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1.
Parkinsonism Relat Disord ; 83: 105-109, 2021 02.
Article in English | MEDLINE | ID: mdl-33497892

ABSTRACT

INTRODUCTION: A dopamine agonist patch could be an important treatment option for Parkinson's disease. This study evaluated the long-term efficacy and safety of the ropinirole hydrochloride patch. The steady state plasma ropinirole concentration was also assessed. METHODS: In a multicenter, open-label, uncontrolled study, Parkinson's disease patients with/without basal levodopa and with/without prior dopamine agonist therapy (any of these four regimens) received application of a ropinirole patch once daily for up to 52 weeks with unforced titration from 8 to 64 mg. For patients with prior dopamine agonist therapy, the initial dose of ropinirole patch was determined from the prior dopamine agonist dose by using a conversion table. RESULTS: Most adverse events were mild or moderate. All application site adverse events were mild, except for moderate application site erythema in one patient. In patients with prior dopamine agonist therapy, switching to ropinirole patch did not lead to a significant early increase of adverse events. A change from baseline in the UPDRS Part III total score, the primary efficacy endpoint, showed improvement until Week 16 compared with baseline, followed by little subsequent change until Week 52, indicating maintenance of efficacy. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase. CONCLUSION: Once-daily application of ropinirole patch showed long-term efficacy and safety (52 weeks) for Parkinson's disease. Switching from other dopamine agonists to ropinirole patch was effective and safe. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase.


Subject(s)
Dopamine Agonists/pharmacology , Indoles/pharmacology , Adult , Aged , Dopamine Agonists/administration & dosage , Dopamine Agonists/adverse effects , Dopamine Agonists/blood , Drug Substitution , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , Indoles/blood , Levodopa/administration & dosage , Longitudinal Studies , Male , Middle Aged , Outcome Assessment, Health Care , Severity of Illness Index , Transdermal Patch
2.
Acta Neuropsychiatr ; 32(6): 303-312, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32418546

ABSTRACT

OBJECTIVE: The purpose of the present study was to evaluate the efficacy and safety of (-)-OSU6162 in doses up to 30 mg b.i.d. in patients suffering from mental fatigue following stroke or traumatic brain injury (TBI). METHODS: This 4 + 4 weeks double-blind randomised cross-over study included 30 patients afflicted with mental fatigue following a stroke or head trauma occurring at least 12 months earlier. Efficacy was assessed using the Mental Fatigue Scale (MFS), the Self-rating Scale for Affective Syndromes [Comprehensive Psychopathological Rating Scale (CPRS)], the Frenchay Activity Index (FAI), and a battery of neuropsychological tests. Safety was evaluated by recording spontaneously reported adverse events (AEs). RESULTS: There were significant differences on the patients' total FAI scores (p = 0.0097), the subscale FAI outdoor scores (p = 0.0243), and on the trail making test (TMT-B) (p = 0.0325) in favour of (-)-OSU6162 treatment. Principal component analysis showed a clear overall positive treatment effect in 10 of 28 patients; those who responded best to treatment had their greatest improvements on the MFS. Reported AEs were mild or moderate in severity and did not differ between the (-)-OSU6162 and the placebo period. CONCLUSION: The most obvious beneficial effects of (-)-OSU6162 were on the patients' activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the MFS. Based on these observed therapeutic effects, in conjunction with the good tolerability of (-)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke- or TBI-induced mental fatigue.


Subject(s)
Brain Injuries, Traumatic/complications , Mental Fatigue/drug therapy , Mental Fatigue/etiology , Piperidines/therapeutic use , Receptors, Dopamine/drug effects , Stroke/complications , Adult , Aged , Case-Control Studies , Cross-Over Studies , Dopamine Agonists/adverse effects , Dopamine Agonists/blood , Dopamine Agonists/therapeutic use , Dopamine Antagonists/adverse effects , Dopamine Antagonists/blood , Dopamine Antagonists/therapeutic use , Double-Blind Method , Female , Humans , Male , Middle Aged , Neuropsychological Tests/standards , Piperidines/adverse effects , Piperidines/blood , Placebos/administration & dosage , Safety , Surveys and Questionnaires , Treatment Outcome
3.
J Agric Food Chem ; 68(7): 1998-2006, 2020 Feb 19.
Article in English | MEDLINE | ID: mdl-31984737

ABSTRACT

Hordenine, a natural constituent of germinated barley, is a biased agonist of the dopamine D2 receptor. This pilot study investigated the biokinetics of hordenine and its metabolites in four volunteers consuming beer equal to 0.075 mg hordenine/kg body weight. A new ultrahigh-performance liquid chromatography method coupled to electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) method determined maximum plasma concentrations of 12.0-17.3 nM free hordenine after 0-60 min. Hordenine phase-II metabolism was first dominated by sulfation, but later by glucuronidation. The elimination half-lives in plasma were 52.7-66.4 min for free hordenine and about 60/80 min longer for hordenine sulfate and hordenine glucuronide. Urinary excretion peaked 2-3.5 h after consumption and accumulated to 3.78 µmol within 24 h, corresponding to 9.9% of the ingested dose. The observed hordenine levels in plasma seem too low to provoke direct interaction with the dopamine D2 receptor related to food reward, but synergistic or additive effects with alcohol or N-methyltyramine may occur.


Subject(s)
Beer/analysis , Dopamine Agonists/pharmacokinetics , Tyramine/analogs & derivatives , Adult , Chromatography, High Pressure Liquid , Dopamine Agonists/blood , Dopamine Agonists/urine , Female , Humans , Male , Middle Aged , Receptors, Dopamine D2/chemistry , Receptors, Dopamine D2/metabolism , Tandem Mass Spectrometry , Tyramine/blood , Tyramine/pharmacokinetics , Tyramine/urine , Young Adult
4.
Clin Ther ; 40(7): 1108-1121.e8, 2018 07.
Article in English | MEDLINE | ID: mdl-30098648

ABSTRACT

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.


Subject(s)
Tetrahydronaphthalenes/pharmacokinetics , Thiophenes/pharmacokinetics , Adolescent , Adult , Area Under Curve , Asian People , Biological Availability , China , Cross-Over Studies , Dopamine Agonists/administration & dosage , Dopamine Agonists/blood , Dopamine Agonists/pharmacokinetics , Female , Healthy Volunteers , Humans , Male , Middle Aged , Parkinson Disease/drug therapy , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/blood , Therapeutic Equivalency , Thiophenes/administration & dosage , Thiophenes/blood , Transdermal Patch , Young Adult
5.
Eur J Mass Spectrom (Chichester) ; 24(5): 397-407, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30012017

ABSTRACT

An efficient, selective, sensitive, and rapid ultra-performance liquid chromatography tandem mass spectrometry method was established and validated for the quantification of pramipexole dihydrochloride monohydrate and levodopa simultaneously in human plasma with the aid of diphenhydramine as an internal standard. A simple protein precipitation technique with HPLC grade acetonitrile was efficiently utilized for the cleanup of plasma. The analysis was performed using a Hypersil gold 50 mm × 2.1 mm (1.9 µm) column and a mobile phase of 0.2% formic acid and methanol (90: 10 v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source operated in the positive mode was set up in the selective reaction monitoring mode (SRM) to detect the ion transitions m/z 212.15 →153.01, m/z 198.10→ 135.16, and m/z 255.75 → 166.16 for pramipexole dihydrochloride monohydrate, levodopa, and diphenhydramine, respectively. The method was thoroughly validated according to FDA guidelines and proved to be linear, accurate, and precise over the range 100-4000 pg/mL for pramipexole dihydrochloride monohydrate and 60-4000 ng/mL for levodopa. The proposed method was effectively applied for monitoring both drugs in plasma samples of healthy volunteers.


Subject(s)
Dopamine Agonists/blood , Levodopa/blood , Pramipexole/blood , Tandem Mass Spectrometry/methods , Administration, Intravenous , Chromatography, High Pressure Liquid/methods , Dopamine Agonists/administration & dosage , Dopamine Agonists/chemistry , Drug Stability , Humans , Levodopa/administration & dosage , Levodopa/chemistry , Pramipexole/administration & dosage , Pramipexole/chemistry
6.
J Chromatogr Sci ; 56(8): 702-708, 2018 Sep 01.
Article in English | MEDLINE | ID: mdl-29800104

ABSTRACT

A sensitive, efficient and stable bioanalytical method has been developed and validated for determination of brexpiprazole in dog plasma with UPLC-MS-MS for the first time. Brexpiprazole and internal standard were extracted from plasma samples by liquid-liquid extraction and separated on an Acquity UPLC BEH C18 column. A gradient elution program was developed employing methanol and 10 mM ammonium acetate aqueous solution as mobile phases. The method was validated for parameters of selectivity, LLOQ, linearity, accuracy, precision, matrix effects and stability in accordance with the regulatory guidance on bioanalytical method validation. The validated method was applied in evaluating the pharmacokinetic profiles of brexpiprazole in beagle dogs after a single-dose oral administration of a 4 mg tablet.


Subject(s)
Dogs/blood , Dopamine Agonists/blood , Quinolones/blood , Thiophenes/blood , Administration, Oral , Animals , Chromatography, High Pressure Liquid/methods , Dopamine Agonists/administration & dosage , Limit of Detection , Quinolones/administration & dosage , Reproducibility of Results , Tandem Mass Spectrometry/methods , Thiophenes/administration & dosage
7.
Eur J Drug Metab Pharmacokinet ; 43(4): 475-481, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29332198

ABSTRACT

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.


Subject(s)
Drug Delivery Systems , Skin Absorption , Tetrahydronaphthalenes/blood , Tetrahydronaphthalenes/pharmacokinetics , Thiophenes/blood , Thiophenes/pharmacokinetics , Transdermal Patch , Adolescent , Adult , Aged , Aged, 80 and over , Biological Availability , Clinical Trials, Phase I as Topic/statistics & numerical data , Dopamine Agonists/blood , Dopamine Agonists/pharmacokinetics , Female , Humans , Male , Middle Aged , Models, Biological , Models, Theoretical , Young Adult
8.
Toxicol Pathol ; 45(6): 764-773, 2017 08.
Article in English | MEDLINE | ID: mdl-28891435

ABSTRACT

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.


Subject(s)
Carbidopa/toxicity , Dopamine Agonists/toxicity , Drug Tolerance , Injection Site Reaction/etiology , Levodopa/toxicity , Animals , Carbidopa/administration & dosage , Carbidopa/blood , Dopamine Agonists/administration & dosage , Dopamine Agonists/blood , Drug Combinations , Drug Evaluation, Preclinical , Female , Infusions, Subcutaneous , Injection Site Reaction/pathology , Levodopa/administration & dosage , Levodopa/blood , Male , Necrosis , Swine , Swine, Miniature , Toxicity Tests, Chronic
9.
Anal Bioanal Chem ; 409(22): 5217-5223, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28702764

ABSTRACT

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.


Subject(s)
Microspheres , Tetrahydronaphthalenes/pharmacokinetics , Thiophenes/pharmacokinetics , Animals , Dopamine Agonists/blood , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacokinetics , Liquid-Liquid Extraction , Male , Molecular Structure , Rats , Surface Properties , Tandem Mass Spectrometry , Tetrahydronaphthalenes/blood , Tetrahydronaphthalenes/chemistry , Thiophenes/blood , Thiophenes/chemistry , Tissue Distribution
10.
Bioanalysis ; 9(9): 683-692, 2017 May.
Article in English | MEDLINE | ID: mdl-28520466

ABSTRACT

AIM: Development of a high-sensitivity chiral LC-MS/MS method was required to evaluate a combination of pramipexole (S-PPX) and its enantiomer dexpramipexole (R-PPX) in a proposed clinical trial. The previously available methods suffered from low sensitivity for the (S)-enantiomer in the presence of the more abundant (R)-enantiomer. Based on the projected dosing regimen in the clinical trial, a 5000-fold improvement in sensitivity was required for the (S)-enantiomer. METHODOLOGY: Spiked human plasma samples were extracted by liquid-liquid extraction using ethyl acetate and injected onto a CHIRALPAK ID column under pH gradient conditions. CONCLUSION: An improved analytical method was developed and validated with a final LLQ for (S)-PPX of 0.1 ng/ml in the presence of 2000 ng/ml of (R)-PPX.


Subject(s)
Antiparkinson Agents/blood , Benzothiazoles/blood , Dopamine Agonists/blood , Liquid-Liquid Extraction/methods , Tandem Mass Spectrometry/methods , Antiparkinson Agents/isolation & purification , Benzothiazoles/isolation & purification , Chromatography, High Pressure Liquid/methods , Dopamine Agonists/isolation & purification , Humans , Limit of Detection , Pramipexole , Reproducibility of Results
11.
J Med Toxicol ; 13(4): 343-346, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28547577

ABSTRACT

INTRODUCTION: Pramipexole is a dopamine D2 receptor agonist used to treat idiopathic Parkinson's disease and primary restless legs syndrome. There is limited information on pramipexole overdose. CASE REPORT: A 59-year-old male ingested 3 mg pramipexole, 2250 mg venlafaxine, 360 mg mirtazapine, with suicidal intent. He presented alert, had normal vital observations and normal pupillary reflexes. He was mildly agitated, reported visual hallucinations and was given 5 mg diazepam. He had a mildly elevated lactate of 1.7 mmol/L, but otherwise normal laboratory investigations. Overnight, he remained agitated with visual hallucinations and developed myoclonus while awake. He had increasing difficulty passing urine on a background of mild chronic urinary retention. On review, 14 h post-ingestion, he was hypervigilant, jittery and mildly agitated. He had pressured speech and difficulty focusing on questioning. He had a heart rate of 110 bpm, but had an otherwise normal examination, with no clonus or extrapyramidal effects. He was unable to mobilize due to dizziness and ataxia. Over the next few hours, he improved, the visual hallucinations and agitation resolved and he mobilized independently. Pramipexole was measured with liquid chromatography mass spectrometry. The initial plasma pramipexole concentration was 34.2 ng/mL (therapeutic range 0.2 to 7 ng/mL), 9 h post-overdose. Concentration time data fitted a one-compartment model with an estimated elimination half-life of 18 h. DISCUSSION: Pramipexole overdose with hallucination, agitation, and myoclonus is consistent with adverse effects reported with therapeutic toxicity, but mirtazapine and venlafaxine may have contributed. Pramipexole concentrations exceeded the therapeutic range for over 24 h. With the increasing use of pramipexole in restless legs syndrome, adult overdoses may become more common.


Subject(s)
Akathisia, Drug-Induced/etiology , Benzothiazoles/poisoning , Dopamine Agonists/poisoning , Drug Overdose/genetics , Hallucinations/chemically induced , Motor Activity/drug effects , Myoclonus/chemically induced , Suicide, Attempted , Visual Perception/drug effects , Akathisia, Drug-Induced/diagnosis , Akathisia, Drug-Induced/physiopathology , Benzothiazoles/blood , Benzothiazoles/pharmacokinetics , Dopamine Agonists/blood , Dopamine Agonists/pharmacokinetics , Drug Overdose/diagnosis , Drug Overdose/physiopathology , Drug Overdose/psychology , Hallucinations/diagnosis , Hallucinations/psychology , Humans , Male , Middle Aged , Models, Biological , Myoclonus/diagnosis , Myoclonus/physiopathology , Pramipexole
12.
Biomed Chromatogr ; 31(9)2017 Sep.
Article in English | MEDLINE | ID: mdl-28168729

ABSTRACT

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.


Subject(s)
Chromatography, High Pressure Liquid/methods , Dopamine Agonists/blood , Parkinson Disease/drug therapy , Tandem Mass Spectrometry/methods , Tetrahydronaphthalenes/blood , Thiophenes/blood , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacokinetics , Dopamine Agonists/therapeutic use , Humans , Limit of Detection , Linear Models , Reproducibility of Results , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/therapeutic use , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Thiophenes/therapeutic use
13.
Life Sci ; 151: 300-304, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26976325

