Pharmacokinetics and effects of levodopa in advanced Parkinson's disease

Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant k_e0 using model-independent analysis.The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was >4–5 g·ml^–1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min.The patients remained clinically stable during the period of the intraduodenal infusion.     

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.     

Effect of entacapone,a COMT inhibitor,on the pharmacokinetics of levodopa and on cardiovascular responses in patients with Parkinson's disease

Summary In an open, randomised, cross-over study we investigated the effect of a single 200 mg oral dose of entacapone, a novel catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa/carbidopa, and on the cardiovascular responses (blood pressure and pulse rate variation to standard stimuli) in eight parkinsonian patients.Entacapone significantly increased the mean area under the plasma concentration curve (AUC) of levodopa by 46%, from 3620 to 5280 h·ng·ml^–1 and prolonged its elimination half-life (t_1/2el) from 1.5 h to 2.0 h. The mean AUC of 3,4-dihydroxyphenylacetic acid (DOPAC), the monoamine oxidase-dependent metabolite of levodopa, was significantly increased from 122 to 343 h·g·ml^–1 by entacapone. A small decrease in the AUC of homovanillic acid (HVA), the COMT dependent metabolite of levodopa, was observed (from 455 to 303 h·ng·ml^–1). Entacapone also decreased the excretion of HVA but not that of 3-methoxytyramine in the urine.Cardiovascular autonomic responses to sympathetic and parasympathetic stimuli were not changed by entacapone.We conclude that a single dose of entacapone moderately increases the AUC and prolongs the t_1/2el of levodopa in man and that that does not affect cardiovascular autonomic regulation.     

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients

Objective: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson’s disease using parametric, non-linear mixed effect modelling with the program NONMEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid E_Max representation of the Hill equation via an equilibration rate-constant, ke₀. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. Results: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. Conclusion: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug’s beneficial motor activity in patients with mild to severe Parkinson’s disease (Hoehn and Yahr status I–IV). Received: 13 November 1995/Accepted in revised form: 13 February 1996     

Effect of meal timing on the kinetic-dynamic profile of levodopa/carbidopa controlled is release in parkinsonian patients

Objective: The aim of the study was to assess the effect of the time of ingestion of a meal on the pharmacokinetics and pharmacodynamics of a levodopa/carbidopa controlled-release formulation in parkinsonian patients on chronic levodopa therapy. Methods: The kinetic-dynamic profile of one tablet of controlled-release levodopa/carbidopa 200/50 mg was monitored in eight patients, according to an intrasubject randomized cross-over design in two different sessions. A standard meal was consumed by the patients after they had fasted for 15–17 h, on one occasion 30 min before the ingestion of the test dose, and on the other occasion 2 h after the ingestion of the same drug dose. Blood venous samples for analysis of plasma levodopa and its metabolite 3-O-methyldopa were drawn at 20-min intervals up to 6 h after dosing. Motor response to the levodopa test dose was assessed by the finger tapping and walking speed tests at the same times as blood was drawn. Results: Controlled is release levodopa intake after meals resulted in a significant delay in drug absorption, with an almost twofold increase in time of initial appearance of levodopa in plasma and time to peak plasma concentration. Peak plasma drug concentrations were not significantly different in the two experimental conditions; the area under the 6-h plasma concentration-time curve showed an average reduction of 24% in the fed condition, partly reflecting the incomplete assessment of levodopa absorption, within the 6 h of examination, due␣to 5-h delayed peak plasma levodopa concentration␣in two patients. With reference to levodopa pharmacodynamics, time to onset of motor response was significantly delayed and duration of motor response significantly curtailed in the fed condition, while the magnitude and overall extent of motor effect were unchanged. Conclusions: In keeping with previous findings on levodopa standard-release preparations, these data show that time of meal ingestion is an important determinant of levodopa disposition, even from controlled-release preparations in parkinsonian patients. From a clinical point of view, these results help to explain some of the delayed, curtailed and even lacking responses that often complicate afternoon motor performances in patients at the more advanced stages of the disease. Received: 17 July 1997 / Accepted in revised form: 24 February 1998     

高同型半胱氨酸血症对帕金森病的影响

目的研究高同型半胱氨酸血症对帕金森病的发病与药物治疗的影响。方法选择正常老年组30例和未治疗帕金森病(PD)患者组30例,应用高效液相色谱法测定血浆同型半胱氨酸(hcy)水平。选择治疗中的PD患者60例,分为治疗组(应用美多巴)30例和对照组30例(应用其他抗震颤麻痹药物),同样方法测定其血浆中hcy水平。结果未治疗PD组、治疗组和对照组的hcy水平分别为:18.79±2.14、21.30±3.57和19.82±2.80,与正常老年组(12.31±1.26)比较显著升高(P<0.05),治疗组与未治疗PD组、对照组比较hcy水平无明显差异。结论高同型半胱氨酸血症是PD的危险因素,但对PD的治疗无明显影响。     

