Dopamine and human information processing: a reaction-time analysis of the effect of levodopa in healthy subjects

RATIONALE: Dopamine is involved in a variety of motor and non-motor information-processing operations. One way to determine its contribution to human information processing is to study reaction time (RT) performance after oral absorption of its precursor, levodopa, which increases its concentration in the nervous system. OBJECTIVE: The purpose of the present study was to investigate the effect of a single dose of levodopa on information processing in healthy human subjects using the additive-factor method. After oral absorption of a single dose of levodopa (200 mg) or a placebo (randomized, double-blind, cross-over design), eight adults (aged 21-28 years, mean 25 years) performed a two-choice visual RT task. Signal intensity, stimulus-response mapping and foreperiod duration were manipulated. RESULTS: The effects of these three variables were found additive on RT, indicating that that three independent stages - namely, stimulus preprocessing, response selection and motor adjustment - were manipulated. Levodopa improved RT performance in a specific way: it interacted with signal intensity but its effect was additive with those of stimulus-response mapping and foreperiod duration. CONCLUSION: These results show that levodopa specifically affects the stimulus preprocessing stage, which suggests that the dopaminergic system plays a role in sensory processing, possibly by acting on the level of arousal.     

Sensorimotor effects of pergolide, a dopamine agonist, in healthy subjects: a lateralized readiness potential study

Objective The major purpose of the present study was to further elucidate dopaminergic modulation of sensorimotor processing in healthy human subjects. Materials and Methods To more specifically analyze dopaminergic effects on premotor and motor stages of sensorimotor processing, lateralized readiness potentials (LRPs) were obtained. In a randomized double-blind crossover design, either 0.075 mg of the D1/D2 dopamine (DA) agonist pergolide or placebo were administered to 12 healthy male volunteers ranging from 19 to 25 years in age. The subjects performed a two-choice visual reaction time task. In addition to behavioral measures, such as response speed and error rate, stimulus-locked LRP (S-LRP) and response-locked LRP (LRP-R) latencies were determined. To better dissociate potential central and peripheral motor effects, measures of response dynamics and response-locked electromyogram (EMG-R) recordings were also obtained.Observations Pergolide reliably enhanced speed of stimulus-related information processing as indicated by shorter S-LRP latencies while LRP-R latencies, reaction time, and indicators of response dynamics were not influenced by DA agonistic treatment. Furthermore, lower EMG-R amplitudes and an increased number of wrong-hand responses were observed under pergolide compared to placebo.Conclusion The results indicate that dopaminergic neurotransmission effectively modulates early perceptual and cognitive stages of information processing as suggested by neural network models of the functional role of prefrontal DA. The lack of an effect on aspects of motor processing may be due to a higher capacity of the nigrostriatal compared to the mesocortical DA system to compensate pharmacologically induced changes in dopaminergic activity.     

The influence of levodopa on gastric emptying in healthy elderly volunteers

Summary Paracetamol absorption and ⁹⁹Tc-DTPA measurements have been used to determine the influence of levodopa on gastric emptying in 8 healthy elderly volunteers.In the absence of levodopa 7 subjects showed a rapid gastric emptying pattern by gamma-camera and a single major peak in the plasma concentration-time curve of paracetamol. One subject showed two rapid phases of gastric emptying separated by a period of negligible emptying and had 2 separate peaks in the paracetamol plasma concentration-time curve.In the presence of levodopa, the gamma-camera data for 6 subjects showed a pattern of gastric emptying consisting of 2 rapid phases separated by a plateau. In each case secondary peaks in the plasma concentration-time curve of paracetamol occurred about 30 min after the end of the plateau. The time to 90% emptying on the gamma scan was increased significantly from 40 min to 65 min in the presence of levodopa.Comparison of the present data with those reported previously indicates that levodopa affects gastric emptying in the both elderly and young volunteers to a similar extent.     

