Somatodendritic dopamine in the substnatia nigra of the rat. Biochemical charachterization and effects of dopaminergic agents

In this thesis, an attempt has been made to characterize the storage and release of somatodendritic dopamine in the substantia nigra, and to elucidate its role within the basal ganglia circuitry. The role of somatodendritic dopamine release in the pathophysiology of disabling motor syndromes, like Parkinson's disease and neuroleptic induced tardive dyskinesias, was investigated by using animal models. These studies will increase our understanding of basal ganglia pathology and might lead to more effective (pharmaco)therapeutic strategies in the future. ... Zie: Summary

A Randomized, Dose-Response Study of Sugammadex Given for the Reversal of Deep Rocuronium- or Vecuronium-Induced Neuromuscular Blockade Under Sevoflurane Anesthesia

BACKGROUND: Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a close-response relationship with sugammadex for reversal of neuromuscular blockade in patients induced and maintained under propofol anesthesia. However, sevoflurane anesthesia, unlike propofol, can prolong the effect of neuromuscular blocking drugs (NMBDs) such as rocuronium and vecuronium. METHODS: We designed this randomized, open-label, dose-response trial to explore the dose-response relationship of sugammadex for the reversal of deep neuromuscular blockade induced by rocuronium or vecuronium under propofol-induced and sevoflurane-maintained anesthesia. As a secondary objective, the safety variables of sugammadex were evaluated. After anesthesia induction with propofol, 102 patients aged >= 20 and RESULTS: The per-protocol population consisted of 48 patients in the rocuronium group and 47 in the vecuronium group. A dose-response effect was demonstrated for decreased mean time to recovery of the T-4/T-1 ratio to 0.9 with increasing sugammadex dose in both NMBD groups (per-protocol Population): rocuronium group, 79.8 (SD 33.0) min (sugammadex 0.5 mg/kg) to 1.7 (07) min (4.0 mg/kg) and 1.1 (0.3) min (8.0 mg/kg subgroup); vecuronium group, 68.4 (31.9) min (0.5 mg/kg) to 3.3 (3.5) min (4.0 mg/kg), and 1.7 (0.8) min (8.0 mg/kg subgroup). Neuromuscular monitoring showed recurrent neuromuscular blockade in 5 patients, all in the rocuronium group (2 given sugammadex 0.5 mg/kg and 3 given 1.0 mg/kg), but there were no clinical events attributable to recurrent or residual neuromuscular blockade. CONCLUSION: Sugammadex at doses of 4 mg/kg provides rapid reversal of deep rocuronium- and vecuronium-induced neuromuscular blockade under sevoflurane maintenance anesthesia. (Anesth Analg 2010;110:74-82

Declining incidence of sudden cardiac death from 1990-2010 in a general middle-aged and elderly population: The Rotterdam Study

BACKGROUND Although sudden cardiac death (SCD) is relatively common, contemporary data on its incidence are lacking. OBJECTIVE The purpose of this study was to investigate the current incidence of SCD and its trend over the past 2 decades in a general middle-aged and elderly population. METHODS This study was performed within the Rotterdam Study, a prospective population-based cohort study of persons aged 45 years and older. Age-standardized incidence rates of SCD were calculated. To study trends in incidence, we compared 2 subcohorts within the total study population, 1 followed from 1990-2000 and the other from 2001-2010. RESULTS From 1990-2010, 5512 of 14,628 participants died, of whom 583 (4.0%) were classified as SCD. The overall incidence was 4.2 per 1000 person-years. The incidence was higher in men (5.2 per 1000 person-years) than in women (3.6 per 1000 person-years). Age-adjusted hazard ratio (HR) 1.84 (95% confidence [CI] 1.562.17) and risk of SCD increased with age (HR 1.10 per year; 95% CI 1.09-1.11). The incidence rate from 1990-2000 was 4.7 per 1000 person-years vs 2.1 per 1000 person-years from 2001-2010 (age- and sex-adjusted HR of SCD 0.60, 95% CI 0.44-0.80). To check for cohort effects, we also analyzed the incidence of total mortality and found an age- and sex-adjusted HR of total mortality of 0.82 (95% CI 0.75-0.90) for the second compared to the first subcohort, which was significantly higher than the decline in SCD incidence. CONCLUSION We found an incidence of SCD of 4.2 per 1000 person-years. The incidence decreased from 1990-2010, a period during which the diagnosis and treatment of heart disease greatly improved

Declining incidence of sudden cardiac death from 1990-2010 in a general middle-aged and elderly population: The Rotterdam Study

BACKGROUND: Although sudden cardiac death (SCD) is relatively common, contemporary data on its incidence are lacking. OBJECTIVE: The purpose of this study was to investigate the current incidence of SCD and its trend over the past 2 decades in a general middle-aged and elderly population. METHODS: This study was performed within the Rotterdam Study, a prospective population-based cohort study of persons aged 45 years and older. Age-standardized incidence rates of SCD were calculated. To study trends in incidence, we compared 2 subcohorts within the total study population, 1 followed from 1990-2000 and the other from 2001-2010. RESULTS: From 1990-2010, 5512 of 14,628 participants died, of whom 583 (4.0%) were classified as SCD. The overall incidence was 4.2 per 1000 person-years. The incidence was higher in men (5.2 per 1000 person-years) than in women (3.6 per 1000 person-years). Age-adjusted hazard ratio (HR) 1.84 (95% confidence [CI] 1.56-2.17) and risk of SCD increased with age (HR 1.10 per year; 95% CI 1.09 -1.11). The incidence rate from 1990-2000 was 4.7 per 1000 person-years vs 2.1 per 1000 person-years from 2001-2010 (age- and sex-adjusted HR of SCD 0.60, 95% CI 0.44-0.80). To check for cohort effects, we also analyzed the incidence of total mortality and found an age- and sex-adjusted HR of total mortality of 0.82 (95% CI 0.75-0.90) for the second compared to the first subcohort, which was significantly higher than the decline in SCD incidence. CONCLUSION: We found an incidence of SCD of 4.2 per 1000 person-years. The incidence decreased from 1990-2010, a period during which the diagnosis and treatment of heart disease greatly improved

Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer : multi-centre phase I/II study

BACKGROUND: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumour activity in in vitro and in vivo preclinical models. MATERIAL AND METHODS: This first-in-man phase I/II study utilised a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed. RESULTS: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part. CONCLUSIONS: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity