Reversed lipid micellar hollow-fiber liquid-phase microextraction of rotigotine in rat plasma.

A hollow fiber liquid phase microextraction (HF-LPME) based on a reversed lipid micelle as the extraction phase was proposed and combined with high performance liquid chromatography (HPLC) for the determination of rotigotine in biological matrix. In the proposed procedure, pieces of hollow fibers were fastened on a magnetic stir bar using a thread to provide better precision. Rotigotine was extracted from 5 mL of diluted plasma sample phase with pH 6 into reversed lipid micelle (5 mmol/L of dipalmitoyl phosphatidyl choline in n-octanol/water) impregnated in both the wall pores and the lumen of the hollow fiber. After the extraction at 900 rpm and room temperature for 30 min, the acceptor phase of reversed lipid micelle was collected for HPLC analysis. Various parameters affecting the extraction efficiency, such as type of surfactant and organic solvent, surfactant concentration, sample phase pH, salt amount, extraction time, stirring rate, and dilution factor of the plasma sample, were investigated and optimized. Furthermore, the formed reversed lipid micelle was characterized by fluorescence method. Under the optimal conditions, the linear range of rotigotine was between 2 ng/mL and 100 ng/mL with determination coefficient (r2) ≥ 0.9913. It is shown from results of method validation that the satisfactory accuracy (the relative errors between -8.5% and 3.3%), precision (the relative standard deviations from 3.8% to 8.9%), stability and matrix effect were obtained. The enrichment factor (EF) of the reversed lipid micelle-based HF-LPME for rotigotine reached 126. And the feasibility of the proposed method was confirmed by the application to the pharmacokinetic study of rotigotine in rat plasma.

In Vivo Induction of P-Glycoprotein Function can be Measured with [18F]MC225 and PET.

P-Glycoprotein (P-gp) is an efflux pump located at the blood-brain barrier (BBB) that contributes to the protection of the central nervous system by transporting neurotoxic compounds out of the brain. A decline in P-gp function has been related to the pathogenesis of neurodegenerative diseases. P-gp inducers can increase the P-gp function and are considered as potential candidates for the treatment of such disorders. The P-gp inducer MC111 increased P-gp expression and function in SW480 human colon adenocarcinoma and colo-320 cells, respectively. Our study aims to evaluate the P-gp inducing effect of MC111 in the whole brain in vivo, using the P-gp tracer [18F]MC225 and positron emission tomography (PET). Eighteen Wistar rats were treated with either vehicle solution, 4.5 mg/kg of MC111 (low-dose group), or 6 mg/kg of MC111 (high-dose group). Animals underwent a 60 min dynamic PET scan with arterial-blood sampling, 24 h after treatment with the inducer. Data were analyzed using the 1-tissue-compartment model and metabolite-corrected plasma as the input function. Model parameters such as the influx constant (K1) and volume of distribution (VT) were calculated, which reflect the in vivo P-gp function. P-gp and pregnane xenobiotic receptor (PXR) expression levels of the whole brain were assessed using western blot. The administration of MC111 decreased K1 and VT of [18F]MC225 in the whole brain and all of the selected brain regions. In the high-dose group, whole-brain K1 was decreased by 34% (K1-high-dose = 0.20 ± 0.02 vs K1-control = 0.30 ± 0.02; p < 0.001) and in the low-dose group by 7% (K1-low-dose = 0.28 ± 0.02 vs K1-control = 0.30 ± 0.02; p = 0.42) compared to controls. Whole-brain VT was decreased by 25% in the high-dose group (VT-high-dose = 5.92 ± 0.41 vs VT-control = 7.82 ± 0.38; p < 0.001) and by 6% in the low-dose group (VT-low-dose = 7.35 ± 0.38 vs VT-control = 7.82 ± 0.37; p = 0.38) compared to controls. k2 values did not vary after treatment. The treatment did not affect the metabolism of [18F]MC225. Western blot studies using the whole-brain tissue did not detect changes in the P-gp expression, however, preliminary results using isolated brain capillaries found an increasing trend up to 37% in treated rats. The decrease in K1 and VT values after treatment with the inducer indicates an increase in the P-gp functionality at the BBB of treated rats. Moreover, preliminary results using brain endothelial cells also sustained the increase in the P-gp expression. In conclusion, the results verify that MC111 induces P-gp expression and function at the BBB in rats. An increasing trend regarding the P-gp expression levels is found using western blot and an increased P-gp function is confirmed with [18F]MC225 and PET.