中国青年男性左旋多巴药动学研究

目的探讨左旋多巴在中国青年人药动学。方法征集14名健康男性志愿者,口服200／50mg左旋多巴／苄丝肼片,给药后10,20,30,45．60,90．120,180,240．360,480,600min采血,高效液相色谱-电化学法测定左旋多巴血药浓度．3P87药动学软件计算药动学参数。结果左旋多巴t1／2β AUC0-∞CL／F、Cmax、tmax和V／F分别为54．97±12．4min、351．10±64．12ug·min／mL、589．12±118．54mL·min^-1、2．41±0．98μg·mL^-1、55．60±16．55min和45．82±20．02L。结论积累了左旋多巴在青年人药动学资料．可为临床合理用药提供参考。     

A study to evaluate the effect of ondansetron on psychomotor performance after repeated oral dosing in healthy subjects

The aim of the study was to determine the effect of repeated oral administration of ondansetron, a 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist, on psychomotor performance. The study was of a randomised, double-blind, four-way, cross-over design in 12 healthy subjects, with 1 mg and 8 mg ondansetron, placebo and 2 mg lorazepam evaluated. Each subject received five administrations per treatment period. Ondansetron, 1 mg and 8 mg, and placebo were given as twice daily dosing for 2 1/2 days. Lorazepam was administered as a 2 mg single oral dose which was taken as the fifth administration; placebo was given for the remaining four doses. Within each treatment period, subjects underwent a baseline (pre-dose) assessment of psychomotor performance using four commonly used and validated psychomotor tests, and were then re-assessed after the fifth and final dose over a 7-h, post-dose period. Following dosing with lorazepam, statistically significant changes were seen in five of the six test variables compared with placebo. Ondansetron, at both the 1 mg and the 8 mg doses, did not produce a statistically significant effect on any measure of psychomotor performance compared with placebo.     

Comparative pharmacokinetics of midazolam and loprazolam in healthy subjects after oral administration

The pharmacokinetics of oral midazolam (Dormicum, 15 mg) and loprazolam (Dormonoct, 1 mg) were studied in eight healthy young volunteers in a cross-over design. Plasma concentrations of midazolam were measured with a gas chromatographic method and loprazolam concentrations were determined by a radio-receptor technique. Absorption of midazolam proceeded very rapidly (median tmax = 0.4 h) and a rapid onset of sedative action was observed. Loprazolam absorption was relatively slow (median tmax = 3 h) and its absorption profile was often irregular. Most subjects fell asleep before peak concentrations were reached. Median peak concentrations were 94 ng ml-1 and 3.1 ng ml-1 for midazolam and loprozolam, respectively. The median elimination half-life of midazolam was 1.8 h and that of loprazolam 15 h. It is possible that the elimination half-life of loprazolam as determined by radioreceptor assay is determined by active metabolites rather than by loprazolam itself. Midazolam elimination half-life was the same when determined by radioreceptor assay or by GLC. There was no significant correlation between the half-lives of the two drugs.     

Analysis of sleep EEG microstructure in subchronic paroxetine treatment of healthy subjects

Paroxetine is a selective and potent serotonin reuptake inhibitor and its efficacy for the treatment of depression has been proven. Under acute and subchronical treatment regimens, disturbances of the regular sleep pattern are a reported side effect of the drug. The present study was therefore performed to investigate the impact of subchronic treatment with the selective serotonin reuptake inhibitor paroxetine on the microstructure of the sleep EEG. The study especially addressed the question of subchronic effects of paroxetine medication (30 mg/day) in eight healthy male volunteers in a double blind, placebo-controlled crossover design. Conventional sleep EEG parameters and a spectral power analysis for different sleep stages after 4 weeks of treatment were computed. Additionally, the correlation of certain EEG rhythms across the night was calculated in order to detect subtle dynamical EEG alterations, not necessarily obvious when regarding conventional EEG analysis. Although we could not detect any alterations of the spectral power values in certain frequency bands either during NREM nor during REM sleep following subchronic paroxetine medication, the dynamical EEG attributes across the night revealed a significant enhancement of the correlation between certain EEG rhythms mainly during NREM sleep. Received: 18 July 1996 /Final version: 19 February 1997     

