Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Objectives

To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC).

Methods

Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson’s disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included C_min, C_max, C_max???C_min, AUC, t_1/2, and t_max.

Results

In healthy volunteers and PD patients, mean trough levels (C_min), C_max, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to C_min, C_max, and AUC, differences between the treatments in variability of levodopa concentrations (C_max???C_min) were less consistent.

Conclusions

The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson’s disease using similar dosing regimens.     

Biological Markers of Alcohol Consumption and Effect of Calcitonin in Nonalcoholic Men: A Prospective, Double-Blind Study

The objective of this study was to study the ability of biological markers of alcohol consumption in differentiating subjects below weekly consumption of 400 or 600 g of absolute ethanol from those above, and to study the effect of intranasal calcitonin on alcohol drinking. A prospective 12-week double-blind study that used anonymous data collection with drinking diaries was done. The drug that was studied (calcitonin or placebo) was used during study weeks5–8. This study was performed at the research unit of a university hospital. The subjects consisted of 59-nine men aged 26 to 57 years who considered themselves as regular but modest drinkers and were recruited by advertisements. The measurements were obtained from monthly questionnaires and daily anonymous diaries for alcohol drinking data, and biological markers of alcohol consumption (aspartate ami-notransferase, alanine aminotransferase, y-glutamyt transpepti-dase, beta hexosaminidase, and carbohydrate deficient transferrin). The results indicated intranasal calcitonin with a dose of 2001U three times a week had no effect on alcohol use. All biological markers studied had only a modest ability to differentiate those with weekly alcohol consumption of 400 or 600 g or over from those below these limits. The areas under receiver operating characteristic (ROC) curve with the limit 400 g/week were 0.71 for aspartate aminotransferase, 0.61 for alanine aminotransferase, 0.74 for γ-glutamyl transpepti-dase, 0.68 for β-hexosaminidase, and 0.78 for carbohydrate deficient transferrin. Respective numbers for the 600-g limit were more uniform. As evaluated by ROC analysis, carbohydrate deficient transferrin was the best biological marker to find men with weekly alcohol consumption over 400 g. lntranasal salmon calcitonin had no affect on alcohol drinking.     

Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study

BACKGROUND: Clinical studies with opioid antagonists for treatment of problem drinking have mainly been conducted in specialized alcohol treatment centers, included structured psychosocial treatment, and have focused on maintaining abstinence after a period of abstinence from alcohol. METHODS: This multisite, randomized double-blind study investigated targeted nalmefene in reducing heavy drinking. Specialized alcohol treatment centers and private general practices enrolled 403 subjects (328 men, 75 women). Subjects were instructed to take nalmefene 10 to 40 mg (n=242) or placebo (n=161) when they believed drinking to be imminent. After 28 weeks, 57 subjects from the nalmefene group continued into a 24-week randomized withdrawal extension. Concomitant psychosocial intervention was minimal and no treatment goals were imposed. Alcohol consumption was recorded using the time-line follow-back method. Biochemical indicators of alcohol use were also measured. RESULTS: The mean monthly number of heavy drinking days (HDDs) during the 12-week period before inclusion was 15.5 (SD 6.9) in the nalmefene group and 16.2 (SD 6.9) in the placebo group. During treatment, the mean numbers of HDDs were 8.6 to 9.3 in the nalmefene group and 10.6 to 12.0 in the placebo group (p=0.0065). The levels of serum alanine aminotransferase and gamma-glutamyl transferase decreased in the nalmefene group compared with the placebo group (p=0.0088 and 0.0023). During the randomized withdrawal period, subjects randomized to placebo apparently returned to heavier drinking. Subjects receiving nalmefene reported more nausea, insomnia, fatigue, dizziness, and malaise than subjects on placebo. CONCLUSIONS: Nalmefene appears to be effective and safe in reducing heavy drinking, even when accompanied by minimal psychosocial support.     

BRAF V600E mutation does not predict recurrence after long-term follow-up in TNM stage I or II papillary thyroid carcinoma patients

The BRAF V600E mutation may serve as a marker of disease recurrence in well-differentiated papillary thyroid cancer (PTC). Our aim was to study if TNM stage I or II PTC patients, with and without recurrence after long-term follow-up would differ in BRAF status. BRAF status was retrospectively determined in tumour tissue from a cohort of low-risk PTC patients (n = 461) with and without recurrence after 16 years of follow-up. Initial treatment was total thyroidectomy (TTE) and radioiodine remnant ablation (RRA). Forty-six patients (9.9%) experienced disease recurrence. BRAF mutation was positive in 66% (17/26) of patients with and 68% (17/25) without recurrence (p = NS). Fifty per cent of BRAF positive and 53% of BRAF negative patients experienced disease recurrence (p = NS). Time to recurrence was 52 (range 18-144) and 36 (range 16-71) months, respectively (p = NS). Primary tumour size, nodal metastasis and local infiltration at presentation did not differ between BRAF positive and negative patients (2.0 vs 2.2 cm, 21% vs 35% and 6% vs 12%, respectively, all p = NS). Taken together, BRAF V600E is common in Finnish patients with low-risk PTC but does not predict recurrence after long-term follow-up after initial treatment with TTE and RRA.     

Eosinophilia is a favorable prognostic marker for oral cavity and lip squamous cell carcinoma

Eosinophils are frequently encountered with squamous cell carcinomas (SCC) and it has been proposed that tumor‐associated tissue eosinophilia (TATE) could be of prognostic significance in oral SCC. The aim was to evaluate TATE in 83 oral cavity and 16 lip SCCs as well as the best possible use of TATE as a prognostic marker. The number of eosinophils was counted per high power fields (HPF, ×400) in three different representative areas of the tumor and its stroma. The degree of TATE was analyzed in relation to clinicopathological features of tumors and patients’ survival (follow‐up mean 40.7 months) using Fisher's exact test. TATE was detected in 58 (70%) oral and 8 (50%) lip SCC samples. The median number of eosinophils between oral and lip SCC was different (p = 0.028) but TATE was similar per HPF (p = 0.085). Totally, 6% of lip and 21% of oral SCC patients died during the follow‐up. The patients with the higher TATE had significantly better survival than the patients with the lower TATE (p = 0.0136). The best cut‐off value predicting the survival was 4 eosinophils/HPF. TATE is a prognostic marker for oral and lip SCC: more than 4 eosinophils/HPF may predict more favorable prognosis.