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study.

AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL-both peak and AUC are reduced versus baseline-and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.

Effects of Dexmedetomidine on the Pharmacokinetics of Dezocine, Midazolam and Its Metabolite 1-Hydroxymidazolam in Beagles by UPLC-MS/MS.

OBJECTIVE: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. MATERIALS AND METHODS: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 µg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 µg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. RESULTS: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. CONCLUSION: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug-drug interaction should be paid attention to when the drugs were used in combination.

Pharmacokinetics, Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects.

PURPOSE: The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature-stable (PR2.2.1) formulations of rotigotine in healthy Chinese men. METHODS: In treatment period 1 of SP0913, subjects received a single application of rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2-6); treatment period 2 (days 6-14) involved multiple doses of rotigotine 2 mg/24 hours (days 7-9) followed by multiple doses of rotigotine 4 mg/24 hours (days 10-12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring. RESULTS: Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total rotigotine increased to a plateau beginning at ∼8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic Tmax was observed for unconjugated and total rotigotine. The respective geometric mean Cmax, Cmax,ss, AUC from zero up to the last analytically quantifiable concentration, and AUC0-24,ss values for unconjugated and total rotigotine were similar when rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean Cmax,ss and AUC0-24,ss of both unconjugated and total rotigotine were ∼2-fold higher for rotigotine 4 mg/24 hours than for rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature-stable formulation of rotigotine were highly comparable to the cold-chain formulation. Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures. IMPLICATIONS: PK profiles and derived PK parameters of unconjugated and total rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the rotigotine transdermal patch. Single and repeated daily doses of the rotigotine transdermal patch were well tolerated. Room temperature-stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796.

Simultaneous determination of AM80 (tamibarotene) and WJD-A-1 in rat plasma by ultra high-performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

A compound (WJD-A-1) was previously reported as a candidate prodrug of Am80 (tamibarotene), which was approved in Japan in 2005 as a therapeutic agent for recurrent refractory acute promyelocytic leukaemia. A rapid, selective and sensitive ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed for the first time to simultaneously determine WJD-A-1 and its major phase-I metabolites AM80 in rat plasma. After a simple sample preparation procedure by protein precipitation with methanol and acetonitrile, WJD-A-1, AM80 and the internal standard were chromatographed on an ACQUITY UPLCTM BEH C18 column. The mobile phase consisted of methanol-0.1% formic acid (80:20, v/v) and the flow rate was 0.20 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. Each plasma sample was chromatographed within 2.6 min. The linear calibration curves for WJD-A-1 and the AM80 were obtained in the concentration range of 5.40-5.40 × 103 and 5.08-5.08 × 103 ng/mL, respectively (r ≥ 0.99). The intra- and inter-day precision (relative standard deviation, RSD) values were less than 8% and the accuracy (relative error, RE) was within ±6.8%, determined from quality control (QC) samples for the analytes. The method herein described was fully validated and successfully applied to pharmacokinetic study of WJD-A-1 following an intravenous administration of 300 µg/kg WJD-A-1 to rats.

Drug Delivery and Transport into the Central Circulation: An Example of Zero-Order In vivo Absorption of Rotigotine from a Transdermal Patch Formulation.

