Inter- and intra-individual variation in L-dopa pharmacokinetics in the treatment of Parkinson's disease.

Parkinson's disease is a neurodegenerative, slowly progressive, age-related disorder. Numerous medications have been developed for its treatment and the prognosis of the disorder has improved greatly over recent years. However, the effects of medicines are variable among patients, and there are also daily fluctuations in the effects of medications in the same person. The factors that cause individual variations in the effects of medicines, the causes, and strategies to cope with these fluctuations are reviewed.

[Subjective syndromes of perimenopausal women in China assessed using a multidimensional inventory: a canonical correlation analysis between the severity of subjective symptoms and the self-efficacy score].

We assessed subjective menopausal symptoms in Chinese women using a multidimensional inventory that covered five dimensions: sexual function, mental condition, interpersonal anxiety, autonomic balance, and other subjective symptoms. We elucidated its relationship with the score on a self-efficacy scale. We surveyed subjective menopausal symptoms in 281 women between 40 and 59 years old, who resided in an urban area in northwest China using both 60-item self-reported subjective menopausal symptoms and 16-item general self-efficacy scales. The dimensional structure was evaluated statistically using confirmatory factor analysis. The five-factor model appeared to fit the data, with sufficient validity (RMSEA = 0.075) and the instrument had appropriate internal consistency, with an average Cronbach's alpha of 0.964. The subjects were divided into pre-menopause, menopause-transition, and post-menopause groups based on the number of menstruations per year. Factorial analysis of variance revealed a significant difference in the severity of subjective symptoms among the three groups. The correlation between the severity of subjective symptoms and the self-efficacy score was determined using canonical correlation analysis. All factors except sexual function had a negative influence on the self-efficacy score.

[Development of a new multidimensional inventory to assess subjective symptoms in perimenopause women, using a confirmatory factor analysis].

The multidimensional inventory is a 60-item self-report instrument designed to measure perimenopausal subjective symptoms. It covers the following 5 dimentions: sexual function, mental condition, interpersonal anxiety, autonomic balance, and the other subjective symptoms. We conducted a survey of perimenopausal subjective symptoms in 670 women between 40 and 59 years old, who were living in an urban (n=329) or rural area (n=341). The dimensional structure was determined statistically using confirmatory factor analysis. The hypothesized five-factor model appeared to fit the data in all samples tested, with enough validity (RMSEA=0.050, GFI=0.802, and AGFI=0.786). The instrument was found to have appropriate internal consistency, with an average Chronbach's alpha coefficient of 0.959. There was no significant difference in the severity of subjective symptoms between the residential areas. We found a positive correlation between the severity of subjective symptoms and the level of stress (urban women: r=0.465, P<0.01; rural women: r=0.455, P<0.01). Our findings suggest that the new multidimentional inventory may provide a useful instrument for evaluating the effect of a drug on subjective symptoms in perimenopausal women.

Effect of clarithromycin on the pharmacokinetics of cabergoline in healthy controls and in patients with Parkinson's disease.

Cabergoline is used in the treatment of Parkinson's disease (PD). Clarithromycin is a potent inhibitor of CYP3A4 and P-glycoprotein and is often co-administered with cabergoline in usual clinical practice. We studied the effect of clarithromycin co-administration on the blood concentration of cabergoline in healthy male volunteers and in PD patients. Study 1: Ten healthy male volunteers were enrolled and were randomized to take a single oral dose of cabergoline (1 mg/day) for 6 days or a single oral dose of cabergoline plus clarithromycin (400 mg/day) for 6 days. Study 2: Seven PD patients receiving stable cabergoline doses were enrolled. They were evaluated for the plasma cabergoline concentration before and after the addition of clarithromycin 400 mg/day for 6 days, and again 1 month after discontinuation of clarithromycin. The dose and duration of clarithromycin were decided according to usual clinical practice. In healthy male volunteers, mean Cmax and AUC(0-10 h) of cabergoline increased to a similar degree during co-administration of clarithromycin. Mean plasma cabergoline concentration over 10 h post-dosing increased 2.6-fold with clarithromycin co-administration. In PD patients, plasma cabergoline concentration increased 1.7-fold during clarithromycin co-administration. Co-administration with clarithromycin may increase the blood concentration of cabergoline in healthy volunteers and in PD patients.

[Inter- and intraindividual pharmacokinetic variations in the treatment of Parkinson's disease].

In the treatment of Parkinson's disease, levodopa, DCI, MAO-B inhibitor, COMT inhibitors, dopamine receptor agonists, amantadine, anticholinergics have been applied and new drugs are being developed. Levodopa is still the golden standard in the treatment of Parkinson's disease. The study on levodopa bioavailability showed 3-4 times differences in individual patients. Drug-food interactions are prominent in levodopa. Low protein food increased levodopa bioavailability and improved no ON or delayed ON in the treatment of Parkinson's disease. Vitamine C or magnesium did not alter the bioavailability of levodopa. The bioavailability of levodopa between the levodopa/carbidioa (100/12.5) group and the levodopa/benserazide (100/25) group was studied in patients with Parkinson's disease by population PK study. C(max) of levodopa in levodeopa/benserazide group was twice as high as in levodopa/carbidopa group. Domperidone, a dopamine receptor antagonist applied as an antiemetic inceases vowel movement. The effect of domperidone on levodopa bioavailability was studied, and the combination of domperidone with levodopa increased AUC of levodopa. Clarythromycin or grape fruit juice inhibits both of CYP3A4 and P-glycoprotein which work on metabolism and absorption of drugs. Coadministration of clarythromycin with ergot alkaloids such as cabergoline or bromocriptine increased the AUC up to 2-3 times. Amantadine is excreted through kidney without being metabolized and renal function is the most important factor in the blood concentration of amantadine. In elder women with the body weight of 50 kg or less, creatinine clearance is less than 50 ml/min even though the serum creatinine is within the normal range. Selegiline is metabolized through CYP2D6 and 3A4. Coadministration of qunidine, cimetidine, maclorides, antifungals, grape fruit juice increase the bioavailability of selegiline and may augment the antiparkinsonian effect.

Pharmacokinetics of L-dopa in plasma and extracellular fluid of striatum in common marmosets.

L-3, 4-Dihydroxyphenylalanine (L-dopa) has been widely used for the treatment of Parkinson's disease (PD), but its pharmacokinetics in the striatum have hardly been investigated, especially in primates. In this study, we examined the concentration of L-dopa in plasma and in the extracellular fluid (ECF) of the striatum in common marmosets using microdialysis and high-performance liquid chromatography (HPLC) with electrochemical detection. With a clinically therapeutic dosage of L-dopa/benserazide (20/5 mg/kg, p.o.), the t(max) of L-dopa was 30 min in plasma and 60-90 min in ECF of striatum. Mean C(max) was 20.3 microM in plasma and 442.9 nM in ECF of striatum, which is about 2.2% of that in plasma. The L-dopa concentration in ECF is much lower than those previously applied during in vivo studies for L-dopa toxicity.