT-internal is found. An accumulation of the known arrhythmias or an appearance of new disturbed rhythms, frequently Torsade de pointes, may occur. Holter-ECG and programmed stimulation are suited for recognition, which are together to be applied in malignant tachyarrhythmias. The prophylaxis deals with a careful indication, aimed selection of the antiarrhythmic drugs and a subtile control of therapy in the first days after the beginning of the therapy and after every increase of dosage.

[Transvascular intracardiac ablation--on the current status of the method in the treatment of tachyarrhythmias]. / Transvasale intrakardiale Ablation--zum gegenwärtigen Stand der Methode in der Behandlung von Tachyarrhythmien.

A survey is given on the method of the transvasal intracardiac ablation in the treatment of atrial and ventricular tachyarrhythmias. Experimental fundaments, indication, method and possible complications are reported. Own results on five patients with His bundle ablation are described. A possible further development of the method is the enlargement of the His bundle ablation to the ablation of focal arrhythmias, Kent's fibres and ventricular tachycardias without evocation of a total atrioventricular block. Alternative techniques of the cauterization, the laser ablation and the high frequency coagulation are described.

Anterograde conduction of a concealed accessory pathway after transvenous electric catheter ablation.

An 18-year-old woman with a concealed right midseptal accessory pathway and refractory supraventricular tachycardia with a cycle length of 280-400 ms and a wide echo zone of 280-520 ms is reported. The transvenous electric catheter ablation with two shocks of 200 and 300 J, each on a separate occasion, was followed by anterograde and retrograde atrioventricular block. The patient received an implantable pacemaker (VVI). Four weeks later we observed a stable anterograde conduction of the pathway in spite of a persisting retrograde block. It is concluded that the site of unidirectional block in this patient is at the origin of the concealed accessory pathway in the ventricular septal muscle. The necrosis after ablation changed conduction conditions at the site of unidirectional block. Presently, the patient has been free of tachycardia for 19 months. This observation is of importance for the patient because another mechanism of tachycardia might be possible after ablation.

[Differential therapeutic problems in sinus node syndrome--drug or electrical therapy?]. / Differentialtherapeutische Probleme beim Sinusknotensyndrom--medikamentöse oder elektrische Therapie?

121 hospitalised patients with electrophysiologically ascertained sick sinus syndrome were ambulatorily observed for two and a half years. The knowledge of the electrophysiological parameters allowed in every case an exact estimation of the degree of severity. Patients with preponderantly isolated disturbance of the sino-atrial node automatism, the sino-atrial conduction and the nervous regulation (patients with carotid sinus syndrome) as well as the majority of patients with bradycardia-tachycardia-syndrome were conservatively treated. Patients with high-degree combined disturbances of the sinus node partial functions were electrically treated. Every cardiac syncope in the medicamentously treated sick sinus node syndrome is the absolute indication for a pacemaker implantation. The further observation in the outpatient department showed that in many patients with symptomatic sick sinus node syndrome an attempt of conservative treatment is justified.

[Clinico-electrophysiologic studies on the action of the anti-arrhythmic substance 3-carbethoxyamino-5-dimethylamino-acetyl-10,11-dihydro-5H- dibenz[b,f]azepine hydrochloride (Bonnecor, AWD 19-166, GS 015)]. / Klinisch-elektrophysiologische Untersuchungen zur Wirkung der antiarrhythmischen Substanz 3-Carbethoxyamino-5-dimethylamino-acetyl-10,11- dihydro-5H-dibenz[b,f]azepinhydrochlorid (Bonnecor, AWD 19-166, GS 015).

The effects of the new antiarrhythmic drug 3-carbethoxy-amino-5-dimethyl-amino-acetyl-iminodibenzyl-hydroc hlorid (Bonnecor) (B.) were investigated by means of clinical-electrophysiologic methods (His-bundle electrography, programmed electrical stimulation) in 11 patients with normal cardiac output and paroxysmal supraventricular tachycardias. In a maximal dosage of 0.24 mg/kg body mass. B. affects several compartments of the impulse initiation and conduction. B. has positive chronotropic actions on the sinus node automaticity, negative dromotropic effects on the sinu-atrial, intraatrial, AV nodal and intraventricular conduction and finally negative bathmotropic actions on the myocardium of the atria and ventricles. B. suppress the artificial induction of paroxysmal supraventricular tachycardias in patients with AV nodal reentry. These results help to recognize indications (supraventricular and ventricular premature beats or tachycardias) and contraindications (sick sinus syndrome, atrio-ventricular block of higher degreé and bifascicular blocks).

[Importance of PQ time in the evaluation of bifascicular block]. / Zur Bedeutung der PQ-Zeit bei der Beurteilung bifaszikulärer Blockbilder.

In 103 patients with bifascicular block was tested by means of the His bundle electrography, whether with the help of the PQ-time an indirect estimation of the conduction capacity of the still conducting fascicle (HV-interval) is possible. In 70% of the cases with bifascicular blocking and AV-block of first degree the HV-interval was prolonged. However, also 45% of the patients with bifascicular block showed a prolonged HV-interval despite normal PQ-time. Of 21 patients with syncopes due to an intermitting trifascicular block 10 had a normal PQ-time in phases of the transduction. Thus a normal PQ-time in patients with bifascicular block is no guarantee for a good transduction via the still conducting fascicle. If in patients with bifascicular block additionally an AV-block of first degree is existing, the place of the primary retardation of the conduction should more exactly be analysed. For this purpose offer themselves an atropine test or the His bundle electrography.