AbstractLevodopa is a promising candidate for administration via the transdermal route because it exhibits a short plasma half-life and has a small window of absorption in the upper section of the small intestine. The aim of this study was to prepare stable levodopa transdermal patches. Both xanthan gum and Carbopol 971 polymers were selected with ethylcellulose constituting the backing layer of the prepared patches. The effect of adding β-cyclodextrin on the prepared patches was investigated. The uniformity in thickness, weight and content of the studied patches was acceptable. Physicochemical characterization revealed that there was no interaction between levodopa and the applied polymer. The results proved that levodopa precipitated as an amorphous form in carbopol patches. Controlled drug release was achieved for all the tested patches over a 6?h period. However, increased permeation was achieved for the carbopol patches. Although cyclodextrin did not enhance levodopa permeation, the stability study confirmed that levodopa stability was enhanced when complexed with β-cyclodextrin. The cumulative amount of drug released from carbopol patches is slightly higher than that of xanthan patches. The optimal stability was achieved in the carbopol/levodopa:β-cyclodextrin patch. The levodopa-β-cyclodextrin complex was successfully characterized using X-ray diffraction, NMR analysis and molecular dynamics simulations. In conclusion, carbopol/levodopa:β-cyclodextrin patches can be considered as a promising stable and effective transdermal drug-delivery system. 相似文献
Background: PD0013 was a 6-month noninterventional study in clinical practice comparing effectiveness/tolerability of rotigotine+levodopa in younger (<70 years) vs. older (≥70 years) Parkinson’s disease (PD) patients.
Methods: Patients previously received levodopa for ≥6 months as monotherapy/in combination with another dopamine-agonist (DA). Primary variable: Unified PD Rating Scale (UPDRS) Part-II change from baseline to end-of-observation-period (EOP).
Results: 91 younger/99 older patients started rotigotine; 68 younger/62 older patients completed the study. Most switched from levodopa+another DA. Addition of rotigotine as first DA was more common in older patients (20.2% vs.15.4%). Mean ± SD rotigotine-exposure: 6.1 ± 3.4 mg/24h younger vs. 4.9 ± 2.4 mg/24h older. Eleven patients changed levodopa dose.
At EOP, improvement in mean UPDRS-II was greater in younger patients (p = 0.0289). UPDRS-II responder-rate (≥20% decrease in UPDRS-II score) was higher in younger patients (42.3% vs. 25.9%). Improvement across age groups was similar on PD Sleep Scale-2 and Clinical Global Impressions-Improvement Scale. Adverse drug reactions (ADRs), and discontinuations because of ADRs, were more common among older patients. There were no new safety signals.
Conclusions: Despite low rotigotine doses, when added to levodopa/switched from levodopa+another DA, rotigotine led to greater improvement in UPDRS-II in younger patients (<70 years). Individual patient data revealed clinically meaningful improvements in UPDRS-II in both groups. 相似文献
Six monkeys were rendered hemiparkinsonian with a unilateral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These
monkeys displayed ipsilateral circling under basal conditions, and after dopaminergic stimulation with levodopa they decreased
their ipsilateral circling and started turning to the contralateral side of their lesion. The effect of 17β-estradiol and
dehydroepiandrosterone (DHEA) was investigated in these animals. 17β-Estradiol (0.1 mg/kg) added to a threshold dose of levodopa
significantly potentiated contralateral circling (mean/30 min) compared to saline or threshold levodopa treatment whereas
the duration of circling remained unchanged. DHEA (1–15 mg/kg) alone induced contralateral circling, compared to saline treatment,
for 90 min. In addition, DHEA (1–15 mg/kg) potentiated the contralateral circling (mean/30 min) induced by a threshold dose
of levodopa and did not change the duration of levodopa circling. A maximal response was observed with 1 or 5 mg/kg of DHEA
combined with levodopa depending on the monkey. No correlation was found between the dose for the maximal DHEA response and
baseline circling or threshold dose of levodopa. These results suggest that 17β-estradiol or DHEA is able to potentiate locomotor
activity of hemiparkinsonian monkeys. The DHEA doses investigated are similar to those presently used in humans. DHEA may
be an alternative to 17β-estradiol to modulate dopaminergic activity. 相似文献
