Interactive effects of GPI stimulation and levodopa on postural control in Parkinson's disease.

INTRODUCTION: Postural instability is a major source of disability in idiopathic Parkinson's disease (IPD). Deep brain stimulation of the globus pallidus internus (GPI-DBS) improves clinician-rated balance control but there have been few quantitative studies of its interactive effects with levodopa (L-DOPA). The purpose of this study was to compare the short-term and interactive effects of GPI-DBS and L-DOPA on objective measures of postural stability in patients with longstanding IPD. METHODS: Static and dynamic posturography during a whole-body leaning task were performed in 10 IPD patients with bilateral GPI stimulators under the following conditions: untreated (OFF); L-DOPA alone; DBS alone; DBS+L-DOPA, and in 9 healthy Control subjects. Clinical status was assessed using the UPDRS and AIMS Dyskinesia Scale. RESULTS: Static sway was greater in IPD patients in the OFF state compared to the Control subjects and was further increased by L-DOPA and reduced by GPI-DBS. In the dynamic task, L-DOPA had a greater effect than GPI-DBS on improving Start Time, but reduced the spatial accuracy and directional control of the task. When the two therapies were combined, GPI-DBS prevented the L-DOPA induced increase in static sway and improved the accuracy of the dynamic task. CONCLUSION: The findings demonstrate GPI-DBS and L-DOPA have differential effects on temporal and spatial aspects of postural control in IPD and that GPI-DBS counteracts some of the adverse effects of L-DOPA. Further studies on larger numbers of patients with GPI stimulators are required to confirm these findings and to clarify the contribution of dyskinesias to impaired dynamic postural control.

Modulation of corticomotor excitability after maximal or sustainable-rate repetitive finger movement is impaired in Parkinson’s disease and is reversed by levodopa

Objectives: In healthy subjects, fatiguing exercises induce a period of post-exercise corticomotor depression (PECD) that is absent in Parkinson’s disease (PD). Our objective is to determine the time-course of corticomotor excitability changes following a 10-s repetitive index finger flexion–extension task performed at maximal voluntary rate (MVR) and a slower sustainable rate (MSR) in PD patients OFF and ON levodopa.
Methods: In 11 PD patients and 10 healthy age-matched controls, motor evoked potentials (MEPs) were recorded from the extensor indicis proprius (EIP) and first dorsal interosseous (FDI) muscles of the dominant arm immediately after the two tasks and at 2-min intervals for 10 min.
Results: In the OFF condition the PECD was absent in the two test muscles after both the MVR and MSR tasks. In the ON condition finger movement kinematics improved and a period of PECD comparable to that in controls was present after both tasks.
Conclusion: The absence of PECD in PD subjects off medication indicates a persisting increase in corticomotor excitability after non-fatiguing repetitive finger movement that is reversed by levodopa.

Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.
Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.
Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).
In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Comparing kinematic changes between a finger-tapping task and unconstrained finger flexion-extension task in patients with Parkinson's disease.

Repetitive finger tapping is a well-established clinical test for the evaluation of parkinsonian bradykinesia, but few studies have investigated other finger movement modalities. We compared the kinematic changes (movement rate and amplitude) and response to levodopa during a conventional index finger-thumb-tapping task and an unconstrained index finger flexion-extension task performed at maximal voluntary rate (MVR) for 20 s in 11 individuals with levodopa-responsive Parkinson's disease (OFF and ON) and 10 healthy age-matched controls. Between-task comparisons showed that for all conditions, the initial movement rate was greater for the unconstrained flexion-extension task than the tapping task. Movement rate in the OFF state was slower than in controls for both tasks and normalized in the ON state. The movement amplitude was also reduced for both tasks in OFF and increased in the ON state but did not reach control levels. The rate and amplitude of movement declined significantly for both tasks under all conditions (OFF/ON and controls). The time course of rate decline was comparable for both tasks and was similar in OFF/ON and controls, whereas the tapping task was associated with a greater decline in MA, both in controls and ON, but not OFF. The findings indicate that both finger movement tasks show similar kinematic changes during a 20-s sustained MVR, but that movement amplitude is less well sustained during the tapping task than the unconstrained finger movement task. Both movement rate and amplitude improved with levodopa; however, movement rate was more levodopa responsive than amplitude.

Highly specific changes in antioxidant levels and lipid peroxidation in Parkinson's disease and its progression : disease and staging biomarkers and new drug targets.

There is evidence that immune-inflammatory, stress of reactive oxygen and nitrogen species (IO&NS) processes play a role in the neurodegenerative processes observed in Parkinson's disease (PD). The aim of the present study was to investigate peripheral IO&NS biomarkers in PD. We included 56 healthy individuals and 56 PD patients divided in two groups: early PD stage and late PD stage. Plasma lipid hydroperoxides (LOOH), malondialdehyde (MDA), nitric oxide metabolites (NOx), sulfhydryl (SH) groups, catalase (CAT) activity, superoxide dismutase (SOD) activity, paraoxonase (PON)1 activity, total radical trapping antioxidant parameter (TRAP) and C-reactive protein (CRP) were measured. PD is characterized by increased LOOH, MDA and SOD activity and lowered CAT activity. A combination of five O&NS biomarkers highly significantly predicts PD with a sensitivity of 94.5% and a specificity of 86.8% (i.e., MDA, SOD activity, TRAP, SH-groups and CAT activity). The single best biomarker of PD is MDA, while LOOH and SOD activity are significantly associated with late PD stage, but not early PD stage. Antiparkinson drugs did not affect O&NS biomarkers, but levodopa+carbidopa significantly increased CRP. It is suggested that MDA may serve as a disease biomarker, while LOOH and SOD activity are associated with late PD stage characteristic. New treatments for PD should not only target dopamine but also lipid peroxidation.