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A reversed-phase high-performance liquid chromatographic procedure with UV detection at 280 nm is presented for levodopa determination in pharmaceutical preparations. The method is fast and specific for levodopa in the presence of its most likely impurities and degradation products.
Since motor fluctuations in Parkinsonian patients might be, at least in part, explained by an antagonism between levodopa (LD) and its metabolite 3-O-methyldopa (3-OMD) at blood-brain-barrier (BBB), we decided to study LD and 3-OMD plasma and cerebrospinal fluid (CSF) levels in subjects undergoing lumbar puncture for diagnostic purposes. After informed consent, 70 subjects took a tablet of carbidopa-levodopa association (Sinemet or Sinemet-CR) 0.5, 1, 2, 4, 8, 12 h before blood and lumbar cerebrospinal fluid collection. LD and 3-OMD were determined by an HPLC-electrochemical method. The subjects treated with Sinemet-CR had lower LD cerebrospinal fluid concentrations along with lower LD and higher 3-OMD plasma concentrations. This pattern of LD cerebrospinal fluid concentrations may be explained by means of a transport competition between LD and 3-OMD at blood brain barrier level.
A new procedure is described for the simultaneous determination of levodopa methyl ester (LDME) and its biotransformation products levodopa (L-DOPA), 3-O-methyldopa (3-OMD) and dopamine (DA) in stabilized plasma samples, using reversed-phase high-performance liquid chromatography. A coulometric detector equipped with a dual-electrode system operating in the redox mode was used to simultaneously quantitate all compounds. This system generated a double signal monitored by a dual-channel acquisition data system and allowed quantitation of compounds at the nanogram level. The intra- and inter-assay precision varied in the 2.4-6.9% and 3.2-9.1% ranges respectively, whereas the recoveries were close to 85% for L-DOPA and 3-OMD and 70% for DA and LDME. Samples may be stored at -80 degrees C for 15 days before analysis. The method was applied to plasma samples after oral administration of LDME to rats, but it may also be suitable for human pharmacokinetic studies.
We switched 50 patients with Parkinson's disease and motor fluctuations from standard levodopa (L-S) to controlled-release carbidopa/levodopa (L-CR). Ten (20%) patients stopped treatment due to adverse events. Data on the 40 patients who completed 6 months of treatment were analyzed. Parkinsonian assessments were performed using the Unified Parkinson's Disease Rating scale (UPDRS) and a nocturnal rating scale. During treatment with L-CR the total daily dose of levodopa increased and the number of daily doses decreased. After changing to L-CR, patients also experienced significant improvement on sub-scales II and III of UPDRS and on the Schwab and England and nocturnal mobility scales. The proportion of "off" time decreased but the duration and severity of dyskinesias increased. Most of the patients who dropped out of the L-CR group had already experienced some type of adverse event during treatment with L-S. At the end of the study, the number of patients preferring L-CR was significantly higher than the number preferring L-S.
Clinical idiopathic Parkinson's disease (PD) diagnosis requires following strict clinical criteria. Final definitive diagnosis can only be made after pathological confirmation and, despite following clinical criteria, several cases are misdiagnosed. We assessed sensitivity and specificity of acute challenge with levodopa (L-dopa) to predict sustained long-term L-dopa responsiveness as a major criterion for clinical diagnosis of PD. A consecutive series of 82 patients first seen at a movement disorders clinic with a parkinsonian syndrome without specific diagnosis was included. A second examiner, blind to the presumptive diagnosis, performed in each patient an acute challenge with 250/50 mg of L-dopa-carbidopa and rated the test as positive or negative according to whether values reached a minimal 30% of improvement on UPDRS scores. Positive tests were considered supportive of presumptive clinical diagnosis of Parkinson's disease. Blind to test results and according to clinical presumption, the first examiner started patient treatment with the necessary L-dopa dose or, alternatively, until reaching 1 g for 1 month in those who failed to display a positive test response. At 24 month follow-up, they were re-tested with 1 g for 1 month when required. At this point, clinical criteria of the U.K. Parkinson's Disease Society Brain Bank were applied and definitive clinical diagnosis of PD was made. Sensitivity, specificity, and positive predictive ratio for acute challenge were calculated. Overall sensitivity and specificity of acute L-dopa challenge to predict clinical diagnosis of PD was 70.9% and 81.4%, respectively; positive predictive ratio was 88.6%. When patients were divided into three groups according to their UPDRS motor section score at initial examination, sensitivity and specificity varied: Group I ( or=21), 36.4% and 87%, respectively. Positive predictive ratio increased to 100% in Group I and to 87.5% in Group III. The positive result of initial acute L-dopa challenge predicts chronic L-dopa responsiveness as major criterion of PD in all patients with UPDRS motor scores lower than 10.
The relationships between magnitude of response to orally administered carbidopa/levodopa (CD/LD) and serum/cerebrospinal fluid (CSF) concentrations of levodopa (LD), 3-O-methyldopa (3-O-MD), and homovanillic acid (HVA) were studied in 15 patients with chronic LD-treated Parkinson disease. The degree of clinical benefit derived from a 25/250 tablet of CD/LD could not be correlated with absolute serum levels of LD, 3-O-MD or LD/3-O-MD ratios. CSF levels of LD and 3-O-MD were also not associated with improvement. CSF levels of HVA, however, did significantly correlate with magnitude of response to LD. Furthermore, CSF HVA levels were not dependent on previous LD dosage. Our data suggest that in chronic LD-treated patients, central factors related to the integrity of the nigrostriatal tract may be a more important determinant of magnitude of response to LD than peripheral elements affecting the amount of LD entering the central nervous system.
