Plasma Levodopa Levels Research Articles

Frequent administration of levodopa/carbidopa microtablets vs levodopa/carbidopa/entacapone in healthy volunteers

An oral dispersible microtablet formulation of levodopa/carbidopa 5/1.25 mg (LC-5) was developed for individualized repeated dosing. The aim was to compare pharmacokinetic profiles of LC-5 and levodopa/carbidopa/entacapone (LCE). A randomized, crossover study was carried out in 11 healthy subjects. Plasma concentrations of levodopa, carbidopa and 3-O-methyldopa were determined after intake of 300 mg levodopa during the day, either as three intakes of 100/25/200 mg LCE or as a morning dose of 75/18.25 mg followed by five repeated doses of 45/11.25 mg LC-5. Repeated dosing (2.4-hourly) with LC-5 microtablets compared to LCE (6-hourly) avoided long periods with low plasma levodopa levels. Time to maximum plasma concentrations was significantly shorter for LC-5. LC-5 showed lower fluctuation index (FI) in plasma compared to LCE (ANOVA P = 0.0028). FI for dose 2-5 was on average 1.26 for levodopa in LC-5, and 2.23 for dose 1-2 of LCE. The ratio between the two mean FI:s is 0.565; that is, LC-5 gave nearly half the FI as compared to LCE. Fractionation of levodopa with LC-5 into small, frequent administrations as compared to standard administrations of LCE decreased the FI in plasma for both levodopa and carbidopa by nearly half.

L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease

ObjectiveThe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of l-3,4-dihydroxyphenylalanine (l-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single l-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma l-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients. MethodsWe administered acute challenges of l-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of l-DOPA using high-performance liquid chromatography–mass spectrometry/mass spectrometry. ResultsThe maximal plasma concentration of l-DOPA (Cmax) was 18.2 ± 3.8 nmol/ml and was achieved 1.6 ± 0.3 h after administration (tmax). Half-life was 58.8 ± 22.7 min. l-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 ± 0.7 μg/g tissue protein while they were 1.5 ± 0.1 nmol/ml in the CSF. ConclusionsAlthough therapeutically-active doses of l-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to l-DOPA Cmax similar to those achieved with 200 mg l-DOPA in clinic. l-DOPA tmax and half-life are also similar to those reported in human.

Cysteine decrease following acute Levodopa intake in patients with Parkinson's disease

The thiol homeostasis determines the redox milieu and thus scavenging of free radicals by antioxidants like glutathione (GSH). GSH is formed out of cysteine in combination with l-glycine and glutamine acid. An up regulation of free radical occurrence is looked upon as one key feature of chronic neurodegeneration. Levodopa (LD) is under suspicion to support synthesis of free radicals via the degradation of its derivative dopamine in abundant mitochondria. Objectives were to investigate the impact of LD on free cysteine turnover in plasma. 200mg LD/50mg carbidopa (CD) were administered to 13 patients with Parkinson's disease under standardised conditions. Plasma levels of LD and free cysteine were measured before, 60- and 80-min after the LD/CD application. Cysteine concentrations decayed, expectedly LD levels increased. Cysteine decrease may result from an up regulation of GSH synthesis to encounter augmented appearance of free radicals associated with LD turnover via mitochondrial monoaminooxidase.

Ghrelin prevents levodopa‐induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Levodopa (L-dopa) is the most commonly used treatment for alleviating symptoms of Parkinson's disease. However, L-dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents L-dopa action on gastric emptying and enhances circulating L-dopa in rats. Gastric emptying of non-nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) L-dopa, or intravenous (i.v.) ghrelin 10 min before orogastric L-dopa. Plasma L-dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 μg kg(-1)) 10 min before i.p. L-dopa. Levodopa (5 and 15 mg kg(-1)) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 μg kg(-1), i.v.) completely prevented L-dopa's (15 mg kg(-1), orogastrically) inhibitory action on gastric emptying and enhanced plasma L-dopa and dopamine levels compared with vehicle 15 min after orogastric L-dopa. Levodopa (5 mg kg(-1)) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg(-1), i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. Ghrelin counteracts L-dopa-induced delayed gastric emptying but not Fos induction in the brain and enhances circulating L-dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson's disease patients treated with L-dopa remain to be investigated.

