Levodopa with benserazide or carbidopa in Parkinson disease

Plasma levodopa and therapeutic responses to treatment with levodopa in combination with benserazide or carbidopa were studied in 49 patients with Parkinson disease not previously treated with levodopa in a blind randomized crossover trial. The treatment periods were 12 weeks; similar dosage schedules were used, with doses that induced equal levels of plasma levodopa in both combinations. In pretrial studies of plasma levodopa responses, 200 mg of levodopa and 50 mg of benserazide was equal to 250 mg of levodopa combined with 25 mg of carbidopa. Equal plasma levodopa responses to both combinations were also found during the trial. There was no significant difference between the treatment groups in beneficial effects on parkinsonian disability and individual symptoms or in the frequency of involuntary movements. However, nausea and vomiting occurred significantly more often during treatment with levodopa and carbidopa than during treatment with levodopa and benserazide. This difference was probably due to inadequate inhibition of peripheral decarboxylase inhibitor by the 1:10 ratio of carbidopa to levodopa.     

Combination therapy with lisuride and L-dopa in the early stages of Parkinson's disease decreases and delays the development of motor fluctuations. Long-term study over 10 years in comparison with L-dopa monotherapy

A randomized, prospective study was carried out in order to investigate the efficacy of a dopamine agonist, lisuride, alone or in combination with levodopa, to minimize or postpone the development of motor fluctuations, compared with levodopa alone during 10 years' treatment of 90 patients with early Parkinson's disease. Only a small, and with time gradually decreasing number of patients obtained enough therapeutic benefit during long-term treatment with lisuride alone. Consequently, levodopa had to be added to the patients' regimen. During combined treatment with lisuride and levodopa the daily dose of levodopa needed for optimal therapeutic response was significantly lower than when using levodopa alone. The addition of levodopa to the lisuride regimen either from the beginning or at any time during long-term treatment according to clinical need, resulted in a therapeutic response in parkinsonian disability equal to that achieved with levodopa alone, but significantly decreased and postponed the development of motor fluctuations, end-of-dose failure and dyskinesias. Severe dopaminergic adverse events leading to withdrawal of the treatment were more frequent during treatment with lisuride and levodopa than with levodopa alone, but the lower mortality rate did not reach the level of statistical significance. In conclusion, according to the results obtained, it seems reasonable to consider a treatment strategy in early Parkinson's disease using a dopamine agonist, like lisuride, as the primary treatment and to delay the addition of levodopa until parkinsonian disability cannot be adequately controlled by a dopamine agonist.     

New strategies in the treatment of early Parkinson's disease

Over recent years I have been studying whether dopamine agonist treatment alone, or in early combination with levodopa, might institute a better long-term treatment in Parkinson's disease than levodopa alone. Indeed, early combination of levodopa with bromocriptine, pergolide or lisuride has indicated that this kind of treatment results in better management of Parkinson's disease with fewer fluctuations in disability, especially end-of-dose disturbances and dyskinesias, than treatment with levodopa alone. Furthermore, similar results were obtained by using lisuride in combination with selegiline and levodopa. However, during long-term treatment the changes in parkinsonian disability were equal in all treatment groups with or without selegiline. Thus, the possible efficacy of selegiline in slowing down the progression of Parkinson's disease requires further investigations. As a new treatment strategy it appears advisable to initiate the dopaminergic treatment in early Parkinson's disease by using initially selegiline and a dopamine agonist and by adding levodopa when the therapeutic response is insuifficient. Another alternative would be to start with selegiline alone, then add a dopamine agonist and, finally, levodopa.     

The detrimental effect of levodopa on behavioral efficacy of fetal dopamine neuron grafts in rats is reversible following prolonged withdrawal of chronic dosing

In previous studies, we observed that chronic levodopa treatment resulted in impaired morphology and function of grafted dopamine neurons in rats. To begin to better understand how levodopa treatment might influence dopamine neurons, we examined whether subsequent discontinuation of chronic levodopa treatment might allow for recovery of graft efficacy. Function of embryonic mesencephalic tissue grafts was assessed by monitoring rotational behavior elicited by amphetamine in lesioned, grafted rats initially treated for 6 weeks with levodopa followed by a 6 week drug-free period. As observed previously, control grafted animals, but not levodopa treated animals, showed behavioral improvement. However, following a 6 week withdrawal period, the levodopa animals demonstrated a significant reduction in amphetamine rotations which was reminiscent of control animals. This suggests that grafted neurons can recover functionally after levodopa treatment is withdrawn, which may be of significance in clinical transplantation trials.     

Effects of 2,3-benzodiazepine AMPA receptor antagonists on dopamine turnover in the striatum of rats with experimental parkinsonism

Although levodopa is the current "gold standard" for treatment of Parkinson's disease, there has been disputation on whether AMPA receptor antagonists can be used as adjuvant therapy to improve the effects of levodopa. Systemic administration of levodopa, the precursor of dopamine, increases brain dopamine turnover rate and this elevated turnover is believed to be essential for successful treatment of Parkinson's disease. However, long-term treatment of patients with levodopa often leads to development of dyskinesia. Therefore, drugs that feature potentiation of dopamine turnover rate and are able to reduce daily levodopa dosages might be used as adjuvant in the treatment of patients suffering from Parkinson's disease. To investigate such combined treatment, we have examined the effects of two non-competitive AMPA receptor antagonists, GYKI-52466 and GYKI-53405, alone or in combination with levodopa on dopamine turnover rate in 6-hydroxydopamine-lesioned striatum of the rat. We found here that repeated administration of levodopa, added with the peripheral DOPA decarboxylase inhibitor carbidopa, increased dopamine turnover rate after lesioning the striatum with 6-hydroxydopamine. Moreover, combination of levodopa with GYKI-52466 or GYKI-53405 further increased dopamine turnover enhanced by levodopa administration while the AMPA receptor antagonists by themselves failed to influence striatal dopamine turnover. We concluded from the present data that potentiation observed between levodopa and AMPA receptor antagonists may reflect levodopa-sparing effects in clinical treatment indicating the therapeutic potential of such combination in the management of Parkinson's disease.     