Assessment of the pharmacokinetics of co-administered metformin and lobeglitazone,a thiazolidinedione antihyperglycemic agent,in healthy subjects

Abstract

Objective:

Lobeglitazone as a thiazolidinedione antihyperglycemic agent activates peroxisome proliferator-activated receptor (PPAR) γ and may be suitable as monotherapy or in combination with other antihyperglycemic agents. The primary objective of this study was to investigate potential pharmacokinetic interactions between lobeglitazone and metformin in healthy Korean subjects.     

健康人动脉结构及功能改变与室间隔厚度的相关性研究

目的 研究健康人中动脉结构和功能改变与心室间隔厚度的关系.方法 以颈动脉内膜中层厚度( IMT)和肱动脉血流介导的血管舒张反应(FMD)二指标反应动脉结构和功能改变.采用超声多普勒测定68例健康人(男16人,女52人)的IMT、FMD和室间隔厚度( IVST).结果 健康人中IVST与IMT呈正相关(r=0.394,P=-0.001),与FMD呈负相关(r=0.337,P＜ 0.01),IVST也与年龄和收缩压呈正相关.以IVST为因变量的多因素回归分析显示,IMT和FMD是其独立影响因素.结论 健康人中IMT、FMD和IVST相关,动脉结构和功能改变影响心室间隔厚度.     

正常青年女性畸变产物耳声发射测试分析

目的：检查正常青年人DPOAE范围，为临床应用提供良好依据。方法：对30例（60耳）听力正常青年人，用CAPELLA机型耳声发射仪进行DPOAE测试，选择初始音强度L1＝70dBSPL,L2=60dBSPL，水平差10dBSPL。结果：DPOAE总检出率为100％，正常青年人DPOAE幅值差距大，显示出明显个体差异，不同频率处DPOAE幅值有所不同，1KHz，8KHz处幅值最大，信噪比各频率均在10dBSPL以上（明显高出3dBSPL）。结论：发现不同频率下DPOAE图形非光滑曲线，而呈双峰型，双耳显著差异（P＞0．05).     

Human reward system activation is modulated by a single dose of olanzapine in healthy subjects in an event-related,double-blind,placebo-controlled fMRI study

Rationale Olanzapine is a neuroleptic drug widely prescribed to treat schizophrenia and bipolar disorder. Although it is long known that modulation of the dopamine system is a basic mechanism of action of neuroleptics, their impact on reward functions mediated by dopamine is still poorly understood. Objective Using functional magnetic resonance imaging (fMRI), we intended to reveal the effects of a single dose of olanzapine on reward-related brain activation. Methods Eight healthy subjects were each scanned twice, once 5 h after intake of 5 mg of olanzapine and once after intake of placebo in a double-blind cross-over design. Subjects performed a delayed incentive paradigm with monetary reward to investigate reward functions and a breath-holding task as a hypercapnic challenge to reveal unspecific drug effects on the fMRI signal. Results Reward-related brain activation in the ventral striatum, anterior cingulate and inferior frontal cortex was reduced on olanzapine compared to placebo. Only the differential effects (high>no reward) in the ventral striatum were independent of overall drug effects as measured with the breath-holding task. Parallel to the differential effects in the ventral striatum, the acceleration of reaction times in the trials with higher rewards was diminished in the olanzapine sessions. Conclusions Our behavioural and fMRI results can be interpreted as first evidence from neuroimaging that olanzapine affects the assignment of incentive salience represented by differential activation in dopaminergic brain areas and acceleration of reaction times. This can help to better understand neuroleptic effects in psychiatric diseases. Furthermore, we demonstrate the value of a hypercapnic challenge in functional pharmaco-MRI.     