Parkinson's disease (PD) is characterized by widespread neural interactions in cortico‐basal‐ganglia networks primarily in beta oscillations (approx. 10–30 Hz), as suggested by previous findings of levodopa‐modulated interhemispheric coherence between the bilateral subthalamic nuclei (STN) in local field potential recordings (LFPs). However, due to confounding effects of volume conduction the existence of ‘genuine’ interhemispheric subcortical coherence remains an open question. To address this issue we utilized the imaginary part of coherency (iCOH) which, in contrast to the standard coherence, is not susceptible to volume conduction. LFPs were recorded from eight patients with PD during wakeful rest before and after levodopa administration. We demonstrated genuine coherence between the bilateral STN in both 10–20 and 21–30 Hz oscillations, as revealed by a non‐zero iCOH. Crucially, increased iCOH in 10–20 Hz oscillations positively correlated with the worsening of motor symptoms in the OFF medication condition across patients, which was not the case for standard coherence. Furthermore, across patients iCOH was increased after levodopa administration in 21–30 Hz oscillations. These results suggest a functional distinction between low and high beta oscillations in STN‐LFP in line with previous studies. Furthermore, the observed functional coupling between the bilateral STN might contribute to the understanding of bilateral effects of unilateral deep brain stimulation. In conclusion, the present results imply a significant contribution of time‐delayed neural interactions to interhemispheric coherence, and the clinical relevance of long‐distance neural interactions between bilateral STN for motor symptoms in PD. 相似文献
Levodopa‐induced dyskinesias (LIDs) and graft‐induced dyskinesias (GIDs) are serious and common complications of Parkinson's disease (PD) management following chronic treatment with levodopa or intrastriatal transplantation with dopamine‐rich foetal ventral mesencephalic tissue, respectively. Positron emission tomography (PET) molecular imaging provides a powerful in vivo tool that has been employed over the past 20 years for the elucidation of mechanisms underlying the development of LIDs and GIDs in PD patients. PET used together with radioligands tagging molecular targets has allowed the functional investigation of several systems in the brain including the dopaminergic, serotonergic, glutamatergic, opioid, endocannabinoid, noradrenergic and cholinergic systems. In this article the role of PET imaging in unveiling pathophysiological mechanisms underlying the development of LIDs and GIDs in PD patients is reviewed. 相似文献
Introduction: We compared the role of subthalamic nucleus deep brain stimulation (STN‐DBS) in the management of medically refractory idiopathic Parkinson's disease in patients with relatively young onset (<40 years of age) Parkinson's disease (YOPD) and patients with relatively late onset Parkinson's disease (≥56 years of age, rLOPD). Methods: A total of 33 patients with YOPD (18 patients, median age 32.5 years, range, 20–40 years) and rLOPD (15 patients, median age 58.0 years, range, 56.0–67.0 years) underwent STN‐DBS between May 2000 and May 2008. We divided the patients into YOPD and rLOPD as the age of disease onset. The median follow‐up period was 43 months (range, 12–95 months). We assessed Hoehn and Yahr stages, activities of daily living, and Unified Parkinson's Disease Rating Scale (UPDRS) motor scales (III) for all patients preoperatively and at six months postoperatively. We measured levodopa equivalent doses (LEDD) and stimulation parameters preoperatively, six months postoperatively, and 12 months postoperatively. Results: There were no significant differences in UPDRS motor scales between two groups at preoperative and six‐month postoperative drug off/stim on, but UPDRS III was lower in rLOPD at six‐month postoperative drug on/stim on state. A significant difference was noted in the improvement of UPDRS III between two groups for preoperative drug off and drug on conditions, but no difference was seen between two groups in a comparison of drug off/stim on vs. drug on/stim on conditions. Stimulation parameters and postoperative LEDD were not different between the two groups. Preoperative dyskinesia was more common in YOPD patients and, psychotic problems were more common in rLOPD patients. Conclusions: Patients with YOPD and rLOPD exhibited comparable UPDRS motor scores and LEDD six months postoperatively. Levodopa could be prescribed at optimum doses following STN‐DBS in patients with YOPD as abnormal movements are better controlled following STN‐DBS implantation. Stimulation parameters were not different between the two groups. Our results suggest the age of onset does not influence response to STN‐DBS Parkinson's disease patients. 相似文献