Hirotaka Iwaki

Coadministration of domperidone increases plasma levodopa concentration in patients with Parkinson disease.

ObjectivesThe aim of this study was to examine the effects of the peripheral dopamine D2-receptor antagonist, domperidone, on the plasma kinetics of levodopa in patients with Parkinson disease (PD). MethodsIn a randomized crossover design, 18 hospitalized patients with PD received a single dose of levodopa/benserazide, 100/25 mg, with or without domperidone, 10 mg, under fasting conditions. Plasma levodopa concentrations were determined up to 3 hours after dose administration. ResultsMean ± SEM levodopa maximum plasma concentration (Cmax) (14.1 ± 2.9 vs 9.7 ± 1.6 &mgr;mol/L; P < 0.01), plasma concentration at 30 min (C30 min) (13.7 ± 3.0 vs 8.1 ± 2.0 &mgr;mol/L; P < 0.01), and area under the plasma concentration-time curve from 0 to 3 hours (AUC0–3 hr) (15.9 ± 3.1 vs 12.1 ± 2.4 &mgr;mol/L · hour; P < 0.05) were significantly higher after coadministration of levodopa with domperidone compared to levodopa alone. Thus, domperidone increased levodopa Cmax and AUC0–3 hr by 1.5- and 1.3-fold, respectively. There were no exacerbations of PD by concomitant domperidone administration. ConclusionsThe results demonstrate that coadministration of domperidone increased the bioavailability of levodopa. This may be the reason for no exacerbation of PD in concomitant administration of domperidone, a dopamine D2-receptor blocker.

Zonisamide up-regulated the mRNAs encoding astrocytic anti-oxidative and neurotrophic factors

Zonisamide has been proven as an effective drug for the recovery of degenerating dopaminergic neurons in the animal models of Parkinsons disease. However, several lines of evidence have questioned the neuroprotective capacity of zonisamide in animal models of Parkinsons disease. Although it suppresses dopaminergic neurodegeneration in animal models, the cellular and molecular mechanisms underlying the effectiveness of zonisamide are not fully understood. The current study demonstrates the effects of zonisamide on astrocyte cultures and two 6-hydroxydopamine-induced models of Parkinsons disease. Using primary astrocyte cultures, we showed that zonisamide up-regulated the expression of mRNA encoding mesencephalic astrocyte-derived neurotrophic factor, vascular endothelial growth factor, proliferating cell nuclear antigen, metallothionein-2, copper/zinc superoxide dismutase, and manganese superoxide dismutase. Similar responses to zonisamide were found in substantia nigra where the rats were pre-treated with 6-hydroxydopamine. Notably, pharmacological inhibition of 6-hydroxydopamine-induced toxicity by zonisamide pre-treatment was also confirmed using rat mesencephalic organotypic slice cultures of substantia nigra. In addition to this, zonisamide post-treatment also attenuated the nigral tyrosine hydroxylase-positive neuronal loss induced by 6-hydroxydopamine. Taken together, these studies demonstrate that zonisamide protected dopamine neurons in two Parkinsons disease models through a novel mechanism, namely increasing the expression of some important astrocyte-mediated neurotrophic and anti-oxidative factors.

Effect of nicotine on the pharmacokinetics of levodopa.

ObjectivesSome patients with Parkinson disease improved their symptoms on treatment with nicotine patch or gum. Nicotine has also been studied for its antidyskinetic effect on levodopa-induced dyskinesia. We determined the effects of nicotine on levodopa pharmacokinetics and gastric emptying in healthy subjects and on levodopa transport in Caco-2 monolayers in vitro. MethodsHealthy subjects received transdermal nicotine patch application followed by oral levodopa/benserazide, 100/25 mg, in a fasting state and with enteral nutrition. Levodopa pharmacokinetics was determined, and gastric emptying was evaluated by carbon 13 (13C)-labeled acetic acid breath testing. In vitro studies using intestinal Caco-2 cell monolayers evaluated whether the intestinal transport of levodopa was affected by nicotine and its metabolite, cotinine. ResultNicotine did not increase mean plasma concentration significantly during fasting or with enteral nutrition, although the extent of levodopa absorption was reduced by 34% to 60% in some individuals and the mean plasma concentration of levodopa was statistically decreased by nicotine in subjects who received enteral nutrition. However, gastric parameters were not significantly affected by nicotine. Nicotine and cotinine at 0.1 &mgr;mol/L significantly reduced levodopa uptake by Caco-2 cells (P < 0.01). ConclusionsWe found that nicotine reduced plasma levodopa concentration in some healthy subjects but with no alteration of gastric emptying rate. In vitro, nicotine inhibited levodopa transport by Caco-2 cell monolayers in an &agr;-methyl amino isobutyric acid-independent, 2-amino-norbornanecarboxylic acid-dependent manner. These results suggest that nicotine may inhibit the transport of levodopa by the system L-amino acid transporter.