BACKGROUND AND OBJECTIVE: Pharmacokinetic studies using deconvolution methods and non-compartmental analysis to model clinical absorption of drugs are not well represented in the literature. The purpose of this research was (1) to define the system of equations for description of rotigotine (a dopamine receptor agonist delivered via a transdermal patch) absorption based on a pharmacokinetic model and (2) to describe the kinetics of rotigotine disposition after single and multiple dosing. METHODS: The kinetics of drug disposition was evaluated based on rotigotine plasma concentration data from three phase 1 trials. In two trials, rotigotine was administered via a single patch over 24 h in healthy subjects. In a third trial, rotigotine was administered once daily over 1 month in subjects with early-stage Parkinson's disease (PD). A pharmacokinetic model utilizing deconvolution methods was developed to describe the relationship between drug release from the patch and plasma concentrations. Plasma-concentration over time profiles were modeled based on a one-compartment model with a time lag, a zero-order input (describing a constant absorption via skin into central circulation) and first-order elimination. Corresponding mathematical models for single- and multiple-dose administration were developed. RESULTS: After single-dose administration of rotigotine patches (using 2, 4 or 8 mg/day) in healthy subjects, a constant in vivo absorption was present after a minor time lag (2-3 h). On days 27 and 30 of the multiple-dose study in patients with PD, absorption was constant during patch-on periods and resembled zero-order kinetics. CONCLUSION: Deconvolution based on rotigotine pharmacokinetic profiles after single- or multiple-dose administration of the once-daily patch demonstrated that in vivo absorption of rotigotine showed constant input through the skin into the central circulation (resembling zero-order kinetics). Continuous absorption through the skin is a basis for stable drug exposure.

Validated LC-MS/MS method for the simultaneous determination of rotigotine and its prodrug in rat plasma and an application to pharmacokinetics and biological conversion in vitro.

Rotigotine behenate (RGTB), a long chain alkyl ester of the prodrug of rotigotine (RGT), has been synthesized for use in a sustained delivery system. The aim of the present report was to develop and validate a simple, sensitive and reliable LC-MS/MS method for the simultaneous determination of RGT and its prodrug RGTB in rat plasma samples. Detection was performed on a 1290 Infinity UPLC coupled Triple Quad 4500 mass spectrometer operated in positive MRM mode using an Eclipse XDB-CN chromatography column (2.1mm×100mm, 3.5µm) by isocratic elution using a 0.2% formic acid aqueous solution and acetonitrile, with stable isotope labeled RGT as an internal standard. The sample preparation method employed 50µL of a plasma sample and liquid-liquid extraction with a mixture of diethyl ether-dichloromethane (3:2, v/v) as the extraction solvent. The proposed method was fully validated by assessing its specificity, linearity, precision and accuracy, recovery, matrix effects and stability. Good linearity was found within the range of 0.1-10.0ng/mL for both analytes (r>0.996). This method was successfully applied to a pharmacokinetic study of a slow release RGTB formulation in rats following a single intramuscular injection and biological conversion in vitro.

The direct analysis of drug distribution of rotigotine-loaded microspheres from tissue sections by LESA coupled with tandem mass spectrometry.

The direct analysis of drug distribution of rotigotine-loaded microspheres (RoMS) from tissue sections by liquid extraction surface analysis (LESA) coupled with tandem mass spectrometry (MS/MS) was demonstrated. The RoMS distribution in rat tissues assessed by the ambient LESA-MS/MS approach without extensive or tedious sample pretreatment was compared with that obtained by a conventional liquid chromatography tandem mass spectrometry (LC-MS/MS) method in which organ excision and subsequent solvent extraction were commonly employed before analysis. Results obtained from the two were well correlated for a majority of the organs, such as muscle, liver, stomach, and hippocampus. The distribution of RoMS in the brain, however, was found to be mainly focused in the hippocampus and striatum regions as shown by the LESA-imaged profiles. The LESA approach we developed is sensitive enough, with an estimated LLOQ at 0.05 ng/mL of rotigotine in brain tissue, and information-rich with minimal sample preparation, suitable, and promising in assisting the development of new drug delivery systems for controlled drug release and protection. Graphical abstract Workflow for the LESA-MS/MS imaging of brain tissue section after intramuscular RoMS administration.