普拉克索与多巴丝肼治疗帕金森病的成本效果分析

目的 比较单用多巴丝肼与合用普拉克索治疗帕金森病两种方法效果.方法 采用对照研究方法,比较多巴丝肼治疗组(A组)及合用普拉克索治疗组(B组)的治疗效果及治疗成本.结果 B组虽然在药物费用及治疗费用方面较A组明显增加(P＜0.01),但其帕金森病综合量表评分显著下降(P＜0.05),而且在帕金森病各期均可应用.结论 联合应用普拉克索虽会加重药物成本及治疗成本,但在改善帕金森病各期临床症状方面效果更好,且可应用于不同分期的帕金森病患者,应个体化推荐.     

Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition

Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions. Methods: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1–2 and 6–7, and twice daily on study days 3–5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1–2 and 6–7 were compared with each other. Results: There were no differences in maximal plasma concentration (C_max), time to maximal drug concentration in plasma (t_max), elimination half-life (t_1/2) and area under the plasma concentration–time curve (AUC) of entacapone between day 1 and day 6. The mean t_1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in C_max, t_1/2 (2.4 h on days 1–2 and 2.3 h on days 6–7) or AUC of levodopa, whereas t_max occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (C_max, t_max and AUC) of carbidopa. Conclusion: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity. Received: 28 December 1998 / Accepted in revised form: 29 March 1999     

Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson's disease

Summary Motor performance of five patients with advanced Parkinson's disease was investigated during their optimum oral therapy (conventional tablets and/or depot capsules) and during a continuous duodenal infusion of levodopa. Due to the low water solubility of the drug, conventional tablets of levodopa + carbidopa (Sinemet^®) were milled and dispersed in a 1.8% aqueous methylcellulose solution. The dispersion was delivered nasoduodenally by a portable pump. The effect of levodopa in the two dosing regimens was estimated optico-electronically every 15 min and was also evaluated from videorecordings every 30 min and plasma levels of levodopa was regularly measured. Each dosage regimen the was studied twice, at a 2–4 day interval.Duodenal infusion improved motor function in all five patients and the fluctuations were reduced when compared to the oral therapy. Variation in plasma levodopa concentrations was 3–10 fold during oral therapy, while during the infusion a stable concentration was obtained. The therapeutic concentration varied from 0.3–3 g ml^–1 between patients. The relative bioavailability of levodopa in the solid preparation compared to the dispersion was in all patients 100%.Our results encourage further development of a duodenal infusion system with a levodopa dispersion for clinical use in parkinsonian patients who show severe fluctuation.     

In vivo pharmacokinetics of levodopa and 3-O-methyldopa in muscle

Summary In the present study in vivo microdialysis sampling coupled to high-performance liquid chromatography with electrochemical detection, was used to study the pharmacokinetics of levodopa and 3-O-methyldopa in skeletal muscle in dog, after intravenous administration of levodopa. For comparison, the pharmacokinetic parameters of both compounds were simultaneously determined in plasma using blood collection. Muscle microdialysis samples and blood were continuously collected for 4 h after the administration of levodopa (25 mg/kg). Pharmacokinetic profiles of levodopa in plasma and muscle were different. The mean Tmax value of levodopa in plasma and muscle was 0.16 h and 1.0 h, respectively.The AUC_0inf for levodopa in plasma was nearly 18-fold higher in plasma than in muscle. The 3-O-methyldopa concentration increased very rapidly after the administration of levodopa, to reach a plateau after 2.5 h and 3 h in plasma and muscle, respectively. The AUC₀₄ for 3-O-methyldopa was 3.6-fold higher in plasma than in muscle. The ratio levodopa/3-O-methyldopa, reflecting the metabolic rate of levodopa, was 3.5 times higher in plasma than in muscle, at the peak value of levodopa, and then rapidly declined to values lower than 1, one hour after administration of the drug. We compared our results with literature data from postmortem studies done in rat experiments.We concluded that levodopa is not accumulating in muscle as such, but is converted to 3-O-methyldopa probably before leaving the plasma compartment. Send offprint requests to D. Deleu at the above address     