Pharmacokinetics of levodopa/benserazide versus levodopa/carbidopa in healthy subjects and patients with Parkinson's disease

There are two formulations of levodopa in Japan and a few other countries, levodopa/benserazide 100/25 mg and levodopa/carbidopa 100/10 mg, which have been generally regarded as interchangeable in Parkinsons disease treatment.

Evaluation of the effect of pregabalin on simulated driving ability using a driving simulator in healthy male volunteers

Pregabalin, a novel agent for treating partial epilepsy and peripheral neuropathic and central pain, was studied for its effect on driving performance in healthy volunteers. Sixteen healthy male volunteers who drove regularly were enrolled in a double-blind, parallel-group, placebo-controlled study assessing the effect of pregabalin on driving performance. Subjects received an oral dose of pregabalin 75 mg or placebo, and a second dose 12 hours later. A driving simulator was used to test simple and complicated braking reaction time, and simple and complicated steering-wheel techniques before the first dose, and 1 hour and 3 hours after the second dose of pregabalin or placebo. The effect of training during the driving test on the driving performance of each group was also evaluated. There were no statistically significant differences in driving performance between the pregabalin and the placebo groups. However, the pregabalin group showed no significant improvement in steering-wheel skills with training, whereas the placebo group showed a significant (P<0.05) improvement with training. In this study using a driving simulator, pregabalin did not impair driving performance but mildly reduced the training effects of driving experiments. Although pregabalin caused sleepiness, it had no severe effect on driving ability after a second dose of 75 mg after the initial introduction of pregabalin.

One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan

BACKGROUND Epidemiological studies have repeatedly reported that increased serum urate level is associated with a slower progress of Parkinsons disease (PD). The urate precursor, inosine, raises the serum urate level and is therefore a candidate for a disease modifying treatment. However, an elevated serum urate level is a risk factor for gout, urolithiasis, and cardiovascular diseases. Although there have been previous clinical studies, the use of inosine in a clinical setting is still limited, and its safety is unclear, especially in an Asian population. METHODS We conducted a single-arm, single-center clinical trial to assess the safety of inosine for PD patients with relatively low urate levels. After informed consent, 10 subjects were orally administered inosine to maintain a target urate level between 6.0mg/dl and 8.0mg/dl for one year. All adverse effects were recorded and categorized by severity. Also, the efficacy of using inosine to raise the serum urate level was reported. RESULTS We did not observe any adverse events requiring termination or reduction of the study drug, although uric acid crystalluria was transiently observed in a single subject. An inosine dosage of 1070 (SD=501) mg/day significantly raises the urate level from 3.5 (0.84)mg/dl at baseline to 6.68 (1.11)mg/dl at the 52nd week. CONCLUSIONS Inosine was safely used for one year and effectively raised urate levels in a small group of subjects. Our study is the first report to use inosine for patients with PD in an Asian population.

Acute ischemic stroke associated with nephrotic syndrome: Incidence and significance — Retrospective cohort study

We report 10 cases with arterial ischemic stroke (AIS) with nephrotic syndrome (NS), and clarified its incidence and clinical characteristics. The patients having albumin less than 3.0 g/dl and serum cholesterol greater than 250 mg/dl at the same time were retrospectively screened from 11,161 cases of stroke. Furthermore, the patients of AIS showing heavy proteinuria were selected. The 10 cases were diagnosed as AIS with NS. Its incidence was 0.09% of all kinds of stroke and 0.12% of AIS. Their subtypes were 6 large-artery atherosclerosis, 3 small-vessel occlusion, and 1 cardioembolism. We carried out a retrospective cohort study to assess the association between NS and atherosclerosis progression in AIS patients. Seven AIS patients with NS due to diabetic nephropathy (cases; NS group) were compared with patients with AIS and diabetes mellitus (DM) without NS (control group). Control group subjects were matched in a 2:1 ratio to cases by age, sex, use of medications for DM, and hemoglobin A1c (HbA1c) level. The NS group had high cerebral artery atherosclerosis scores, especially in the anterior circulation. The NS group demonstrated atherosclerosis of the internal carotid and lower extremity arteries, although there were no statistical differences between the two groups. Study subjects had high serum fibrinogen and D-dimer levels, suggesting that AIS patients with NS have a greater degree of hypercoagulability than AIS patients without NS.