ABSTRACT

Pramipexole is a dopaminergic agonist used in Parkinson's disease treatment. It is thought to exert its therapeutic and side effects through actions on dopamine D3 receptors. In a recent study, we found that at doses occupying D3 but not D2 receptors pramipexole reduced locomotion and operant responding for primary and conditioned reinforcement. These effects, however, were not blocked by a D3 receptor antagonist and were present in D3 knockout mice, suggesting non-D3 receptor mechanisms. Among the next highest affinity binding sites of pramipexole are adrenergic α2 receptors. Here we explored α2 receptor involvement in the behavioural effects of pramipexole. We found that the α2 antagonist atipamezole, which was itself behaviourally silent, counteracted pramipexole's reduction of locomotion, but not operant responding for water or a conditioned reinforcer. The resulting behavioural profile was similar to that of a higher dose of pramipexole, leading to the hypothesize that atipamezole mediates its behavioural effects by increasing pramipexole effective dose. In support of this hypothesis, we found that atipamezole increased pramipexole concentration in blood plasma. This is not likely due to an effect on drug metabolism since pramipexole is not known to undergo metabolic transformation. Future work should examine two alternative hypotheses; that pramipexole plasma concentration is elevated as the result of 1) competition with atipamezole for renal excretion, or 2) atipamezole blockade of peripheral α2 binding sites, thereby preventing pramipexole distribution to α2-rich tissues. The suggestion of adrenergic effects of pramipexole is important in light of recent interest in adrenergic pathophysiology in Parkinson's disease.


Subject(s)
Benzothiazoles/blood , Benzothiazoles/pharmacology , Conditioning, Operant/drug effects , Imidazoles/pharmacology , Locomotion/drug effects , Adrenergic alpha-2 Receptor Antagonists/pharmacology , Animals , Benzothiazoles/antagonists & inhibitors , Dopamine Agonists/blood , Dopamine Agonists/pharmacology , Male , Pramipexole , Rats
14.
J Vet Pharmacol Ther ; 39(2): 202-4, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26763106

ABSTRACT

Fenoldopam is a selective dopamine-1 receptor agonist that improves diuresis by increasing renal blood flow and perfusion and causing peripheral vasodilation. Fenoldopam has been shown to induce diuresis and be well-tolerated in healthy cats. It is used clinically in cats with oliguric kidney injury at doses extrapolated from human medicine and canine studies. The pharmacokinetics in healthy beagle dogs has been reported; however, pharmacokinetic data in cats are lacking. The goal of this study was to determine pharmacokinetic data for healthy, awake cats receiving an infusion of fenoldopam. Six healthy, awake, client-owned cats aged 2-6 years old received a 120-min constant rate infusion of fenoldopam at 0.8 µg/kg/min followed by a 20-min washout period. Ascorbate stabilized plasma samples were collected during and after the infusion for the measurement of fenoldopam concentration by HPLC with mass spectrometry detection. This study showed that the geometric mean of the volume of distribution, clearance, and half-life (198 mL/kg, 46 mL/kg/min, and 3.0 mins) is similar to pharmacokinetic parameters for humans. No adverse events were noted. Fenoldopam at a constant rate infusion of 0.8 µg/kg per min was well tolerated in healthy cats. Based on the results, further evaluation of fenoldopam in cats with kidney disease is recommended.


Subject(s)
Cats/blood , Dopamine Agonists/pharmacokinetics , Fenoldopam/pharmacokinetics , Animals , Dopamine Agonists/administration & dosage , Dopamine Agonists/blood , Female , Fenoldopam/administration & dosage , Fenoldopam/blood , Half-Life , Injections, Intravenous , Male
15.
Expert Rev Neurother ; 15(6): 695-710, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25955028

ABSTRACT

AIM: The aim of this study was to investigate the brain targeting potential of chitosan-coated oil in water nanoemulsions (CSNE(ROP)) delivered intranasally in haloperidol-induced Parkinson's disease rat models. METHODS: Chitosan-coated nanoemulsion (CSNE(ROP)) was developed through aqueous titration followed by a high pressure homogenization method. RESULTS: Gamma-scintigraphy study showed a significantly high mucoadhesive potential of CSNE(ROP) and least for conventional and homogenized formulations. Confocal study showed deep localization of formulations in the brain confirming the permeation potential of CSNE(ROP). Pharmacokinetic results of CSNE(ROP) in Wistar rat brain and plasma showed a significantly high (p** < 0.005) AUC0→24 and amplified Cmax over i.v treatment group. Neurobehavioral activity (rotarod and swim tests) and biochemical parameters (glutathion, TBARS and SOD) corroborated well with the pharmacokinetic results. The order of dopamine recovery in haloperidol-induced Wistar rats was found to be (i.n)CSNEROP group>(i.n)SolnROP group>(i.v)SolnROP group>haloperidol group. CONCLUSIONS: Finally, the investigation demonstrated that intranasal delivery of mucoadhesive nanocarrier might play as a potential candidate in the management of Parkinson's disease and related brain disorders.


