Disease progress and response to treatment as predictors of survival, disability, cognitive impairment and depression in Parkinson's disease.

AIM: To describe the time to clinical events (death, disability, cognitive impairment and depression) in Parkinson's disease using the time course of disease status and treatment as explanatory variables. METHODS: Disease status based on the Unified Parkinson's Disease Rating Scale (UPDRS) and the time to clinical outcome events were obtained from 800 patients who initially had early Parkinson's disease. Parametric hazard models were used to describe the time to the events of interest. RESULTS: Time course of disease status (severity) was an important predictor of clinical outcome events. There was an increased hazard ratio for death 1.4 (95% CI 1.31, 149), disability 2.75 (95% CI 2.30, 3.28), cognitive impairment 4.35 (95% CI 1.94, 9.74), and depressive state 1.43 (95% CI 1.26, 1.63) with each 10 unit increase of UPDRS. Age at study entry increased the hazard with hazard ratios of 49.1 (95% CI 8.7, 278) for death, 4.76 (95% CI 1.10, 20.6) for disability and 90.0 (95% CI 63.3-128) for cognitive impairment at age 60 years. Selegiline treatment had independent effects as a predictor of death at 8 year follow-up with a hazard ratio of 2.54 (95% CI 1.51, 4.25) but had beneficial effects on disability with a hazard ratio of 0.363 (95% CI 0.132, 0.533) and depression with a hazard ratio of 0.372 (95% CI 0.12, 0.552). CONCLUSIONS: Our findings show that the time course of disease status based on UPDRS is a much better predictor of future clinical events than any baseline disease characteristic. Continued selegiline treatment appears to increase the hazard of death.

Progression of motor and nonmotor features of Parkinson's disease and their response to treatment.

AIMS: (i) To describe the progression of the cardinal features of Parkinson's disease (PD); (ii) to investigate whether baseline PD subtypes explain disease progression; and (iii) to quantify the symptomatic and disease-modifying effects of anti-parkinsonian treatments. METHODS: Data were available for 795 PD subjects, initially untreated, followed for up to 8 years. Cardinal features [tremor, rigidity, bradykinesia, and postural instability and gait disorder (PIGD)] were derived from the total unified Parkinson's disease rating scale (total UPDRS), cognitive status from the mini-mental status exam score (MMSE) and depression status from the Hamilton depression scale (HAM-D). Analysis was performed using a nonlinear mixed effects approach with an asymptotic model for natural disease progression. Treatment effects (i.e. symptomatic and disease modifying) were evaluated by describing changes in the natural history model parameters. RESULTS: Tremor progressed more slowly (half-time of 3.9 years) than all other motor features (half-time 2-3 years). The MMSE progression was negligible, while HAM-D progressed with a half-time of 5 years. Levodopa had marked symptomatic effects on all features, but low potency for effect on PIGD (ED50 of 1237 mg day⁻¹ compared with 7-24 mg day⁻¹ for other motor and nonmotor features). Other anti-parkinsonian treatments had much smaller symptomatic effects. All treatments had disease-modifying effects on the cardinal features of PD. Baseline PD subtypes only explained small differences in disease progression. CONCLUSIONS: This analysis indicates that tremor progresses more slowly than other cardinal features and that PIGD is less treatment responsive in early PD patients. There was no evidence of baseline PD subtypes as a clinically useful predictor of disease progression rate. Anti-parkinsonian treatments have symptomatic and disease-modifying effects on all major features of PD.

Dexmedetomidine hemodynamics in children after cardiac surgery.

BACKGROUND: Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration-response profile for these hemodynamic effects in children after cardiac surgery. METHODS: A simultaneous pharmacokinetic-pharmacodynamic analysis of data from 29 children given a single bolus of dexmedetomidine 1-4 mcg.kg(-1) following cardiac surgery was undertaken using mixed effects modeling. There were four dexmedetomidine concentrations available from each patient, and mean arterial blood pressure (MAP) was recorded electronically every 5 min for 5 h after drug administration. A composite Emax model was used to relate mean arterial pressure changes to plasma dexmedetomidine concentration. RESULTS: Children had a mean age of 2.67 years (range 4 days-14 years) and a mean weight of 12.34 (range 3.4-48.4) kg. The peripheral vasopressor effect was directly related to plasma concentration with an Emax(pos) of 50.3 (CV 44.50%) mmHg, EC(50pos) 1.1 (48.27%) microg.l(-1) and a Hill(pos) coefficient of 1.65. The delayed central sympatholytic response was described with an Emax(neg) of -12.30 (CV 37.01%) mmHg, EC(50neg) 0.10 (104.40%) microg.l(-1) and a Hill(neg) coefficient of 2.35. The equilibration half-time (T(1/2)keo) was 9.66 (165.23%) min. CONCLUSIONS: Dexmedetomidine administered as a single bolus dose following cardiac surgery produces a biphasic effect on MAP. A plasma dexmedetomidine concentration of above 1.0 microg.l(-1) was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 microg.kg(-1)) followed by a continuous infusion should be used to avoid initial increases in MAP.