Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients.

BACKGROUND: BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1-3, platelet-derived growth factor receptors α and ß, and fibroblast growth factor receptors 1-3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients. METHODS: This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m(-2), every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity. RESULTS: Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ≥50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone. CONCLUSION: Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m(-2) of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.

[Multidisciplinary study of cerebrovascular disorders. II. Cardiovascular profile of occlusive vascular disorders]. / Estudio multidisciplinario de los accidentes vasculares encefálicos. II--Perfil cardiovascular de los accidentes vasculares oclusivos.

Ischemic stroke constitute a mayor cause of morbidity and mortality in the adult population, particularly in the elderly. Heart disease may predispose to ischemic stroke, especially in the presence of transient or permanent precipitating factors such as atrial fibrillation. To elucidate the role of heart disease in predisposing to ischemic stroke we studied the clinical and non invasive cardiac profile (EKG, 2D-Echo, Holter) of 186 consecutive patients, 91 of them embolic (GI) and 96 non embolic (lacunar, atherothrombotic, others) (GII), as determined by brain CT scan and thorough clinical evaluation. Age and male/female ratio were significantly different (71 + 13 vs 65 + 12 years, 40/60 vs 65/35, p < 0.003). Hypertension was equally common in both groups (38 and 40%). Patients in GI had higher prevalence of valvular heart disease (23 vs 1%), atrial fibrillation (67 vs 10%), 2D Echo left atrial enlargement (45 vs 16%) and supraventricular ectopy in Holter (59 vs 32%) p < 0,001. By contrast absence of heart disease (45 vs 19%), ST-T changes in EKG (28 vs 14%), left ventricular hypertrophy in 2D Echo (28 vs 9%) and ventricular ectopy in Holter (54 vs 23%) were more prevalent in GII patients, p < 0.001. Multiple stepwise logistic regression analysis showed age > 70 years (relative risk (RR) 1.67), valvular heart disease (RR 2.25), chronic AF (RR 2.44) and paroxysmal AF (RR 1.89) were significant independent predictors of embolic stroke, whereas the presence of left ventricular hypertrophy in 2D-Echo (RR 0.76) and frequent ventricular premature beats in Holter (RR 0.47) were predictors of occlusive non embolic stroke. Thus, the clinical and non invasive cardiac profile of embolic and non embolic ischemic stroke is significantly different, which is relevant to preventive strategies.

[DDD dual chamber pacemakers. Initial experience]. / Marcapasos bicamerales DDD. Experiencia inicial.

Our preliminary experience with dual-chamber DDD pacemakers is reported. Technological innovations of the device, atrio-ventricular electrode stability and sequential stimulation have contributed to improve the conditions of patients previously submitted to VVI pacemaker implantation. Primary indications for DDD pacemaker implantation in our series included 7 patients with complete atrio-ventricular (A-V) block, 3 with Mobitz type II second-degree A-V block and 2 with sick sinus syndrome. In six of the 12 patients (50%) additional indications included: ventricular tachycardia in 4 patients, atrial fibrillation in one and pacemaker syndrome in one. Other cardiac conditions were diagnosed: dilated cardiomyopathy in 3 patients, ischemic heart disease in 2 patients, valvular heart disease in 2 patients, congenital heart disease in 1 patient and hypertrophic cardiomyopathy in one patient. The implanted pacemakers were: 5 Genesis, 4 Ultra CPI and 3 Versatrax. J-shaped atrial electrodes were used in 8 patients and in 4 instances a screw-in electrode was employed. Improvement of hemodynamic function was achieved by frequent follow up and reprogramming of DDD pacemaker in every patient. While 4 patients died with progressive deterioration of cardiac function, eight patients survived with adequate sequential stimulation. We conclude that DDD pacemakers are reliable and afford symptomatic relief in a broad spectrum of patients.

[Polymorphous ventricular tachycardia: the implant of a permanent atrial pacemaker and long-term follow-up in a case]. / Taquicardia ventricular polimorfa: implante de marcapasos auricular permanente y seguimiento alejado en un caso.

Polymorphous ventricular tachycardia is a malignant arrhythmia associated to reversible conditions such as electrolyte imbalance, drug action, ischemia or Q-T prolongation. It is usually self limited ending with the correction of the triggering factor. We report a 70-year-old woman with a myocardial infarction who developed polymorphous ventricular tachycardia which persisted after several days. A temporary atrial pacing electrode was used effectively to control the arrhythmia, and permanent implantation was finally required. Eighteen months after discharge, the pacemaker function is normal and the arrhythmia has not recurred.

[Are there any differences between myocardial infarction with Q and non-Q in ECG]. / Existen diferencias en el infarto del miocardio con o sin onda Q el ECG?

Recent literature provides evidence that Non-Q wave myocardial infarction (Non-Q MI) has a different intrahospital course and prognosis than Q-wave myocardial infarction (Q-MI). We evaluated clinical and laboratory characteristics, complications and therapeutic requirements of 557 consecutive patients, 440 with Q-MI and 117 with Non-Q MI. Risk factors for coronary artery disease did not differ among groups. Non-Q MI patients had a significantly higher incidence of previous cardiac events such as myocardial infarction, angina pectoris and heart failure. Peak CPK enzyme values were significantly lower in Non Q MI patients (952 +/- 753 vs 1,743 +/- 1,425 VI/l p less than 0.05). Early complications were different for both groups: The incidence of heart failure, ventricular arrhythmias and conduction defects was lower in Non-Q MI patients while the incidence of unstable angina pectoris and need for aorto coronary by-pass surgery was higher (18 vs 12%, 17 vs 7% respectively, p less than 0.05). Mortality was not different (8.4% in Non-Q MI vs 12.3% in Q MI). Thus, Non Q MI appears to have a more benign clinical course than Q-MI in terms of less complications such as heart failure, ventricular arrhythmias and conduction defects. However, Non-Q MI is a potentially unstable clinical entity with a higher incidence of early post MI angina pectoris requiring a more aggressive medical and surgical therapy.

[Idiopathic recurrent ventricular tachycardia: role of verapamil in its treatment]. / Taquicardia ventricular recurrente idiopatica: rol del verapamil en el tratamiento.

Verapamil is a calcium channel blocker ideally suited for the treatment of A-V nodal reciprocating supraventricular tachycardia. Most types of ventricular tachycardia are refractory to treatment with verapamil since they depend on sodium channels. However, a few cases of recurrent ventricular tachycardia are refractory to Type I antiarrhythmic agents and may respond to verapamil. We report 2 such cases.