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     

Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa

Summary The clinical effects and pharmacokinetics of orally and intraduodenally administered levodopa, in four patients with Parkinson's disease have been compared. The patients had unpredictable fluctuations in motor function and episodic unresponsiveness to single doses of levodopa. The pharmacokinetic and clinical data of these patients were compared retrospectively with those of Parkinsonian patients with fluctuations in motor performance but with preserved clinical responses to single oral doses of levodopa.There was a threshold plasma concentration of levodopa associated with the switch on or off effect. In addition, rapid attainment of this critical plasma concentration was associated with a quicker onset of action and a more prolonged clinical response.All the patients had delayed absorption of levodopa related to delayed and erratic gastric emptying, which contributed to the fluctuation in motor response. In contrast, the patients with fluctuating motor effects but a preserved clinical response after levodopa showed an absorption pattern comparable to that of four patients studied after duodenal delivery of levodopa.It is suggested that there is a subgroup of patients with fluctuating responses due mainly to altered peripheral pharmacokinetics of levodopa. The findings demonstrate the relevance of routine measurements of plasma levodopa in patients with Parkinson's disease in whom there are fluctuations in motor performance.     

Optimizing bioavailability in the treatment of Parkinson's disease

The bioavailability of drugs used to treat chronic diseases such as Parkinson's disease may have important implications for their clinical utility. Drugs with low bioavailability may cause a wide variation in clinical response between patients and even in the same patient. In addition, numerous factors - including gender, age, and gastric motility - may affect a drug's bioavailability. This is especially important in patients with Parkinson's disease, who develop response fluctuations as the disease progresses. Strategies that may improve the bioavailability of levodopa, the most efficacious medication for Parkinson's disease, include coadministering levodopa with carbidopa, a decarboxylase inhibitor, or with a catechol-O-methyltransferase inhibitor or using an alternative route of administration. Other adjunctive therapies used to treat Parkinson's disease have a wide range of bioavailabilities, which may also affect clinical outcomes. The bioavailability of adjunctive medications may be improved by the use of alternative formulations as well, such as orally disintegrating tablets or transdermal delivery. Considering bioavailability of a medication when prescribing drugs to treat Parkinson's disease may improve patient response and minimize adverse effects.     

The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on-off fluctuations.

We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on-off fluctuations whilst receiving long-term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32-80 mg h-1 (0.5-1.3 mg kg-1 h-1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l-1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3-OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two-compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on-off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.     

天麻钩藤颗粒联合左旋多巴治疗帕金森病的疗效观察

目的观察天麻钩藤颗粒联合左旋多巴治疗帕金森病的临床疗效。方法选取2015年7月—2016年6月监利县人民医院收治的帕金森患者88例,随机分为对照组和治疗组,每组各44例。对照组口服左旋多巴片,125 mg/次,2次/d,每周调整药物用量,逐渐增量至250 mg/次,3次/d,每日总剂量不超过6 g;治疗组在对照组的基础上口服天麻钩藤颗粒,5 g/次,3次/d。两组均治疗3个月。治疗后,观察两组的临床疗效,比较两组日常生活能力和运动能力评分和不良反应情况。结果治疗后,对照组和治疗组的总有效率分别为61.36%、72.27%,两组比较差异有统计学意义(P0.05)。治疗后,两组日常生活能力和运动能力评分均显著下降,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些评分明显低于对照组,两组比较差异具有统计学意义(P0.05)。两组不良反应发生率比较差异无统计学意义。结论天麻钩藤颗粒联合左旋多巴治疗帕金森病,临床疗效确切,症状改善明显,值得临床推广。     

Population pharmacokinetics of levodopa in subjects with advanced Parkinson's disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets

Aims

Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets (LC-oral) in subjects with advanced Parkinson''s disease (PD).

Methods

A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from an LCIG phase 1 study and a phase 3 double-blind, double-dummy study of the efficacy and safety of LCIG compared with LC-oral in advanced PD patients (n = 68 for model development; 45 on LCIG and 23 on LC-oral). The final model was internally evaluated using stochastic simulations and bootstrap and externally evaluated using sparse pharmacokinetic data from 311 subjects treated in a long term safety study of LCIG.

Results

The final model was a two compartment model with a transit compartment for absorption, first order elimination, bioavailability for LCIG (97%; confidence interval = 95% to 98%) relative to LC-oral, different first order transit absorption rate constants (LCIG = 9.2 h^–1 vs. LC-oral = 2.4 h^–1; corresponding mean absorption time of 7 min for LCIG vs. 25 min for LC-oral) and different residual (intra-subject) variability for LCIG (15% proportional error, 0.3 μg ml⁻¹ additive error) vs. LC-oral (29% proportional error, 0.59 μg ml⁻¹ additive error). Estimated oral clearance and steady-state volume of distribution for levodopa were 24.8 l h⁻¹ and 131 l, respectively.

Conclusions

LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration.     

