Levodopa Concentrations Research Articles

Elicitors and precursor induced effect on L-Dopa production in suspension cultures of Mucuna pruriens L.

Plant cell cultures provide an alternative means for producing secondary metabolites. The present study is an attempt to study the effect of some elicitors and precursor molecules on the production of L-Dopa (3, 4-dihydroxy-L-phenylalanine), which is a neurotransmitter precursor being used for symptomatic relief of Parkinson's disease. It is one of the most highly active allelochemicals present in Mucuna pruriens. Suspension cultures were established on Murashige and Skoog (MS) medium supplemented with 6-benzylaminopurine (BAP) and indole acetic acid (IAA). Elicitors such as methyl jasmonate, chitin, pectin, yeast extract and also a precursor L-tyrosine at different concentrations were supplemented to the suspension cultures at different concentrations, and their effect on L-Dopa production was studied. L-Dopa produced was quantified by high performance liquid chromatography (HPLC). Compared to the control set of suspension cultures a several-fold increase in L-Dopa concentration was observed in elicitors treated and precursor fed suspension cultures. Compared to elicitor treatments precursor feeding resulted in higher concentrations of L-Dopa production.

Enhanced production of L-DOPA in cell cultures of Mucuna pruriens L. and Mucuna prurita H.

A comparative study on the production of 3,4-dihydroxyphenylalanine (L-DOPA) was carried out in cell cultures of two Mucuna species by elicitor treatment and precursor feeding. The influence of elicitors and the precursor molecule on L-DOPA production, polyphenol oxidase (PPO) and tyrosinase activities was also studied. Callus cultures were initiated in Mucuna pruriens L. and Mucuna prurita H. on MS medium supplemented with BAP and IAA at different concentrations. Suspension cultures were established in MS liquid medium supplemented with BAP, IAA, the elicitors methyl jasmonate, chitin and pectin or the precursor L-tyrosine at different concentrations for L-DOPA production. Compared to the controls, several-fold increases in L-DOPA concentration were observed in elicitor-treated and precursor-fed suspension cultures of both plant species. L-DOPA concentrations were comparatively higher in precursor-fed cultures than those receiving elicitor treatments. A parallel increase in tyrosinase and PPO levels was also observed. Loss of cell viability was observed at high concentrations of elicitor-treated cultures, whereas L-tyrosine did not cause any cell death. Compared to elicitor treatments, precursor feeding resulted in higher concentrations of L-DOPA production and tyrosinase activity. The efficacy of L-DOPA production was found to be higher for suspension cultures of M. pruriens compared to M. prurita in all treatments.

The effect of different dosing regimens of levodopa/carbidopa/entacapone on plasma levodopa concentrations

Repeated dosing of levodopa/carbidopa/entacapone (LCE) has shown a favourable pharmacokinetic (PK) profile compared with levodopa/carbidopa (LC), but increases maximum plasma levodopa concentrations (C(max)) during the day. High levodopa concentrations are associated with peak-dose dyskinesias. To determine whether administering LCE 75/18.5/200 and 125/31.5/200mg (LCE 75 and LCE 125) following a morning dose of LCE 100/25/200 and 150/37.5/200mg (LCE 100 and LCE 150), respectively, would avoid the increase in levodopa C(max) values observed during multiple dosing of LCE 100 and LCE 150. This was an open, randomized, three-period, crossover PK trial in healthy volunteers (n = 19). Subjects were randomized to Group 1 or 2. Group 1 received in random sequence: LCE 150 followed by LCE 125 three times daily (tid); LCE 150 four times daily (qid); LC 150 qid. Group 2 received in random sequence: LCE 100 followed by LCE 75 tid; LCE 100 qid; LC 100 qid. Levodopa C(max), minimum plasma concentration (C(min)), area under the curve (AUC(0-14)) and peak-trough fluctuation (PTF) were calculated up to 14 h after the first dose. Levodopa C(max) was not increased when the LCE dose was decreased by 25mg after the morning dose. In comparison to LC, levodopa C(min) levels and AUC(0-14) values for LCE were significantly higher, while the levodopa PTF was significantly smaller. Reducing the dose of LCE by 25mg following the first morning dose results in a more consistent levodopa C(max) profile, avoiding levodopa accumulation while maintaining significantly higher C(min) levels and AUC(0-14) values compared with LC.