We retrospectively compared the clinical state of 14 patients with Parkinson's disease who took pergolide continuously for 63 +/- 17 months (Group I) to that of 12 similar patients who started pergolide and then stopped it after 60 +/- 5 days (Group II). Disability measured during the "on" state did not worsen during the observations period in Group I patients, whereas disability in Group II showed significant deterioration. There were no significant differences in the progression of motor fluctuations between the two groups. Combination treatment with pergolide and levodopa is effective long-term symptomatic therapy for advanced Parkinson's disease and deserves more rigorous study to determine whether or not it also retards progression of Parkinson's disease.
OBJECTIVES: Levodopa (L-dopa) and L-dopa/carbidopa were evaluated to determine their effectiveness in the stimulation of bone healing of fractures at risk for nonunions. METHODS: Forty-two retired breeder female Sprague-Dawley rats were divided into 2 experimental groups and 1 control. Thirty-six rats were evaluated for results. The right femur of each rat was fractured and an intramedullary omega pin was inserted to create a 2 mm bone gap. The rats were administered either 0.2 g/kg/d of L-dopa, 0.2/0.02 g/kg/d L-dopa/carbidopa in their feed, or plain powdered chow (Sham control group). The rats were killed at 5 weeks postsurgery. The femurs were excised, radiographed, and mechanically tested. Bone healing was assessed. Bone stiffness, ultimate load, and energy to failure were determined under 3 point bending using an Instron materials testing system. RESULTS: The femurs of 30% of the Sham rats healed compared with 50% of the L-dopa/carbidopa and 84% of the L-dopa treated femurs. The healed L-dopa rat femurs had significantly greater ultimate load (P = 0.037) and energy to failure (P = 0.004) than the healed Sham rats. There were no significant differences between the L-dopa/carbidopa group and either the Sham or L-dopa group. CONCLUSIONS: These results confirm that L-dopa administration increases the healing in nonunion fractures. The combination of L-dopa/carbidopa did not significantly increase fracture healing.
OBJECTIVES: Contradictory possible cardiovascular side effects of selegiline have been reported. Therefore, we studied the effect of acute administration of selegiline with levodopa (LD) compared with LD alone, on blood pressure, pulse and norepinephrine (NE) plasma levels, during an orthostatic test on chronically treated Parkinson's disease patients (PDpts) and controls. MATERIALS AND METHODS: Twelve PDpts treated with LD (group D), 12 PDpts treated with selegiline and LD (group S) and eight volunteers (CTRL) underwent the orthostatic test. Patients repeated the test twice, before and after acute loading with 125 mg LD (group D) and 125 mg LD +5 mg selegiline (group S). RESULTS: Group S showed more episodes of postural hypotension (n = 10; two symptomatic) than group D (n = 4) and CTRL (n = 2), however not statistically significant. Plasma NE also rose significantly higher (P < 0.001) in group S. CONCLUSION: PD patients treated with selegiline showed more orthostatism and higher plasma NE after submission to the orthostatic test. These findings may be relevant to explain its deleterious effect.
The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.
The paper reports plasma levels of levodopa (LD), its main metabolites [dopamine, dihydroxyphenylacetic acid, homovanillic acid, 3-O-methyldopa (3-O-MD)] and carbidopa in 14 parkinsonian patients first treated with Sinemet and thereafter with Sinemet-CR4. A good relationship was observed between LD plasma levels and pharmacological effects. While the LD area under the curve increased after Sinemet-CR4, the same was not observed with metabolites, except with 3-O-MD. The experiments in volunteer subjects confirmed the increase in 3-O-MD in plasma after Sinemet-CR4. Higher levels were observed also in the CSF with a reduction of LD concentrations. This seems to corroborate the hypothesis of an interference with LD passage through the blood-brain barrier in humans.
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OBJECTIVE: To determine the optimum treatment for early Parkinson's disease. DESIGN: An open, long term, prospective randomised trial conducted by the Parkinson's Disease Research Group of the United Kingdom. SETTING: 93 hospitals throughout the United Kingdom. SUBJECTS: 782 patients with early Parkinson's disease who were not receiving dopaminergic treatment. INTERVENTIONS: Patients allocated to treatment with levodopa/dopa decarboxylase inhibitor alone (arm 1), levodopa/decarboxylase inhibitor/selegiline in combination (arm 2), or bromocriptine (arm 3). MAIN OUTCOME MEASURES: Disability assessment as judged by improvement on Hoehn and Yahr, modified Webster, and North Western University disability scales. Adverse event profile and mortality ratios. RESULTS: Interim results indicate that all three treatment regimens led to improvement in baseline disabilities after 12 months' treatment and that deterioration in control was apparent by three years. No significant differences were found between the results of treatment in arm 1 and arm 2, but both were significantly more effective than bromocriptine (arm 3) and had fewer early adverse reactions. The adjusted difference (95% confidence interval) in Webster rating for arm 3 v 1 was 0.93 points (0.27 to 1.50; p = 0.0058) and for arm 3 v 2 was 1.25 points (0.61 to 1.89; p = 0.0002). The incidence of dyskinesias and motor oscillations, however, was significantly lower in arm 3 (2% and 5%, respectively) than in arm 1 (27% and 33%, respectively) and arm 2 (34% and 35%, respectively). CONCLUSIONS: As there were no marked differences in functional improvement between the three groups the choice of treatment in the early stages of Parkinson's disease may not be critical.
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