Levodopa, placebo and rotigotine change biomarker levels for oxidative stress.

INTRODUCTION: Homocysteine increase and glutathione derivative cysteinyl-glycine fall are indirect biomarkers for oxidative stress, for instance due to dopamine D1 receptor stimulation. OBJECTIVES: To investigate the influence of the D1 receptor agonists levodopa and rotigotine compared with placebo on homocysteine and cysteinyl-glycine in plasma of patients with Parkinson's disease. METHODS: Patients received 100 mg levodopa, 4 mg rotigotine or placebo. Cysteinyl-glycine and homocysteine were measured every 30 min over three hours. RESULTS: Homocysteine rose during levodopa- and placebo administration. Rotigotine had no effect. Cysteine-glycine only increased after placebo- but not after levodopa- or rotigotine. DISCUSSION: Homocysteine elevation results from hepatic and gastrointestinal methylation processes. Transdermal rotigotine circumvents these methylation locations. Turnover of segregated alkyl residuals from rotigotine serves as methyl group donors, which counteract homocysteine increment. The placebo-related cysteinyl-glycine increase results from reduced free radical exposure. Low levodopa dosing and antioxidants in the rotigotine patch matrix prevented cysteinyl-glycine fall.

Novel UHPLC-MS/MS method for the determination of rotigotine in the plasma of patients with Parkinson's disease.

A novel ultra-high-pressure liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of the dopamine receptor agonist rotigotine in human plasma. Following liquid-liquid extraction with tert-butyl methyl ether from 500 µL plasma, the chromatographic analysis was performed on a Gemini NX3 column using 5 mm pH 5.0 ammonium acetate-5 mm ammonium acetate in methanol as binary gradient mobile phase, at a flow rate of 0.3 mL/min. The MS/MS ion transitions were 316.00 → 147.00 for rotigotine and 256.10 → 211.00 for the internal standard (lamotrigine). The lower limit of quantitation was 50 pg/mL and the linearity was determined from 50 to 2500 pg/mL. The mean recovery was 96.9%. Both intra- and interassay imprecision and inaccuracy were ≤15% at all quality control concentrations. The method was successfully applied to measure morning trough plasma rotigotine concentrations in a series of patients with Parkinson's disease on chronic treatment. The present study describes the first fully validated method for rotigotine determination in human plasma.

Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma.

Bexarotene is currently marketed for treatment of cutaneous T-cell lymphoma and there has been growing interest in its therapeutic effectiveness for other cancers. Neuroprotective effects of bexarotene have also been reported. In this study, a simple, sensitive and cost-efficient bioanalytical method for determination of bexarotene in rat plasma was developed and fully validated. The method utilises protein precipitation with acetonitrile and liquid-liquid extraction with n-hexane-ethyl acetate (10:1, v/v). An HPLC-UV system with a Waters Atlantis C18 column and a mobile phase of acetonitrile-ammonium acetate buffer (10mM, pH 4.1) at a ratio of 75:25 (v/v), flow rate 0.2mL/min was used. Chromatograms were observed by a UV detector with wavelength set to 259nm. Intra- and inter-day validations were performed and sample stability tests were conducted at various conditions. The applicability of the method was demonstrated by a pharmacokinetic study in rats. Intravenous bolus dose of 2.5mg/kg was administered to rats and samples were obtained at predetermined time points. As a result, pharmacokinetic parameters of AUCinf (4668±452hng/mL), C0 (6219±1068ng/mL) and t1/2 (1.15±0.02h) were obtained. In addition, the developed method was further applied to human and mouse plasma to assess the suitability of the method for samples from other species.

Simultaneous determination of andrographolide, dehydroandrographolide and neoandrographolide in dog plasma by LC-MS/MS and its application to a dog pharmacokinetic study of Andrographis paniculata tablet.