The effect of carbidopa on the pharmacokinetics and metabolism of intravenously administered levodopa in blood plasma and skeletal muscle

Summary The effect of carbidopa on the pharmacokinetics and metabolism of levodopa (l-dopa) in blood plasma and skeletal muscle extracellular fluid (ECF) has been studied by repeated measurements in one beagle dog.The administration of a single dose of l-dopa (25 mg/kg i.v) without carbidopa pretreatment (controls) resulted in an increase in the concentrations of l-dopa and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle ECF dialysates. This effect was clearly potentiated for l-dopa in blood plasma (186% increase in AUC) and 3-OMD in skeletal muscle dialysates (108% increase in AUC) after pretreatment with carbidopa (100 mg/day). In addition, carbidopa prolonged the halflife of the elimination of l-dopa in blood plasma by 48% and in skeletal muscle ECF by 66% but did not influence its blood plasma distribution half-life (t_1/2 = 0.17 h). The elimination half-life of l-dopa in the controls was higher in muscle (t_1/2 = 1.76 h) than in blood plasma (t_1/2 = 0.50 h). Carbidopa pretreatment resulted in a relatively small increase (29%) in the l-dopa content of skeletal muscle ECF as indicated by the AUC.The accumulation of 3-OMD in muscle dialysates, in contrast to that in plasma, was significantly enhanced after the administration of l-dopa following treatment with carbidopa. In the control experiments, dopamine (DA) was detectable only in the dialysates from muscle ECF 3,4-Dihydroxyphenylacetic acid (DOPAC) concentrations in dialysates from blood plasma and muscle showed similar changes in their pharmacokinetic profiles following carbidopa treatment suggesting that their concentrations reflected the formation of these metabolites at other peripheral organs.Our data support the hypothesis that carbidopa, at least in this experimental setting, exerts a l-dopa sparing effect in skeletal muscle ECF and therefore might play a role in maintaining blood plasma levels of this amino acid.Correspondence to: D. Deleu at the above address     

An additive factor analysis of the effect of sub-anaesthetic doses of nitrous oxide on information processing: evidence for an impairment of the motor adjustment stage

Abstract Rationale. Nitrous oxide (N₂O) inhalation, at subanaesthetic concentrations, impairs choice reaction time (RT). However, the functional locus of this effect remains to be ascertained. In the present study, this issue was investigated by applying the additive factor logic to the RTs of rats performing a visuo-motor task. Method. The task consisted of either a left-side or a right-side body displacement to a visual stimulus displayed in either the left or right hemispace. The experimental design involved the manipulation of two task factors (stimulus luminance and foreperiod duration) the effects of which are additive on RT. Inhaled N₂O (from 0% to 60%) was varied as the third factor of the design. Results. N₂O prolonged RT in a dose-dependent manner and this effect was additive with that of stimulus luminance, whilst it interacted with that of foreperiod duration. Moreover, at low concentrations (10–20%), N₂O abolished the effect of foreperiod, possibly through a disturbance of time estimation processes, whereas at higher concentrations (30–40%) N₂O enhanced the effect of foreperiod, probably by slowing down motor processes. Movement time (MT) was decreased by N₂O at 20–40%. Conclusions. The present data provide evidence that N₂O impairs information processing by altering at least the stage of motor adjustment. In addition, N₂O spares the sensory processes implemented during the stimulus preprocessing stage. A subsidiary result is that at some concentrations, N₂O displays opposite effects on reaction time and movement time. These results demonstrate that the additive factor method constitutes a powerful new tool for studying the pharmacology of information processing in animal models. Electronic Publication     

Pharmacoscintigraphic and pharmacokinetic evaluation on healthy human volunteers of sustained-release floating minitablets containing levodopa and carbidopa