Optimizing levodopa therapy to treat wearing-off symptoms in Parkinson’s disease: focus on levodopa/carbidopa/entacapone

Levodopa has been the mainstay of Parkinson’s disease (PD) therapy for over 40 years, with its efficacy surpassing that of other antiparkinsonian medications. As such, most PD patients eventually require levodopa-based therapy during the course of the disease. However, despite its proven efficacy, long-term levodopa therapy is associated with motor complications, with wearing-off being the most prevalent. Wearing-off occurs, in part, as a result of the short half-life of levodopa, which leads to fluctuations in plasma levodopa levels. A pharmacokinetic profile characterized by a higher trough value of levodopa can be achieved by combining levodopa/carbidopa with entacapone, which inhibits the peripheral breakdown of levodopa, resulting in higher plasma levodopa levels. Here, we review the limitations of conventional levodopa and the clinical data for levodopa/carbidopa/entacapone in treating patients with wearing-off.

Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial

Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added. A short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbidopa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance. Variation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition. According to this small, short-term pilot study, oral catechol-O-methyltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time.

Biodegradable Microspheres Loaded with an Anti-Parkinson Prodrug: An in Vivo Pharmacokinetic Study

During chronic treatment with L-dopa (LD), Parkinsonian patients often experience uncontrolled motor complications due to fluctuations of the plasmatic levels of LD that result in pulsatile dopaminergic stimulation. To overcome these plasmatic fluctuations, a novel prodrug of LD, L-dopa-α-lipoic acid (LD-LA), has been proposed as a tool for achieving continuous dopaminergic stimulation. Due to slower susceptibility toward enzymatic conversion by LD-degrading enzymes (such as catechol-O-methyltransferase and monoamine oxidase), the plasma half-life of this prodrug is longer than that of LD. Moreover, the higher lipophilicity of LD-LA over LD promotes its delivery to the CNS, where the resulting levels of dopamine (DA) are kept high for a longer time than after equimolar administration of LD. To further reduce fluctuations in plasma levels of LD, LD-LA has been entrapped into biodegradable polymeric microspheres to be used as a depot system with the aim to prevent prodrug degradation and to obtain a sustained release of the intact compound. In the present work, a formulation of LD-LA loaded microspheres (characterized for drug loading, size, morphology, thermal properties, and in vitro prodrug release) has been administered subcutaneously to rats, and the resulting levels of LD and DA in plasma and striatal tissue, respectively, have been monitored. A good correlation between the in vitro release kinetics and the time range during which the formulation alters the LD/DA tissue levels in vivo was observed, suggesting that the polymeric microsphere matrix protects the loaded prodrug from chemical and enzymatic degradation and controls its release. Interestingly, LD-LA microspheres provided sustained levels of DA neurotransmitter in the striatum nucleus for up to 4 days after a single administration. In conclusion, a polymeric microsphere formulation of LD-LA is an attractive medicine for treating Parkinson's disease (PD) symptoms, avoiding motor complications.

Unpredictable Rotational Responses to L‐dopa in the Rat Model of Parkinson’s Disease: the Role of L‐dopa Pharmacokinetics and Striatal Dopamine Depletion

L-dopa is still the gold standard in the symptomatic treatment of Parkinson's disease (PD), and thus, it is the most commonly used drug in the non-clinical assessment of new drug therapies to PD, including those intended to improve the effect of L-dopa. In unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, the results from L-dopa-induced rotation tests are often unpredictable. While repeated administration of L-dopa improves the rotation, the exact mechanisms underlying the extensive variability in rotation responses between rats and testing times are unclear. In the present study, we aimed to assess whether the route of administration (oral or intraperitoneal) or the form of L-dopa (base or methyl ester) is associated with the extensive variation in rotation responses to L-dopa in 6-OHDA rats. We also wanted to examine the dependence between L-dopa (base or methyl ester)-induced rotational behaviour and the extent of dopamine and dopa decarboxylase enzyme loss in the lesioned striatum. It was found that variation in plasma levels of L-dopa as well as the administration route explains a part of the variability in rotation. There were small but significant differences in striatal dopamine depletion (indicative of degree of lesion) between the groups, which may partially account for the various patterns in L-dopa-induced rotational behaviour. While apomorphine-induced rotation test is a useful tool for primary screening of the success of 6-OHDA lesion, it is not useful at predicting the rotational performance of 6-OHDA rats to L-dopa. The exact mechanisms and causes of the variability in the rotation responses to L-dopa in 6-OHDA rats still remain to be clarified.