In this study, a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determinate andrographolide (AP), dehydroandrographolide (DP), and neoandrographolide (NP) in plasma of beagle dogs after oral administration of Andrographis paniculata tablet (A. paniculata). The analytes and bilobalide (internal standard) were separated on an Agilent ZORBAX XDB-C18 column (50mm×2.1mm, 3.5µm) by using gradient elution consisting of methanol and water at a flow rate of 0.50mL/min in 7min. Multiple reaction monitoring (MRM) mode was performed to quantify data under monitoring precursor-product ion transitions of m/z 348.8→286.9, 330.9→107.9, 479.1→160.8 and 325.0→163.0 for AP, DP, NP and internal standard (IS) at negative ion mode, respectively. This method was developed at linearity ranging from 0.50 to 250ng/mL for AP, 1.00 to 500ng/mL for DP and 0.20 to 100ng/mL for NP. The accuracy of each analyte ranged between 94.8% and 107.1% and the precision was within 14.6%. No significant matrix effect was observed. AP, DP and NP were stable during sample storage, preparation and analytic procedures. Furthermore, this method was successfully applied in the investigation of the pharmacokinetic profile of AP, DP and NP in beagle dogs after oral administration of A. paniculata tablet (49.5mg for AP, 7.0mg for DP, 22.0mg for NP). Biological half-life (t1/2) was 2.08±0.99, 3.13±1.19 and 1.07±0.38h for AP, DP and NP, respectively. The areas under curves (AUC0-t) of AP, DP and NP was 494.50±150.64, 26.01±8.72 and 78.78±18.29ngh/mL, respectively.

Rotigotine: the first new chemical entity for transdermal drug delivery.

Rotigotine is the first, and to date, the only new chemical entity to be formulated for transdermal delivery. Although first approved for the management of Parkinson's disease in Europe in 2007 and Restless Leg Syndrome in 2008, the story of rotigotine began more than twenty years earlier. In this review we outline the historical development of this molecule and its route to licensed medicine status. It has very favourable physicochemical properties for transdermal delivery but it took a significant period to develop from concept to market. The stability problems which led to the temporary withdrawal of the patch are examined and the major clinical studies demonstrating efficacy and safety are outlined. Alternative new therapeutic modalities are also considered.

A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers.

OBJECTIVE: Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co-agonist with glutamate at N-methyl-D-aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers. METHODS: A randomised, double-blind, parallel-group, single-dose study of Org 25935 and placebo was carried out. Thirty-two healthy male volunteers took either 12-mg Org 25935 or matching placebo and were later assessed with the manikin task, digit span and verbal memory tests. Systematic assessments of cardiovascular and adverse events were also taken. RESULTS: There was no effect of Org 25935 on reaction time, number of correct responses or learning (greater or slower improvement over successive tasks) compared with placebo. Org 25935 caused significantly more dizziness and drowsiness compared with placebo; these side effects were mainly mild. CONCLUSIONS: A single dose of Org 25935 does not improve learning or memory in healthy male individuals. However, the drug was well tolerated, and it remains to be seen whether it would have a positive effect on cognition in patient groups with pre-existing cognitive deficits.

Bexarotene nanocrystal-Oral and parenteral formulation development, characterization and pharmacokinetic evaluation.

Bexarotene (Targretin®) is a synthetic retinoid that selectively activates the retinoid X receptor subfamily of retinoid receptors and exhibits potent anti-tumor activity. However, the poor solubility and bioavailability limit its application. The main aim of this study is to investigate the potential of oral and parenteral nanocrystals in enhancing the bioavailability of bexarotene. In this work, the orthogonal design was used to screen the optimum stabilizers and precipitation-combined microfluidization method was employed to obtain the optimal nanocrystals. According to DSC, X-ray diffraction analysis and Raman examination, the nanocrystals were still in crystalline state after the preparation procedure. By reducing the particle size, the in vitro dissolution rate of bexarotene was increased significantly. The in vivo test was carried out in rats and pharmacokinetic parameters of the bexarotene solution and bexarotene nanocrystals were compared after gavage and intravenous administration. The higher AUC and lower Cmax indicated that oral bexarotene nanocrystals significantly increased the bioavailability of bexarotene and decreased its side effects. Compared to the oral nanocrystals, the intravenous nanocrystals cut losses and increased bioavailability because of the absence of first pass effect and enterohepatic circulation.