Subject(s)
Brain/drug effects , Dopamine Agonists/pharmacokinetics , Dopamine Agonists/therapeutic use , Indoles/pharmacokinetics , Indoles/therapeutic use , Parkinson Disease/drug therapy , Animals , Brain/metabolism , Chemistry, Pharmaceutical , Disease Models, Animal , Dopamine/metabolism , Dopamine Agonists/blood , Dopamine Antagonists/blood , Dopamine Antagonists/pharmacology , Drug Delivery Systems , Glutathione/metabolism , Haloperidol/blood , Haloperidol/pharmacology , Indoles/blood , Microscopy, Confocal , Microscopy, Electron, Scanning Transmission , Motor Activity/drug effects , Nanoparticles/therapeutic use , Psychomotor Performance , Radionuclide Imaging , Rats , Rats, Wistar , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolism , Time Factors
16.
Am J Vet Res ; 76(2): 155-60, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25629913

ABSTRACT

OBJECTIVE: To determine the pharmacokinetics of pergolide after IV administration to horses. ANIMALS: 8 healthy adult horses. PROCEDURES: Pergolide mesylate was administered IV at a dose of 20 µg/kg (equivalent to 15.2 µg of pergolide/kg) to each horse, and blood samples were collected over 48 hours. Pergolide concentrations in plasma were determined by means of high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were determined on the basis of noncompartmental methods. RESULTS: After IV administration of pergolide, mean ± SD clearance, elimination half-life, and initial volume of distribution were 959 ± 492 mL/h/kg, 5.64 ± 2.36 hours, and 0.79 ± 0.32 L/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: With an elimination half-life of approximately 6 hours, twice-daily dosing may be more appropriate than once-daily dosing to reduce peak-trough fluctuation in pergolide concentrations. Further pharmacodynamic and pharmacokinetic studies of pergolide and its metabolites will be necessary to determine plasma concentrations that correlate with clinical effectiveness to determine the therapeutic range for the treatment of pituitary pars intermedia dysfunction.


Subject(s)
Dopamine Agonists/pharmacokinetics , Horses/metabolism , Pergolide/pharmacokinetics , Administration, Intravenous , Animals , Chromatography, Liquid/veterinary , Dopamine Agonists/administration & dosage , Dopamine Agonists/blood , Male , Pergolide/administration & dosage , Pergolide/blood , Tandem Mass Spectrometry/veterinary
17.
Basic Clin Pharmacol Toxicol ; 116(6): 468-75, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25370785

ABSTRACT

Apomorphine is a non-selective dopamine D1/D2 receptor agonist, which has been used for patients with Parkinson's disease and reported to induce QT interval prolongation and cardiac arrest. To clarify their causal link, we assessed the cardiovascular and pharmacokinetic profile of apomorphine with the halothane-anaesthetized canine model (n = 4), whereas pro-arrhythmic potential of apomorphine was analysed with the chronic atrioventricular block canine model (n = 4). In the halothane-anaesthetized model, 0.01 mg/kg, i.v. of apomorphine hydrochloride over 10 min., providing about 10 times of its therapeutic concentration, increased the heart rate and ventricular contraction; 0.1 mg/kg over 10 min., providing about 100 times of the therapeutic, prolonged the ventricular effective refractory period; and 1 mg/kg over 10 min., providing about 1000 times of the therapeutic, decreased the ventricular contraction, mean blood pressure and cardiac output together with the intraventricular conduction delay and prolongation of the effective refractory period, whereas the left ventricular end-diastolic pressure, atrioventricular nodal conduction or ventricular repolarization were hardly affected. Meanwhile, in the atrioventricular block model, 1 mg/kg, i.v. of apomorphine hydrochloride over 10 min. neither prolonged the QT interval nor induced torsade de pointes. These results suggest that apomorphine may possess a wide margin of cardiovascular safety contrary to our expectations.