In-vivo evaluation of prolonged release bilayer tablets of anti-Parkinson drugs in Göttingen minipigs

Patients with Parkinson's disease can benefit from controlled released levodopa dosage forms since there is a clear clinical advantage in obtaining sustained plasma concentrations. The purpose of this study was to obtain a tablet that prolonged the release of levodopa. A novel bilayer tablet, consisting of an immediate release layer containing nebicapone (100 mg) and an erosion-matrix type prolonged release layer containing levodopa (100 mg) and carbidopa (25 mg) was developed (LCN PR). A pharmacokinetic study in Göttingen minipigs was performed to evaluate this formulation. LCN PR tablets prolonged the in-vitro release of levodopa in HCl 0.1 m for more than 3 h. In-vivo plasma levodopa levels peaked at a later time point with LCN PR tablets as compared with that obtained with Sinemet 100/25 (2.7 vs 0.5 h). Nebicapone increased the maximum plasma concentration and area under the plasma concentration-time curve values for levodopa. The results obtained suggested that LCN PR tablets may have decreased the number of tablets and daily intake in the treatment of patients with Parkinson's disease.

Development of a Non-Motor Fluctuation Assessment Instrument for Parkinson Disease

Patients with Parkinson disease are increasingly recognized to suffer from non-motor symptoms in addition to motor symptoms. Many non-motor symptoms fluctuate in parallel with motor symptoms and in relationship to plasma levodopa levels. Though these symptoms are troublesome and result in reduced quality of life to patients and their caregivers, there has not been an objective method of recognizing and quantifying non-motor fluctuations (NMFs). This study sought to develop a patient-based instrument that would accurately capture the experience of patients with NMFs. Patient-based nominal group technique sessions, focus groups, and expert opinion were utilized in developing this questionnaire.

Fatty Acid Amide Hydrolase (FAAH) Inhibition Reduces l-3,4-Dihydroxyphenylalanine-Induced Hyperactivity in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Non-Human Primate Model of Parkinson's Disease

Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and nonmotor complications, such as psychosis, impulse control disorders (ICD), and dopamine dysregulation syndrome (DDS). Nondopaminergic neurotransmitter systems, including the endocannabinoid system, are probably critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating l-3,4-dihydroxyphenylalanine (L-DOPA)-induced behaviors was explored in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) were assessed via bioanalytical (liquid chromatography-tandem mass spectrometry) and behavioral observation approaches. URB597 (3, 10, 30, or 60 mg/kg p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide, and N-palmitoyl ethanolamide by 10.3 ± 0.3-, 7.8 ± 0.2-, and 1.8 ± 0.1-fold (mean of URB597 groups ± S.E.M.), respectively, compared with vehicle (all p < 0.001) 4 h after administration. Treatment with L-DOPA (20 mg/kg s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviors and hyperactivity, a potential correlate of ICD and DDS. During the 2 to 4 h after L-DOPA, corresponding to 4 to 6 h after URB597 administration, URB597 reduced total L-DOPA-induced activity and the magnitude of hyperactivity by 32 and 52%, respectively, to levels equivalent to those seen in normal animals. Treatment with URB597 (10 mg/kg p.o.) did not modify the antiparkinsonian actions of L-DOPA or L-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma L-DOPA levels and was without behavioral effects when administered alone. Inhibition of FAAH may represent a novel approach to reducing L-DOPA-induced side effects, such as ICD and DDS, while maintaining the antiparkinsonian benefits of L-DOPA treatment.