In this study, scintigraphic and pharmacokinetic studies were conducted on 10 healthy, fed volunteers. Two concepts of sustained-release floating minitablets--Levo-Form 1 (matrix) and 2 (coated)--were evaluated and compared to the marketed product Prolopa HBS 125. All the floating forms were radiolabelled with (111)In in order to evaluate their gastric residence time using gamma-scintigraphy. It was shown that the three formulations offered almost the same mean gastric residence time, which was about 240 min. Prolopa HBS 125 and Levo-Form 2 presented intragastric disintegration, which can lead to a more pronounced "peak & valley" effect on the plasma concentration-time profile of levodopa. In contrast, the plasma concentration-time profile of levodopa following the administration of Levo-Form 1 was more evenly distributed. Moreover, Levo-Form 1 provided the lowest variations between men and women in terms of AUC and C(max) values. Finally, when the same amount of inhibitors of extracerebral dopa decarboxylase--carbidopa and benserazide--had been administrated, the mean AUC, C(max) and T(max) values obtained for benserazide were lower than those obtained for carbidopa.     

Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson's disease

Summary The influence of age on the kinetics of a standard oral dose of levodopa administered with an inhibitor of peripheral dopa decarboxylase enzymes (benserazide) has been evaluated in 40 patients with Parkinson's disease (age 34–78 y) on chronic therapy. They were divided into 2 groups, on the basis of age below (21 patients, Group A) or above (19 patients, Group B) 65 y.The area under the plasma concentration-time curve (AUC) of levodopa was significantly greater in the older group (547 versus 428 mol·1^–1·min in Group B), coupled with a reduced apparent oral clearance (8.1 versus 10.7 ml·min^–1 ·kg^–1) and a longer plasma elimination half-life (67.6 versus 54.6 min). The age of the patients was positively correlated with the AUC of levodopa (r=0.474) and its plasma elimination half-life (r=0.391), and was negatively correlated with clearance (r=–0.489).The findings confirm previous data on volunteers that showed a reduction in the systemic clearance of levodopa due to age, which would probably account for the finding of a greater AUC of levodopa in older patients. The observed, age-mediated differences in levodopa pharmacokinetics, albeit statistically significant, were moderate and were likely to be of only minor importance for the dosing schedule.This work was part of the Progetto finalizzato Invecchiamento of the National Research Council of Italy, Grant No. 912012     

A comparative clinical investigation of the therapeutic effect of levodopa alone and in combination with a decarboxylase inhibitor (carbidopa) in cases of Parkinson's disease

Summary

The therapeutic effect of the combination of levodopa and carbidopa (‘Sinemet’) was compared with that of levodopa alone in 21 patients with Parkinson's disease. Eighteen parameters of the clinical condition and of functional impairment were determined quantitatively and the results statistically evaluated. Changing over from levodopa to the combination preparation resulted in an average improvement of 51.9% within 2 weeks. No relationship was found to exist between the degree of improvement and the severity or the progression of the disease. By the use of the combination preparation, the daily dosage of levodopa could be reduced by 77 %. Side-effects connected with the gastro-intestinal tract occurred much less frequently, while hyperkinesia increased. No arrhythmogenic effect was found with the combination product. From the clinical standpoint, combination therapy appeared to be qualitatively superior. By selective maintenance of freshly formed dopamine, it should be possible to assure a directed influence on the disturbed equilibrium of the functional systems of the brain.     

Measuring the bronchial effect of bronchodilating drugs in healthy subjects after methacholine provocation

Summary To study whether it would be possible to assess bronchodilating drugs in healthy subjects with methacholine — induced bronchoconstriction, salbutamol 100, 200 and 300 g was inhaled in random order by 12 healthy volunteers in a double-blind, placebo-controlled study. Dose response slope (DRS = maximum percentage fall in pulmonary function / maximal noncumulative methacholine dose (mol)) was used as an index of bronchial reactivity, and was calculated for forced expiratory flow volume in 1 s (DRS_FEV1) and area under the flow-volume curve (DRS_AEFV).Bronchial reactivity and its reproducibility were first tested by a standard methacholine provocation method. An abbreviated, single-dose method was used to measure the effect of salbutamol. The reproducibility of methacholine provocation was good, and the single-dose and standard methods gave comparable results. The DRS-values of all the doses of salbutamol differed significantly from placebo and from each other. AEFV did not show any advantage over the FEV₁ in this context. A significant negative association between the dose of salbutamol (g/kg) and airway reactivity was observed.In conclusion, use of the DRS showed it possible to evaluate the protective efficacy of ₂-adrenergic agonists against induced bronchoconstriction in healthy subjects.     