Levodopa toxicity and Parkinson disease

Levodopa is the gold standard for the treatment of Parkinson disease (PD). There remains, however, a lingering concern whether levodopa is toxic to dopamine neurons and accelerates the degenerative process.1 The question is not whether the drug is beneficial—clearly it is. Rather, the question is whether the profound symptomatic effects of levodopa mask an underlying toxicity that hastens disease progression. What is the basis for considering this seemingly heretical hypothesis? It revolves around the capacity of levodopa to undergo auto-oxidation and form reactive oxygen species either through its own auto-oxidation to form semiquinones or by way of its conversion to dopamine, whose oxidative metabolism yields the highly reactive hydroxyl radical.1 There is also concern that dopamine interactions with α-synuclein can induce toxicity by promoting the formation of toxic protofibrils2 or by inhibiting chaperone-mediated autophagy, a mechanism for clearing unwanted intracellular proteins and protein aggregates.3 In laboratory studies, levodopa induces degeneration of cultured dopamine neurons in a concentration-dependent manner, but the clinical significance of this finding is uncertain, as the concentrations employed are much higher than are used in treating PD, and cultured cells lack natural protectants such as glial cells and ascorbic acid.1 Moreover, levodopa is not toxic to dopamine neurons in normal, dopamine-lesioned, or oxidatively stressed animals. Further, activation of dopamine receptors can induce phosphorylation of protective molecules (e.g., PI-3kinase, AKT) while sublethal concentrations of levodopa can upregulate anti-apoptotic molecules (e.g., BCL-2) and protect against higher concentrations …

Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease

The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended-release formulation of carbidopa-levodopa, with an immediate-release carbidopa-levodopa formulation in advanced Parkinson's disease. We performed an open-label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate-release carbidopa-levodopa followed by IPX066 or IPX066 followed by immediate-release carbidopa-levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple-dose administration). Following a single dose of IPX066 or immediate-release carbidopa-levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate-release carbidopa-levodopa (P < .0001). Multiple-dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C(max) was approximately 30% compared with immediate-release carbidopa-levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate-release carbidopa-levodopa. Larger, longer-term, well-controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066.

Electrogastrographyc activity in Parkinson's disease patients with and without motor fluctuations

Gastroenteric dysfunctions are very common in Parkinson's disease, but their relationship with dopaminergic response and motor fluctuations is still unclear. Electrogastrography is a noninvasive method for measuring gastric myoelectrical activity. We evaluated the effects of levodopa intake on the motility of empty stomachs in Parkinson's disease patients with and without motor fluctuations. The electrogastrography findings showed a normal pattern not influenced by levodopa intake, unrelated to plasmatic levodopa concentrations and to clinical parameters. Our results suggest that at rest gastric activity of Parkinson's disease patients is normal and plasmatic levodopa variability is not influenced by gastric motility.

Effects of 3,4-dihydroxyphenylpyruvic acid and L-glutamic acid on some pharmacokinetic parameters of L-dopa in the rat.

In the rat, various oral doses of 3,4-dihydroxyphenylpyruvic acid (DHPPA) administered simultaneously with L-dopa were shown to elevate the serum L-dopa and cerebral dopamine concentrations dose-dependently. With increasing DHPPA: L-dopa ratio the L-dopa-sparing effect became greater. Although oral and intravenous doses of DHPPA showed that it was readily converted to L-dopa in the serum, only small amounts of dopamine (DA) were detected in the brain. The high 3-O-methyldopa concentrations, measured in the serum after DHPPA administration, might be responsible for the failure of the L-dopa formed to pass the blood-brain barrier. Concomitant administration of L-dopa and glutamic acid gave significantly higher L-dopa values in the serum and DA and homovanillic acid values in the brain than did the same dose of L-dopa alone. This indicates that the transamination of L-dopa can also be effected by coadministration of L-dopa and an amino group donor in vivo.