Design, synthesis and biological evaluation of l-dopa amide derivatives as potential prodrugs for the treatment of Parkinson’s disease

A range of amide derivatives of l-dopa were synthesized and investigated for their pharmacological activity and their ability to be converted to l-dopa using the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat, as an experimental model of Parkinson’s disease. The diacetyl derivative of l-dopa amide ( 11b) was found to be more active than l-dopa after its oral administration and generated plasma levels of l-dopa in the therapeutic range for an antiparkinsonian effect in man.

Caffeic acid improves the bioavailability of l‐dopa in rabbit plasma

The impacts of caffeic acid (3,4-dihydroxycinnamic acid, CA) on the pharmacokinetics of levodopa (L-dopa) were studied in rabbits. A single dose of 5/1.25 mg kg(-1) L-dopa/carbidopa was administered alone or was co-administered with three different doses of caffeic acid (2.5, 5, and 10 mg kg(-1)), or a single dose of 5 mg kg(-1) caffeic acid was administered alone via an intramuscular route to six rabbits each in a crossover treatment protocol. Plasma levels of L-dopa, 3-O-methyldopa (3-OMD), caffeic acid, and ferulic acid were determined and subsequently used to calculate their pharmacokinetic parameters. The results indicated that caffeic acid administered at a dose of 10 mg kg(-1) decreased about 22% of the peripheral formation of 3-OMD and about 31% of the C(max) of 3-OMD. In addition, the metabolic ratios (MR, AUC of 3-OMD/AUC of L-dopa) decreased by about 22%. Results also indicated that caffeic acid significantly decreased the proportion of 3-OMD (p < 0.05). In contrast, the parameters of neither caffeic acid nor ferulic acid were significantly affected by L-dopa/carbidopa. In conclusion, caffeic acid at a dose of 10 mg kg(-1) can significantly affect the COMT metabolic pathway of L-dopa.

EFFECTS OF L-DOPA ON CIRCADIAN RHYTHMS OF 6-OHDA STRIATAL LESIONED RATS: A RADIOTELEMETRIC STUDY

Temporal variation in the motor function of Parkinson's disease (PD) patients suggests the potential importance of a chronobiological and chronopharmacological approach in its clinical management. We previously documented the effects of striatal injection of 6-OHDA (as an animal model of PD) on the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (A). The present work assessed the possible influence of L-Dopa on these same rhythms in the 6-OHDA animal model of PD. The study began after a four-week recovery period following surgical implantation of telemetric devices to monitor the study variables and/or anaesthesia. The study was divided into an initial one-week control period (W1) for baseline measurement of T, HR, and A rhythms. Thereafter, stereotaxic 6-OHDA lesioning was done. and a second monitoring for two weeks followed (W2, W3). Rats were then randomly divided into two groups: eight control rats received, via a mini-osmotic pump implanted subcutaneously, the excipient saline; the other eight rats received L-Dopa (100 mg/kg SC/day). After a seven-day period (W4), the pumps were removed and the T, HR, and A rhythms were monitored for two weeks (W5 and W6). To control for 6-OHDA striatal dopamine-induced depletion, 12 other rats were injected by identical methods (eight rats with 6-OHDA and four controls with saline) and sacrificed at W1, W3, and W5 for dopamine striatal content determination. To verify the delivery of levodopa from the osmotic pumps, plasma levels of levodopa and its main metabolites 3-OMD, DOPAC, and HVA were determined on separate group of rats receiving the drug under the same experimental conditions (osmotic pumps delivering continuously 10 µl/h for seven days, 100 mg/kg/subcutaneously). Our results agree with previously reported rhythmic changes induced by 6-OHDA—loss of circadian rhythmicity or changes in the main parameters of the registered rhythms. When circadian rhythmicity was abolished, L-Dopa treatment improved or accelerated recovery of the circadian rhythms, the effect being more pronounced for the HR rhythm. When circadian rhythms were not abolished but perturbed, L-Dopa treatment did not improve the 6-OHDA-induced changes in the T and A mesor (24 h mean level), while a significant effect was observed for HR. It appears that constant-rate L-Dopa infusion is unable to totally balance dopamine depletion; taking into account the circadian pattern of many structures implicated in drug effect, a sinusoidal delivery of L-Dopa must be evaluated in future experiments. (Author correspondence: bernard.bruguerolle@univmed.fr)

