Curt R. Freed

Placebo response in Parkinson's disease: Comparisons among 11 trials covering medical and surgical interventions

Placebo‐associated improvements have been previously documented in small series of Parkinsons disease (PD) patients. Using a strict definition of placebo‐associated improvement, we examined rates and timing of placebo responses to identify patient‐ and study‐based characteristics, predicting positive placebo response in several PD clinical trials. We collected individual patient data from the placebo groups of 11 medical and surgical treatment trials involving PD patients with differing PD severities and placebo‐assignment likelihoods. We defined a positive placebo response as ≥50% improvement in total Unified Parkinsons Disease Rating Scale motor (UPDRSm) score or a decrease by ≥2 points on at least two UPDRSm items compared to baseline. We calculated positive placebo response rates at early (3–7 weeks), mid (8–18 weeks), and late (23–35 weeks) stages of follow‐up. Odds ratios for patient‐ and study‐based characteristics were obtained from a model fitted using generalized estimating equations. There were 858 patients on placebo who met inclusion criteria for analysis. Three studies involved patients without need of symptomatic treatment, two involved patients without motor fluctuations needing symptomatic treatment, and six (three medical and three surgical) involved patients with motor fluctuations. The overall placebo response rate was 16% (range: 0–55%). Patients with higher baseline UPDRSm scores and studies that focused on PD with motor fluctuations, surgical interventions, or those with a higher probability of placebo assignment showed increased odds of positive placebo response. Placebo responses were temporally distributed similarly during early, mid, and late phases of follow‐up. Placebo‐related improvements occur in most PD clinical trials and are similarly distributed across all 6 months of follow‐up. Recognition of factors that impact placebo response rates should be incorporated into individual study designs for PD clinical trials.

BRAIN TISSUE AND PLASMA ASSAY OF L-DOPA AND α-METHYLDOPA METABOLITES BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION

Using reverse phase high‐performance liquid chromatography and electrochemical detection with mobile phases composed of simple acids, we have developed an assay technique to measure multiple catecholamines and their catechol metabolites in plasma or brain tissue with sensitivity to the picomole level. Ion‐pairing chromatography with nitric or trichloroacetic acid as the mobile phase permits separation and quantitation of norepinephrine, α‐methylnorepinephrine, epinephrine, dopamine, α‐methyldopamine, l‐DOPA, α‐methyldopa, carbidopa, and DOPAC. Alumina extraction selectively isolates catechols which are then separated on a reverse‐phase column and measured by a commercially available electrochemical detector. This method has been applied to measurement of L‐DOPA metabolites in patients with Parkinsons disease treated with L‐DOPA and carbidopa and to measurement of catecholamines in rat hypothalamus in the course of studies on L‐DOPA and α‐methyldopa metabolism. Dihydroxybenzylamine is added as an internal standard and standard curves are linear over two orders of magnitude in concentration with coefficients of variation averaging 3.1%. Quantitation is routinely done to 20 pmol with absolute sensitivity possible to 0.5 pmol.

Reversed-phase high performance liquid chromatography of catecholamines and their congeners with simple acids as ion-paring reagents

Abstract We have investigated the value of various common acids as ion-pairing reagents for high-efficiency separations of catecholamines and their metabolites in reversed-phase high-performance liquid chromatography. The retention of norepinephrine, α-methylnorepinephrine, dopamine, α-methyldopamine, l -dopa, α-methyldopa, dihydroxybenzylamine, epinephrine, carbidopa and DOPAC was measured in mobile phases composed of nitric, sulfuric, acetic and trichloroacetic acids at pH 2–5 and anion concentrations ranging from 5–500 m M . The solute capacity ratios were dependent on the hydrophobicity and concentration of the ion-pairing reagent and the pH of the mobile phase. Good retention, peak symmetry and high efficiency (3000 theoretical plates for 300 mm) was found for mobile phases composed of the strong inorganic acids and trichloroacetic acid. Chromatography was compared to that seen using the detergent sodium octylsulfate. Trichloroacetic acid gave retention and efficiency similar to sodium octylsulfate. These experiments show that simple acids can replace alkylsulfates as ion-pairing reagents for the separation of the catecholamines and their metabolites.

Hypotension and hypothalamic amine metabolism after long-term α-methyldopa infusions

Abstract In an effort to identify the metabolite of α-methyldopa (α-MD) most responsible for the hypotensive effect of the drug, we infused α-MD (2–20 mg/kg/hr) into the jugular vein of normotensive, conscious, restrained male Sprague-Dawley rats. Changes in blood pressure were measured after 24 hr of drug infusion. Steady-state turnover was then determined by switching infusions to identical doses of deuterated α-MD (2,5,6-α-MD-d 3 ) and the rate of incorporation of deuterium into the metabolites α-methyldopamine (α-MDA) and α-methylnorepinephrine (α-MNE) was followed. Results show that blood pressure reduction correlated with α-MDA concentration but not with α-MNE concentration or turnover rate.