Subject(s)
Apomorphine/toxicity , Dopamine Agonists/toxicity , Long QT Syndrome/chemically induced , Administration, Intravenous , Anesthesia , Animals , Apomorphine/blood , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/physiopathology , Atrioventricular Block/chemically induced , Atrioventricular Block/physiopathology , Blood Pressure/drug effects , Coronary Circulation/drug effects , Dogs , Dopamine Agonists/blood , Dose-Response Relationship, Drug , Electrocardiography, Ambulatory , Female , Hemodynamics/drug effects , Male
18.
Nihon Shinkei Seishin Yakurigaku Zasshi ; 34(5-6): 127-32, 2014 Nov.
Article in Japanese | MEDLINE | ID: mdl-25536763

ABSTRACT

This review discusses the relationship between therapeutic plasma concentrations of antiparkinson dopamine agonists (rotigotine, pergolide, cabergoline, apomorphine, bromocriptine, ropinirole, pramipexole, and talipexole) and their in vitro pharmacology at dopamine D1, D2 and D3 receptors. A significant correlation was found between therapeutic plasma concentrations of these dopamine agonists and their agonist potencies (EC50) at D2 receptors, although no such correlation existed at D1 or D3 receptors, suggesting that D2 receptors could be the primary and common target for the antiparkinson action of all dopamine agonists. However, D1 receptor stimulation is also important for maintaining swallowing reflex, bladder function and cognition. In particular, continuous D1 and D2 receptor stimulation may be reduced to low levels among Parkinson's disease patients. Our findings revealed therapeutic plasma concentrations of rotigotine were similar to its agonist potencies at both D1 and D2 receptors. Thus, rotigotine may be beneficial for the treatment of Parkinson's disease patients in that this dopamine agonist has the potential of continuous stimulation of both D1 and D2 receptors in the clinical setting.


Subject(s)
Antiparkinson Agents/blood , Dopamine Agonists/blood , Dopamine/metabolism , Parkinson Disease/blood , Receptors, Dopamine/metabolism , Animals , Antiparkinson Agents/administration & dosage , Dopamine Agonists/pharmacology , Humans , Parkinson Disease/drug therapy
19.
Eur J Pharm Biopharm ; 88(3): 586-93, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25173087

ABSTRACT

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.


Subject(s)
Dopamine Agonists/administration & dosage , Drug Delivery Systems , Tetrahydronaphthalenes/administration & dosage , Thiophenes/administration & dosage , Administration, Cutaneous , Chemical Phenomena , Clinical Trials as Topic , Dopamine Agonists/blood , Dopamine Agonists/chemistry , Dopamine Agonists/therapeutic use , Humans , Molecular Structure , Parkinson Disease/drug therapy , Restless Legs Syndrome/drug therapy , Tetrahydronaphthalenes/blood , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/therapeutic use , Thiophenes/blood , Thiophenes/chemistry , Thiophenes/therapeutic use , Transdermal Patch
20.
Eur J Drug Metab Pharmacokinet ; 39(3): 155-63, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24052490

ABSTRACT

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.


Subject(s)
Dopamine Agonists/pharmacokinetics , Liver Diseases/metabolism , Liver/metabolism , Tetrahydronaphthalenes/pharmacokinetics , Thiophenes/pharmacokinetics , Administration, Cutaneous , Adult , Area Under Curve , Biological Availability , Biotransformation , Dopamine Agonists/administration & dosage , Dopamine Agonists/adverse effects , Dopamine Agonists/blood , Dopamine Agonists/urine , Humans , Hungary , Liver Diseases/diagnosis , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Risk Assessment , Severity of Illness Index , Slovakia , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/blood , Tetrahydronaphthalenes/urine , Thiophenes/administration & dosage , Thiophenes/adverse effects , Thiophenes/blood , Thiophenes/urine , Transdermal Patch
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