Non-motor extranigral signs and symptoms in Parkinson's disease

Clinical symptoms in Parkinson's disease (PD) comprise both motor and non-motor symptoms. In this disease, synucleinopathic-induced, nigral dopamine deficiency-related dysfunction of the basal ganglia is held responsible for the characteristic levodopa-responsive motor signs and symptoms (bradykinesia, hypokinesia, rigidity), known as parkinsonism and essential for clinical diagnosis in PD, as well as subtle motivational and cognitive dysfunctions. Some motor symptoms, such as tremor and postural instability, and most non-motor symptoms, however, are not fully levodopa-responsive, and suggested to manifest extranigral pathology. These symptoms include autonomic, sleep, sensory and neuropsychiatric symptoms, which in some cases may precede the first signs of motor parkinsonism, closely correlating with the progression of Lewy body pathology in PD. The recognition and treatment of these mostly under-recognized and under-treated symptoms is important, as these symptoms might have more impact on the quality of life in PD patients as compared to motor parkinsonism. On top of this, recognition of these manifestations in the prodromal phase of motor PD is critical to early diagnosis and treatment, as disease-modifying drugs, once identified, should be initiated as soon as possible, preferably in this premotor phase of the disease. On top of this, (non)motor extranigral symptoms in PD might also be of iatrogenic origin, whether directly as indirectly. During conventional, oral, dopaminomimetic treatment, the progressive loss of striatal dopaminergic nerve endings with the loss of cerebral dopamine storage capacity, renders the cerebral dopamine level fully dependent of the plasma levodopa levels, thus changing dopaminergic receptor stimulation from continuous to a more pulsatile pattern. Supposedly due to this process, neuroplastic changes in (sub)cortical dopaminergic pathways might cause therapeutic response fluctuations: motor and nonmotor fluctuations with anxiety- and panic-attacks and/or mood swings, dyskinesias and punding. Finally, dopaminomimetic pharmacotherapy may also induce extranigral non-motor drug-related direct adverse effects, such as impulse control disorders. In this article, non-motor signs and symptoms of extranigral PD-related pathology will be discussed, as well as the (suggested) criteria for diagnosis and treatment. Of course, also the recognition of the signs and symptoms of the prodromal (premotor) phase, suggestive for the presence of the PD, will be discussed. Iatrogenic non-motor symptoms, though, will not be further discussed.

Effect of a slow release preparation of levodopa on Parkinson's disease in combination with a peripheral decarboxylase inhibitor

Plasma concentrations of levodopa were determined after therapeutic oral levodopa-carbidopa doses. The wide fluctuations observed in plasma levodopa levels could be considerably reduced by the addition of a slow release levodopa preparation. This kind of combination medication was given to 15 parkinsonian patients, whose earlier therapy had proved inadequate. With the combination medication, levodopa-carbidopa, on an average 420 mg/42 mg combined with 950 mg of levodopa in slow release form, a statistically significant improvement in parkinsonian signs could be achieved without any worsening of the side effects. The results suggest that parkinsonian patients may tolerate much higher daily levodopa doses if the fluctuations in plasma levels of the drug can be diminished.

Levodopa and executive performance in Parkinson's disease: A randomized study

Parkinson's disease (PD) patients may experience fluctuations in executive performance after oral levodopa (LD). Their relationship with the pharmacokinetic profile of LD and with distinct cognitive processes associated with frontal-basal ganglia circuits is not well understood. In this randomized, double-blind, crossover study we plotted acute cognitive changes in 14 PD patients challenged with faster (immediate-release, IR) versus slower (controlled-release, CR) increases in LD plasma concentrations. We monitored motor status, LD plasma levels, and performance on four tasks of executive function (Wisconsin Card Sorting Test-WCST, Sternberg test, Stroop and Tower of Hanoi), 1 hr before and over +6 hr after IR and CR-LD dose. Analysis of variance demonstrated significant but divergent changes in the Sternberg (6-digit but not 2- and 4-digit) test: improvement after CR-LD and worsening after IR-LD. Marginal improvement (p = .085) was observed with CR-LD in the WCST, while no significant differences were seen for the Stroop or Tower of Hanoi tests. Executive-related performance after LD challenge may differ depending on the LD time-to-peak plasma concentration and specific task demands. A slower rise in LD levels appears to have a more favorable impact on more difficult working memory tests. These results require replication to determine their generalization.