Clinical drug monitoring by microdialysis: application to levodopa therapy in Parkinson's disease

1 We describe the first application of microdialysis to monitor the pharmacokinetics of a drug in the blood of man.
2 The aims of the study were to ascertain patient acceptability and tolerability of a new microdialysis probe and to assess its accuracy in determining the pharmacokinetics of levodopa and its principal plasma metabolite 3-O-methyldopa (3-OMD).
3 Eight patients with parkinsonism on chronic levodopa therapy were investigated.
4 After an overnight fast, a flexible microdialysis probe, perfused with isotonic saline, was inserted into a forearm vein and a blood sampling cannula was inserted in a forearm vein of the other arm. After ingestion of a levodopa preparation (Madopar Dispersible^}}rm), dialysate was collected over 5 or 10  min periods and blood samples were taken every 15 or 30  min for 2–6  h.
5 Dialysate drug profiles were similar to those of plasma, and levodopa and 3-OMD concentrations exhibited significant ( P <0.001) correlation with those observed in the corresponding plasma samples.
6 The mean (±s.d.) blood dialysate concentrations for levodopa and 3-OMD were 36.1±9.2% and 43.4±8.4% respectively of the plasma content.
7 The tolerability of the probe was excellent, and all eight patients found it preferable to conventional blood sampling.
8 Microdialysis of blood is less invasive than frequent intermittent direct blood sampling, and can readily be used to continuously monitor levodopa pharmacokinetics. In a clinical setting, a combination of drug monitoring by this technique together with clinical evaluation of motor function can be used to optimize levodopa treatment in patients with Parkinson's disease.     

国产托卡朋片治疗帕金森病有效性及安全性的临床研究

目的评价国产托卡朋片剂治疗帕金森病(PD)的有效性及安全性.方法观察PD患者80例,采用随机、双盲、安慰剂对照、平行分组研究.将PD患者随机分为托卡朋片治疗组和安慰剂组,每组40例,给予观察药物托卡朋片或安慰剂1片,每天3次,总观察时间为26周.主要疗效指标采用国际通用的评价PD症状的UPDRS评分.次要疗效指标是包括"关"的时间缩短,正在接受左旋多巴制剂治疗的患者从基线到试验结束时,每日左旋多巴制剂剂量减少.结果对稳定性PD患者治疗26周,服用托卡朋片组PD患者的UPDRS评分较安慰剂组明显降低(P＜0.01).用于伴有症状波动的患者:80例PD患者中,有明显"开-关"现象者21例,服用托卡朋组与安慰剂组相比,"关期"平均减少38%、"开期"平均延长22%,有68%伴有剂末现象的PD患者服用托卡朋后出现剂末现象减少,而只有37%伴有剂末现象的PD患者服用安慰剂后出现剂末现象减少(P＜0.01).其中12例口服左旋多巴制剂的患者,加服托卡朋后有5例该制剂减量.患者加用托卡朋前、后,血尿常规,肝肾功能检查结果皆在正常范围内,心率、血压和心电图无明显变化.80例中有35例出现不同类型的不良反应,托卡朋组75%、安慰剂组45%,差异非常显著(P＜0.01).患者出现的异动症、恶心、厌食、肌阵挛、失眠等副作用在减少左旋多巴制剂的用量时,副作用大大降低或消失.结论COMT抑制剂托卡朋能够改善PD患者的运动功能,是治疗PD有效的辅助药物,在波动性PD患者中可出现"关期"的时限缩短,"开期"时限的增加.     

卡左双多巴控释片联合多巴丝肼治疗帕金森病的疗效观察

目的探讨卡左双多巴控释片联合多巴丝肼片治疗帕金森病的临床疗效。方法选取2014年1月—2016年1月眉山市人民医院收治的帕金森患者123例为研究对象,所有患者随机分为对照组(59例)和治疗组(64例)。对照组口服多巴丝肼片,初始剂量为0.125 g/次,3次/d,服用1周后,根据个人病情逐渐增加治疗量至最大剂量,并维持最大剂量不超过1.5 g/d(至少分3次服用)。治疗组在对照组基础上口服卡左双多巴缓释片,125 mg/次,1次/12 h。两组患者均连续治疗12个月。观察两组的临床疗效,比较两组的帕金森病综合评分量表(UPDRS)评分、简易智力状态检查量表(MMSE)评分和蒙特利尔认知评估量表(Mo CA)评分。结果治疗后,对照组和治疗组的总有效率分别为71.19%、84.38%,两组比较差异有统计学意义(P0.05)。治疗后,两组UPDRS各级评分均显著下降,同组治疗前后比较差异有统计学意义(P0.05);且治疗组UPDRS评分明显低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组MMSE评分、Mo CA评分均显著升高,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标明显高于对照组,两组比较差异具有统计学意义(P0.05)。结论卡左双多巴控释片联合多巴丝肼片治疗帕金森病具有较好的临床疗效,可改善患者认知功能,安全性较好,具有一定临床推广应用价值。