Peripheral Pharmacokinetic Handling and Metabolism of L-Dopa in the Rat: The Effect of Route of Administration and Carbidopa Pretreatment

The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of hypoxia in catecholamines synthesis in immortalized human mesangial cell

Catecholamines (CA): dopamine (DA), L-Dopa, epinephrine (EP) and norepinephrine are involved in renal filtration and vasoconstriction, and can be produced by mesangial cells (MC). MC expresses Toll Like Receptor 4, that detect lipopolysaccharide (LPS). LPS and hypoxia are present in sepsis, and can lead to acute renal failure. We analyzed the effect of LPS and hypoxia on the CA production/release from Immortalized Human MC (IHMC) cultured and incubated with LPS [0.1, 1.0, 5.0 and 100 mg/mL], or exposed to hypoxia. CA from the medium and cell lysates were quantified by HPLC-ED. LPS [1 mg/mL] induced a L-Dopa intracellular decrease compared to control (5.3±1.6 vs.10.8±1.0 pg/mg). LPS [5 mg/mL] decreased the L-Dopa intracellularly (4.9±1.3 vs. 10.3±1.0 pg/mg) and increased EP concentration (8.8±1.9 vs. 2.2±0.5 pg/mg). LPS [100 mg/mL] increased intracellular levels of EP (102.7±8.4 vs.65.8±10.1 pg/mg), L-Dopa (48.5±2.4 vs.22.2±4.1 pg/mg) and DA (24.9±2.9 vs.15.9±1.4 pg/mg) and decreased the extracellular concentration of EP (125.2±13.7 vs.205.4±10.4 pg/mg) and L-Dopa (34.6±5.7 vs.57.4±8.6 pg/mg). Tyrosine hydroxylase (TH) expression, step-limiting enzyme of CA formation, was significantly affected by LPS (100 mg/ml). However it did not occur under hypoxic conditions. Taken together these results suggest that LPS can influence the production/release of CA in IHMC. Supported by CNPq.

3D ordered gold nanoshell composite array as sensitive SERS nanosensor for detecting l-DOPA and tyrosinase activity

Here we report a novel method for detecting 3,4-dihydroxyphenylalanine (L-DOPA) and tyrosinase (TR) activity based on surface-enhance Raman scattering (SERS) by employing a large-scale versatile three-dimensionally (3D) ordered nanocomposite (SiO2/GNPs) array as a nanosensor. L-DOPA could reduce AuCl4− to Au0 and enlarge the gold nanoparticles (GNPs) that attach on the surface of the SiO2/GNPs array, the preadsorbed GNPs serve as nucleation sites for Au0 to deposit. As the concentration of L-DOPA increases, the surface coverage of resultant Au0 on silica cores increases accordingly until complete gold nanoshells (GNSs) are formed. During the growth procedure, the SERS-activity of the GNSs arrays correlate well with the concentration of L-DOPA, which indicates that this SiO2/GNPs array is a potential nanosensor for detecting L-DOPA. As TR can catalyze the hydroxylation of L-tyrosine to form L-DOPA, this approach can also be employed to analyze the activity of TR, which possesses vast clinical and food industrial importance. Compounds such as cinnamic acid and p-hydroxybenzoic acid can inhibit the TR activity. Thus, the TR-triggered growth of the GNSs array system can also be used to detect the TR inhibited activity of inhibitors.

Complexity of Motor Response to Different Doses of Duodenal Levodopa Infusion in Parkinson Disease

The aim was to elaborately describe individual pharmacokinetic-pharmacodynamic profiles in patients with difficult-to-treat dyskinesias treated with levodopa/carbidopa intestinal gel infusion. A nonrandomized, partly blinded, investigator-initiated trial was conducted in 5 patients with idiopathic Parkinson disease who were difficult to keep in "on" state without dyskinesia. Levodopa/carbidopa intestinal gel (Duodopa) doses of 80% to 120% of individually and clinically optimized dosage were infused during five 4-hour periods. Pharmacokinetic profiling, blinded assessment of video recordings, and objective movement analysis were applied every 20 to 30 minutes. Individual correlations between plasma levodopa concentrations and corresponding motor scores 20 to 30 minutes after the sampling time were significant in all patients (P < 0.05 and P < 0.001). Motor scores were generally stable during the 4-hour periods. The objective test revealed that motor performance was faster the more dyskinetic the patients were. Mean individual Treatment Response Scale scores were positive in 24 of the 25 steady-state periods. Dystonia was always combined with choreic dyskinesias. Motor response from different doses of levodopa/carbidopa intestinal gel is in a broad sense predictable even in dyskinetic patients although major interindividual differences in dose requirement, plasma levels, and motor response are found. That motor performance was faster the more dyskinetic the patients were implies that motor performance may be better with moderate dyskinesia than with mild dyskinesia. This may explain why patients with persistent dyskinesias choose to keep their doses above the dyskinesia threshold. There is no ideal therapeutic window in such patients, but levodopa infusion offers stable motor response.