The association between restless legs syndrome and premotor symptoms of Parkinson's disease

BACKGROUND Previous studies regarding the association between restless legs syndrome (RLS) and Parkinsons disease (PD) have produced contradictory results. However, the time frame between them has varied across these studies, and also, the longitudinal trajectroy of RLS symptoms has not been considered. OBJECTIVE To investigate if transient or continuous/recurrent RLS identified by questionnaire are associated with the premotor symptoms of PD. METHODS The study population comprised 16,636 men in the Health Professional Follow-Up Study, who answered questions regarding RLS symptoms in both 2002 and 2008, and were not diagnosed with PD. Outcomes were self-reported constipation, possible REM sleep behavior disorder (pRBD) in 2012 and smell identification test score in 2014. RESULTS RLS was associated with increased odds of constipation, but only continuous/recurrent RLS status was associated with higher odds of having pRBD. RLS was not significantly associated with olfactory scores. CONCLUSION In this large-scale longitudinal study, we found moderate associations between the presence of RLS and increased odds of having constipation and pRBD.

The Clinical Findings Useful for Driving Safety Advice for Parkinson's Disease Patients

Objective We conducted a study to obtain information that could be used to provide Parkinsons disease (PD) patients with appropriate advice on safe driving. Methods Consecutive PD patients who visited our office were studied. Among these patients, those who had experienced driving after being diagnosed with PD were interviewed by neurologists and a trained nurse to investigate their previous car accidents, motor function, cognitive function, sleepiness, levodopa equivalent dose (LED), and emotional dysregulation. The rates of major car accidents before and after the onset of PD were compared. Results Fifteen patients had experienced a major car accident resulting in human injury or serious property damage since the onset of PD. When the rates of major car accidents before and after the onset of PD were compared, the ratio was 4.3 [95% confidence interval (CI) 1.9-9.7]. The incidence of accidents after the onset of PD was correlated with age, disease duration, LED, the cognitive function Mini-Mental Scale Examination (MMSE), Japanese translation of the Montreal Cognitive Assessment (MoCA-J), but not the motor symptom score [Unified Pankinsons disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinsons Disease (QUIP) score was also higher in patients with major car accidents. Conclusion The severity of symptoms (Hoehn-Yahr classification), cognitive function, and disease duration were expected to be risk factors for car accidents. However, the motor symptom score (UPDRS part III) was not associated with the incidence of major car accidents. In addition to a low cognitive function and the severity of symptoms, the QUIP score might be an independent factor that can be referenced when advising PD patients to refrain from driving.

Topiramate-induced weight loss depends on level of intellectual disability in patients with epilepsy

OBJECTIVE Intellectual disability (ID) is associated with weight gain caused by antiepileptic drugs such as valproic acid. The present study analyzed the relationship between ID and weight loss caused by topiramate (TPM). METHODS Seventy-eight patients with epilepsy (35 women, aged 18 to 70years) were enrolled in this prospective study. Body weight was measured before and 1, 6, 12, and 18months after initiation of TPM treatment. Both patients and caregivers were provided information about TPM-related weight loss. The patients were divided into the group with no or mild ID (intelligence quotient >50) and the group with moderate to profound ID (intelligence quotient ≤50). RESULTS Body weight of both groups significantly decreased until 6months but stabilized after 12months. Weight loss at 6, 12, and 18months was significantly greater in the group with no or mild ID than in the group with moderate to profound ID. Body weight change at 18months was correlated with intellectual levels (β=0.274, p=0.011) and baseline body mass index (β=-0.322, p=0.002) by multiple linear regression analysis. CONCLUSIONS The present study suggests that the pattern of weight loss during TPM administration differs according to intellectual levels. Patients with ID maintained their body weight. Weight loss due to TPM might be weakened by caregiver control of food intake or inactivity.