Pharmacokinetics and bioequivalence evaluation of risperidone in healthy male subjects with different CYP2D6 genotypes

The aim of this study was to evaluate the bioequivalence of risperidone in healthy male subjects representing different CYP2D6 genotypes with respect to risperidone, 9-hydroxyrisperidone (9-OH-risperidone), and active moiety. A total of 506 Korean subjects were genotyped for CYP2D6*10 by means of allele-specific polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Based on the genotype analysis, 24 subjects, 7 homozygous for CYP2D6*1, 10 for *10, and 7 heterozygous for *10, were recruited and received a single oral dose of 2 mg risperidone tablet in this study. Serum concentrations of risperidone and 9-OHrisperidone up to 48 h were simultaneously determined. There were no significant differences of the active moiety, risperidone, and 9-OH-risperidone between the two preparations in AUC0-proportinal to, and Cmax. The 90% confidence intervals (CIs) for the ratio of means of the log-transformed AUC0-proportional to. and Cmax for the active moiety, risperidone, and 9-OH-risperidone were all within the bioequivalence acceptance criteria of 0.80-1.25. The CYP2D6*10 allele particularly was associated with higher serum concentrations of risperidone and the risperidone/9-OH-risperidone ratio compared with the CYP2D6*1 allele. The results demonstrate that the two preparations of risperidone are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice. Furthermore, the pharmacokinetic parameters of risperidone and the risperidone/9-OH-risperidone ratio are highly dependent on the CYP2D6 genotypes.     

Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease

Summary We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy.Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after.There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30MD]/AUC, did so at the 0.01 level.The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy. This may explain in part the limited reversal of the neurological deficit, which is more typical of later onset Parkinsonism, and, possibly, the decrement in biological half time with duration of therapy, typical of early onset disease. 3-0-Methyldopa is known to compete for active uptake with levodopa; the ratio, [30MD]/AUC, may be a measure of this competition. Intrinsic activity of neuronal uptake mechanisms, capacity of the basal ganglia for storage of dopamine, and post synaptic neuronal activity may, of course, also be determinants of clinical outcome.     

正常青年人脑组织不同回波时间磁共振波谱分析

目的探讨不同回波时间(TE)对正常青年人脑组织代谢物含量的影响。方法选择23名健康青年志愿者,进行二维1H-磁共振波谱(MRS)检查,TE分别为135 ms和270 ms,对比分析N-乙酰门冬氨酸(NAA)/肌酐(Cr)、胆碱(Cho)/Cr及NAA/Cho比值。结果在正常青年人右侧基底节区,TE=135 ms,NAA/Cr、Cho/Cr和NAA/Cho比值分别为2.1±0.6、1.2±0.3和1.7±0.4;TE=270 ms,NAA/Cr、Cho/Cr和NAA/Cho比值分别为2.8±0.8、1.4±0.4和2.0±0.5。TE=135 ms组与TE=270 ms组比较,NAA/Cr、Cho/Cr及NAA/Cho比值差异均有统计学意义(P<0.05)。男性组与女性组比较,NAA/Cr、Cho/Cr及NAA/Cho比值差异均无统计学意义(P>0.05)。结论TE=270 ms所测量的NAA/Cr、Cho/Cr及NAA/Cho比值均高于TE=135 ms所测量的比值,性别不是影响正常青年人脑组织代谢物含量的因素。