Influence of ageing on the pharmacokinetics of levodopa in elderly patients with Parkinson’s disease

Levodopa (LD) is the most effective drug to treat the symptoms of Parkinson’s disease (PD). It has been reported that the bioavailability of LD is higher in elderly patients than in young patients; however, it is not known how ageing changes the bioavailability of LD among elderly patients. In this study, we compared the pharmacokinetics of LD between two groups of elderly PD patients, early- (75 years or younger) and late-elderly (76 years or older). After oral administration of a tablet containing 100 mg LD per 10 mg carbidopa in 155 PD patients, we measured plasma LD concentrations. Peak drug concentration ( C max), time to peak drug concentration ( T max), halftime of drug (T1/2) and area under the curve (AUC) were determined. AUC and T1/2 were significantly higher and longer, respectively, in the late-elderly group than in the early-elderly group ( p < 0.05 and <0.05, respectively). However, C max and T max were not statistically different between the groups. The present data indicate that LD absorption is consistent in PD patients, regardless of age. The difference in oral LD bioavailability between the groups may result from a difference in excretion ability. Physicians should consider LD pharmacokinetics when treating elderly PD patients.

Protective effects of statins on l-DOPA neurotoxicity due to the activation of phosphatidylinositol 3-kinase and free radical scavenging in PC12 cell culture

Neurotoxic effects have been suggested for l-3,4-dihydroxyphenylalanine (l-DOPA), while neuroprotective effects have been proposed for statins. We investigated whether certain statins (simvastatin or pitavastatin) could inhibit l-DOPA neurotoxicity. Neuronally-differentiated PC12 (nPC12) cells were treated with l-DOPA and/or statins for 24h, and their viabilities were measured using a cell counting kit, trypan blue staining, and 4′,6-diamidino-2-phenylindole (DAPI) staining. Free radical and specific intracellular signaling protein levels were measured with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. High concentrations of l-DOPA reduced nPC12 cell viability, but combined treatment with statins restored viability. Treatment with 200μM l-DOPA increased free radical and hydroxyl radical levels, but combined treatment with 5μM statins decreased these levels. Survival-related signaling proteins were decreased in nPC12 cells treated with 200μM l-DOPA, but combined treatment with 5μM statins significantly increased the levels of these proteins. Treatment with 200μM l-DOPA significantly increased death-related signaling proteins, while combined treatment with 5μM statins reduced the levels of these proteins. Pretreatment with LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, before combined treatment with statins and l-DOPA almost completely blocked the protective effects of statins. These results indicate that statins reduce l-DOPA neurotoxicity by lowering oxidative stress and by enhancing survival signals and inhibiting death signals via activation of the PI3K pathway.

An innovative electrochemical approach for voltammetric determination of levodopa using gold nanoparticles doped on titanium dioxide nanotubes

Catalytic nanotubes made from titanium dioxide (TiO2-NTs) and covered with gold nanoparticles (Au-NPs) were prepared via galvanic deposition of the Au-NPs on the TiO2-NTs. The morphology and surface characteristics of the resulting electrodes were investigated using scanning electron microscopy and energy-dispersive X-ray spectroscopy. The results indicated that the Au-NPs were homogeneously deposited on the surface of TiO2-NTs which consist of individual tubes of about 40–80 nm in diameter. The AuNPs with a size of 80–100 nm are well-dispersed on the surface of the TiO2-NTs. The electro-catalytic activity of the electrodes towards the electro-oxidation of levodopa was studied by cyclic voltammetry, differential puls voltammetry. The results showed that the electrodes exhibit a considerably higher activity toward the oxidation of levodopa. The oxidation peak current linearly depends on the concentration of levodopa in the 10 to 70 μM concentration range. Levodopa was determined by the method in pharmaceutical preparations, and results were found to be satisfactory.