Preparation and characterization of sustained-release rotigotine film-forming gel.

OBJECTIVE: The aim of this study was to develop a film-forming gel formulation of rotigotine with hydroxypropyl cellulose (HPC) and Carbomer 934. To optimize this formulation, we applied the Response Surface Analysis technique and evaluated the gel's pharmacokinetic properties. METHODS: The factors chosen for factorial design were the concentration of rotigotine, the proportion of HPC and Carbomer 934, and the concentration of ST-Elastomer 10. Each factor was varied over three levels: low, medium and high. The gel formulation was evaluated and optimized according to its accumulated permeation rate (Flux) through Franz-type diffusion. A pharmacokinetic study of rotigotine gel was performed with rabbits. RESULTS: The Flux of the optimized formulation reached the maximum (199.17 µg/cm(2)), which was 3% rotigotine and 7% ST-Elastomer 10 with optimal composition of HPC: Carbomer 934 (5:1). The bioavailability of the optimized formulation compared with intravenous administration was approximately 20%. CONCLUSION: A film-forming gel of rotigotine was successfully developed using the response surface analysis technique. The results of this study may be helpful in finding an optimum formulation for transdermal delivery of a drug. The product may improve patients' compliance and provide better efficacy.

Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats.

Dexamethasone was given in 2 oral dosing regimens with repeat dose oral administration of the gamma secretase inhibitor (GSI), PF-03084014, in Sprague-Dawley (SD) rats in order to evaluate the effects of coadministration of dexamethasone on GSI-induced goblet cell hyperplasia (GCH) in the intestinal tract. Safety end points were evaluated in 1 week and 1 month studies. The dosing regimens tested in the 1-month studies included a 1-week pretreatment with 1.0 mg/kg dexamethasone followed by a 3-week repeat dose treatment with 100 mg/kg GSI or concurrent intermittent treatment with 1.0 mg/kg dexamethasone on weeks 1 and 3 and repeat dose treatment with 100 mg/kg GSI for 4 weeks. Pretreatment with dexamethasone for 1 week transiently mitigated the severity of intestinal GCH for up to 1 week. Intermittent coadministration of dexamethasone on weeks 1 and 3 with GSI repeat dosing for 4 weeks mitigated intestinal GCH for up to 4 weeks post treatment. Treatment-related morbidity and mortality occurred on day 7 with 150 mg/kg GSI and 5 mg/kg dexamethasone coadministration, and on days 13, 14, and 23 with 100 mg/kg GSI and 1 mg/kg dexamethasone coadministration.

Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist rotigotine.

The transdermally applied dopamine receptor agonist rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child-Pugh class B) received one rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated rotigotine (active parent compound) and total rotigotine (unconjugated rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated rotigotine, point estimates for the ratios of AUC(0-24)SS and C max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC(0-24)SS, 0.90 (90 % CI 0.59, 1.38) and C max,SS, 0.94 (90 % CI 0.66, 1.35); t max,SS and t 1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total rotigotine, C max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function (P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the rotigotine patch was well tolerated in subjects with moderate hepatic impairment.

Wearing off, dyskinesia, and the use of continuous drug delivery in Parkinson's disease.

Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of Parkinson's disease (PD). The basis of both is considered to be a reflection of the progression of neuronal degeneration, coupled with the nature of drug treatment used to control motor symptoms. The concept of continuous dopaminergic stimulation has been used to explain both the onset of wearing off and dyskinesia and their avoidance through pharmacologic manipulation. This review focuses on using with the transdermal dopamine agonist, rotigotine, for continuous dopaminergic drug delivery in the treatment of PD.