Ninety-day Local Tolerability and Toxicity Study of ND0612, a Novel Formulation of Levodopa/Carbidopa, Administered by Subcutaneous Continuous Infusion in Minipigs.

A 90-day study in Göttingen minipigs was conducted to test the local tolerability and systemic toxicity of ND0612, a novel aqueous solution of carbidopa (CD)/levodopa (LD) intended for the treatment of Parkinson's disease by continuous subcutaneous administration using a discrete infusion pump. To evaluate tissue site reactions, we used a unique study design involving multiple infusion sites to evaluate the effect of dose per site (270/63, 360/45, and 360/84 mg LD/CD), volume of infusion per site (4.5 and 6 ml per site), formulation concentration (60/14 and 60/7.5 mg/ml LD/CD), daily rate of infusion per site (240 µl/hr for16 hr and 80 µl/hr for 8 hr, 320 µl/hr for 16 hr and 100 µl/hr for 8 hr, or 750 µl/hr for 8 hr), frequency (once every 5, 10, 15, or 20 days), and number of infusions (4, 6, or 9) to the same infusion site. No systemic adverse effects were observed. Histopathological changes at infusion sites started with localized minimal necrosis and acute inflammation that progressed to subacute and chronic inflammatory and reparative changes with evidence of progressive recovery following the final infusion. None of the infusion site effects were judged to be adverse, and clinical exposures to ND0612 are not expected to result in adverse responses.

Thorough QT/QTc study in patients with advanced Parkinson's disease: cardiac safety of rotigotine.

The potential effects of the dopamine agonist rotigotine on cardiac repolarization were studied in patients with Parkinson's disease, which affects electrocardiogram (ECG) quality. The parallel-group trial was double-blind and placebo- and positive (moxifloxacin 400 mg)-controlled. After two 24-h baseline ECGs, patients were randomized to rotigotine (n = 66) or placebo (n = 64). Twenty four-hour ECGs were recorded on days 14/15, 21/22, 28/29, 35/36, and 42/43 of a regimen involving weekly dose escalations of 4 mg/24 h (4 mg/24 h-24 mg/24 h). In 10-s ECGs (n = 357,948) selected from 24-h records, QT measurements were manually verified and individually rate-corrected (QTc). Assay sensitivity showed maximum mean 13.5 ms QTc prolongation after moxifloxacin with 95% confidence interval (CI) 11.8-15.2 ms. Rotigotine vs. placebo differences in time-matched changes from baseline (54 data points/24 h) showed mean effects close to zero with upper one-sided 95% CI <5 ms. Accurate, thorough QTc studies are possible even in patients with diseases that profoundly affect ECG quality. Rotigotine in supra- and therapeutic doses was shown not to affect cardiac repolarization.

Determination of apomorphine in human plasma by alumina extraction and high-performance liquid chromatography with electrochemical detection.

Apomorphine is a powerful agonist of dopaminergic receptors which several years ago was introduced into the therapy of Parkinson's Disease. The pharmacological activity of apomorphine already appears significant at low doses. Unfortunately, the difficulty in determining the drug in plasma at low concentrations hampers the completion of accurate pharmacokinetic studies in humans. Considering the analogy of apomorphine with the molecular structure of catecholamines, the extraction of the drug from plasma was optimized by using adsorption on alumina, a technique widely used for noradrenaline and adrenaline analysis in clinical chemistry laboratories. This method proved particularly efficient and selective in apomorphine extraction from plasma prior to high-performance liquid chromatographic analysis. After pretreatment of 200 microliters of plasma sample with 40 mg of alumina and 10 microliters of tris buffer (pH 8.6), the drug was eluted with 200 microliters of an acidic-organic solution. One volume of the supernatant was mixed with two volumes of phosphate buffer (pH 3.6), and 100 microliters of the obtained mixture were injected into the HPLC system. The chromatograph was equipped with a C18 reversed-phase column and with an electrochemical coulometric detector fitted with a high-sensitivity cell (first electrode 0.00 volts, second electrode +0.35 volts). Sensitivity (20 pg of injected drug), precision (CV within assay and between assays of 3.7% and 5.6%, respectively) and accuracy were comparable to more complex analytical procedures. The miniaturisation of the entire sample pretreatment proved very advantageous for pharmacokinetics studies and, in principle, for therapeutic drug monitoring and toxicological investigations.