Mechanisms of L-DOPA-induced cytotoxicity in rat adrenal pheochromocytoma cells: implication of oxidative stress-related kinases and cyclic AMP

L-DOPA therapy for Parkinson's disease has a double-edge effect on nigrostriatal dopaminergic neurons: L-DOPA increases the intracellular level of dopamine, but it induces neuron cytotoxicity in a concentration-dependent manner. To investigate the molecular signaling mechanisms that underlie the concentration-dependent effects of L-DOPA on cell viability, the activities of mitogen-activated protein kinases (MAPKs) and apoptotic enzymes were measured in rat adrenal pheochromocytoma (PC12) cells in the presence of a low concentration (20 μM) and high concentrations (100–200 μM) of L-DOPA. At the low concentration, L-DOPA was not cytotoxic and its presence increased the activities of extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, BadSer112, Bcl-2, and caspase-12. At the high concentrations, L-DOPA was cytotoxic and stimulated the activities of ERK1/2, p38 MAPK, c-Jun N-terminal kinase (JNK)1/2, BadSer155, caspase-12 and caspase-3. The increased levels of ERK1/2 and BadSer155 in the presence of high concentrations of L-DOPA did not protect against L-DOPA-mediated cytotoxicity. In addition, the levels of L-type Ca2+ channel-sensitive intracellular cyclic AMP (cAMP) and Ca2+ were elevated in the presence of L-DOPA, and the increase in the levels of intracellular cAMP may also play a role in cellular viability, since cAMP levels and cytotoxicity increased in parallel with L-DOPA concentrations and the addition of forskolin in the medium increased cytotoxicity in a concentration-dependent manner. These results suggest that, at a low and non-toxic concentration, L-DOPA may promote cell survival by increasing the activities of ERK1/2, BadSer112 and Bcl-2, while, at high concentrations, L-DOPA activates the caspase-3 cell death enzyme through the JNK1/2 and p38 MAPK signaling pathways as well as endoplasmic reticulum stress that activates caspase-12. Intracellular cAMP levels may also play a role here. The results may lead to an effective therapy for Parkinson's disease.

Factors Associated With Motor Fluctuations and Dyskinesia in Parkinson Disease

Parkinson disease is a progressive movement disorder caused by loss of dopaminergic neurons in the substantia nigra. Of unknown etiology, Parkinson disease is characterized by 4 cardinal symptoms: tremor at rest, bradykinesia, postural instability, and rigidity. The current criterion-standard drug used in the management of parkinsonian symptoms is levodopa (l-dopa). However, long-term l-dopa therapy is associated with the development of motor complications; approximately 50% to 80% of patients will develop motor complications within 5 to 10 years of l-dopa treatment initiation. Motor complications can be divided into motor fluctuations, caused largely through pulsatile dopamine stimulation and low l-dopa concentrations, and dyskinesia, associated more often with peak l-dopa concentrations. Ultimately, the main goal was to provide steady l-dopa concentrations, without peaks and troughs. Empirical investigations using parenteral infusions of l-dopa and highly soluble l-dopa prodrugs have shown that there is benefit in ameliorating the peaks and troughs associated with traditional oral l-dopa formulations. Recently, the development of highly soluble oral l-dopa prodrugs has facilitated rapid, regular, and reliable l-dopa availability. This review evaluates some of the pharmacologic strategies in the management of motor complications in Parkinson disease and therapy optimization, with a focus on the use of CHF 1512 (Sirio), a combination of melevodopa (l-dopa methylester, a highly soluble prodrug of l-dopa) plus carbidopa in an effervescent tablet formulation.

Sensitive spectrophotometric detection of dopamine, levodopa and adrenaline using surface plasmon resonance band of silver nanoparticles

A simple and effective procedure is proposed for spectrophotometric determination of catecholamines; Dopamine (1), L-Dopa (2) and Adrenaline (3). It was found that the reduction of Ag+ to silver nanoparticles (Ag-NPs) by these catecholamines in the presence of polyvinylpyrrolidone (PVP) as a stabilizing agent produced very intense surface plasmon resonance peak of Ag-NPs. The plasmon absorbance of the Ag-NPs allows the quantitative spectrophotometric detection of the catecholamines. The calibration curves derived from the changes in absorbance at λ = 440 nm were linear with concentration of Dopamine, Levodopa and Adrenaline in the range of 3.2×10−6− 2.0×10−5 M, 1.6×10−7 − 1.0×10−5 M, 1.5×10−6− 4.0×10−5 M, respectively. The detection limits (3σ) were 1.2×10−6 M, 8.6 ×10−8 M, 9.7 ×10−7 M for the Dopamine, L-Dopa and Adrenaline, respectively. The method was applied successfully to the determination of catecholamines in Ringer’s injection serum.