Levodopa/DDCI and entacapone is the preferred treatment for Parkinson’s disease patients with motor fluctuations in routine practice: a retrospective, observational analysis of a large French cohort

Levodopa is the gold standard drug for the symptomatic control of Parkinson's disease (PD). However, long-term treatment with conventional formulations [levodopa and a dopa decarboxylase inhibitor (DDCI)], is associated with re-emergence of symptoms because of wearing-off and dyskinesia. Treatment with levodopa/DDCI and entacapone extends the half-life of levodopa, avoiding deep troughs in levodopa plasma levels and providing more continuous delivery of levodopa to the brain. In this open-label, retrospective, observational study we investigated the effects of levodopa/DDCI and entacapone therapy in 800 PD patients with motor fluctuations. Levodopa/DDCI and entacapone treatment was assessed as good/very good in improving motor fluctuations (64%) and activities of daily living (ADL; 62%). The therapeutic utility was considered to be good/very good in 70% of cases. Moreover, there was a reduction in levodopa dose in 20% of patients. Neurologists preferred levodopa/DDCI and entacapone compared with increasing levodopa dosage, dose-fractionation or addition of a dopamine agonist (63%, 29% and 23% of patients respectively). Reasons included achieving more continuous dopaminergic stimulation (40%), reducing motor fluctuations (54%) and improving ADL (41%). This analysis reveals the preference of neurologists for levodopa/DDCI and entacapone over conventional levodopa-modification strategies for the effective treatment of PD motor fluctuations in clinical practice.

Optimizing levodopa therapy for Parkinson&amp;rsquo;s disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective

After 40 years of clinical experience, levodopa remains the gold standard treatment for Parkinson's disease (PD) despite the recent emergence of a host of new therapies. Some physicians are cautious when prescribing levodopa because of its association with motor complications. Evidence now suggests that levodopa-associated complications are a result of deep troughs in delivery of levodopa to the brain caused by the short plasma half-life of conventional levodopa formulations (levodopa and a dopa decarboxylase inhibitor [DDCI]). Dosing strategies, such as dose increases and dose fractionation, may be effective in the short term. For the longer-term, levodopa/carbidopa/entacapone provides pharmacokinetically optimized levodopa therapy that significantly increases the plasma half-life and bioavailability of levodopa, providing more consistent plasma levodopa levels without deep troughs. Evidence from clinical trials in PD patients experiencing re-emergence of symptoms due to wearing-off has consistently shown that levodopa/DDCI and entacapone significantly increases ON-time and affords greater functionality, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) with conventional levodopa. These trials have also shown that levodopa/DDCI and entacapone is generally well tolerated, with notable adverse events including worsening dyskinesia, nausea and diarrhea. Patients experiencing re-emergence of symptoms due to wearing-off may benefit from optimized levodopa therapy with levodopa/carbidopa/entacapone.

Pharmacokinetics and pharmacodynamics of levodopa

The pharmacokinetics and pharmacodynamics of levodopa are dominated by two features: the short plasma half-life of the drug and the portion of the antiparkinsonian response that parallels the plasma levodopa levels, the so-called short-duration response. These features are the basis of motor fluctuations that complicate long-term therapy with levodopa. Motor fluctuations will predictably improve with measures that prolong the elevations of plasma levodopa or prolong the efficacy of dopamine synthesized from exogenous levodopa. Because dyskinesia is closely linked to the short-duration response and conceivably part of the short-duration response, it is less clear that dyskinesia will be improved by therapeutic strategies that reduce motor fluctuations.