Entacapone

Importance of the field: Levodopa (LD) is an efficient drug for patients with Parkinson's disease (PD). Its short half-life supports peaks and troughs. These plasma fluctuations support alternating stimulation of striatal postsynaptic dopamine receptors and thus onset of motor complications. They are significant components for the quality of treatment of PD patients.Areas covered in this review: This review discusses peripheral components of motor complication manifestation related to LD metabolism.What the reader will gain: LD troughs are associated with wearing off, which is reappearance of motor symptoms with decreasing drug effect. The addition of the catechol-O-methyltransferase inhibitor entacapone (EN) to LD/carbidopa (CD) improves wearing off, as EN prolongs LD half-life and avoids troughs. LD peaks are mostly related to peak dose dyskinesia, which are involuntary movements due to a central overstimulation with dopamine. One time addition of EN to LD/CD showed no increase of maximum LD concentration, but repeat EN supplementation to LD/CD elevated LD bioavailability and peaks.Take home message: These pharmacokinetic data may explain the failure of the STRIDE-PD study, which aimed to show a delayed interval of dyskinesia onset with LD/CD/EN therapy. This study only allowed up titration with a fixed LD intake every 4 h. But dyskinesia occurrence may require down titration of LD dose or delay of next LD intake.

Levodopa and 3-OMD levels in Parkinson patients treated with Duodopa

We studied 19 patients (14 men, 5 women, Hoehn and Yahr (H&Y) ≥ 3) with advanced Parkinson's disease (PD) attending the Parkinson Institute, Milan, whose motor fluctuations and dyskinesia were not controlled by oral medications. After all oral PD medications had been withdrawn, they received a duodenal levodopa infusions (Duodopa, Solvay Pharmaceuticals) for 14 h/day through a transabdominal port; levodopa boluses were administered in the morning and during “off” periods. The patients were evaluated by means of the UPDRS in the morning (“off”) and 60–120 min after the infusion (“on”) at baseline and for a mean follow-up of 13.5 ± 12.5 months (up to 36 months in 10 patients:). Levodopa ( l-DOPA) and its metabolites were determined by HPLC with electrochemical detection. l-DOPA concentrations tended to higher in the afternoon (2008 ± 345 vs 1713 ± 274 ng/mL) and correlated with the daily dose. O-methyldopa (OMD) levels correlated with l-DOPA levels, and the OMD/ l-DOPA ratios were stable over the day. There was a relationship between decreasing UPDRS III scores and decreasing OMD/ l-DOPA ratios. Dyskinesia (UPDRS IV, items 32–34) showed a clear improvement over time but there was no clear relationship with l-DOPA and OMD levels, or the OMD/ l-DOPA ratio. The l-DOPA/dose ratio was stable over time, whereas OMD levels and the OMD/ l-DOPA ratio decreased. It is conceivable that continuous infusion decreases metabolism possibly due to a reduction in methyl donor availability, as demonstrated by the increase in total homocysteine levels. Our results do not support the development of tolerance even after several months of continuous infusion, and indicate that pharmacodynamic factors play a role in afternoon off periods.

Pharmacokinetic-Pharmacodynamic Modeling of Levodopa in Patients With Advanced Parkinson Disease

The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (l-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of l-dopa in 1 patient with severe dyskinesias and fluctuations. The pharmacokinetics (plasma concentrations of l-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of l-dopa (plus the peripheral decarboxylase inhibitor 1:4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and fluctuations, pk/pd of l-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium. The highest levels of l-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement.Univariate analysis showed some significant correlations (P < 0.05) between l-dopa pk/pd parameters and patients' age, duration of l-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of l-dopa (P = 0.034). The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of l-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received l-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central l-dopa pharmacokinetics, which led to a decrease of l-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.