Effect of late initiation of levodopa treatment in patients with long-standing Parkinson's disease

The time of initiation of levodopa therapy in patients with Parkinson's disease (PD) is still debatable, as is the hypothesis of levodopa toxicity Some researchers argue that late initiation of treatment will delay the appearance of response fluctuations. In the present study, 11 patients in whom treatment with low doses of levodopa was delayed for a mean of 7.9 +/- 3.1 years were followed for a mean of 15.7 +/- 3.3 years. Time of onset of response fluctuations and disease severity were compared with those in 17 patients with fluctuating PD who were treated with levodopa from disease onset. There was no significant change in time to onset of response fluctuations and dyskinesias once levodopa treatment was started, and late initiation of levodopa did not affect disease progression. The authors conclude that the decision of when to initiate levodopa treatment should be taken according to the patient's needs.     

Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease

OBJECTIVES: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa. METHODS: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. RESULTS: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. CONCLUSIONS: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.     

左旋多巴甲酯可增加斜视性弱视模型猫视皮质17区神经生长因子的表达

实验以处于发育敏感期的猫建立斜视性弱视动物模型,比较左旋多巴甲酯及左旋多巴对斜视性弱视猫视皮质17区神经生长因子表达的影响。图形视觉诱发电位结果和免疫组织化学检测结果显示,左旋多巴及左旋多巴甲酯均能缩短斜视性弱视模型猫P100波潜时,增大P100波幅,还能使其视皮质各层的内源性神经生长因子免疫阳性细胞数量增加,但左旋多巴甲酯的治疗效果优于左旋多巴。     

Problems associated with long-term levodopa treatment of Parkinson's disease

ABSTRACT — Levodopa treatment improves significantly not only the parkinsonian disability but also the mortality rate. However, during long-term levodopa treatment the therapeutic benefit gradually declines. Furthermore, most cognitive skills improve initially, but long-term levodopa treatment is associated with declining intellectual capacity and dementia.
In patients on long-term levodopa treatment there seems to be a low threshold for certain clinical side-effects, especially postural hypotension, psychiatric disturbances and various types of fluctuations in disability. Low age at onset of Parkinson's disease, and at the commencement of levodopa therapy, the duration of levodopa treatment and a high dose of levodopa seem to be significant risk factors for the development of response fluctuations, but not the pretreatment duration of Parkinson's disease nor the disability of the patients.
A readjustment of the levodopa dosage, and as an adjuvant drug treatment, deprenyl, a specific inhibitor of MAO type B, or a direct-acting dopamine agonist may prove helpful in the management of fluctuations in disability. It is important, moreover, to try to prevent these phenomena by taking into account the predictive risk factors of response fluctuations in the treatment strategy of Parkinson's disease.     

Combination of a dopamine agonist, MAO-B inhibitor and levodopa — a new strategy in the treatment of early Parkinson's disease

Abstract– During 3 years'treatment of de novo parkinsonian patients with lisuride in combination with selegiline and levodopa the optimal therapeutic dose of levodopa was significantly lower than that when given alone or together with lisuride. The improvement in parkinsonian disability was equal in all these patient groups, but treatment with an early combination of lisuride and levodopa without or with selegiline resulted in significantly and equally reduced end-of-dose disturbances and dyskinesias than treatment with levodopa alone. This finding, together with the possible retardation of the progression of the disease with selegiline suggests that dopaminergic treatment in early Parkinson's disease should be initiated using a dopamine agonist such as lisuride in combination with selegiline and levodopa.     

Normal activation of the supplementary motor area in patients with Parkinson''s disease undergoing long-term treatment with levodopa.

Regional cerebral blood flow (rCBF) changes in cortical motor areas were measured during a movement of the dominant right hand in 15 patients with Parkinson's disease deprived of their usual levodopa treatment, in 11 patients with Parkinson's disease undergoing long-term treatment with levodopa, and in 15 normal volunteers. The supplementary motor areas were significantly activated in the normal subjects and in the patients receiving levodopa but not in the patients deprived of levodopa. The contralateral primary sensory motor area was significantly activated in all three groups. The ipsilateral primary sensory motor cortex was not activated in the normal subjects and the non-treated patients but was in the patients treated with levodopa. It is concluded that the supplementary motor area hypoactivation which is observed in akinetic non-treated patients with Parkinson's disease is not present in patients undergoing long-term treatment with levodopa. This result suggests that (a) levodopa improves the functional activity of supplementary motor areas in Parkinson's disease and (b) there is no pharmacological tolerance to this effect. The ipsilateral primary motor cortex activation observed in the patients treated with levodopa could be related to levodopa-induced abnormal involuntary movements.     

Levodopa dependency in Parkinson's disease: case report and review

Only a few patients with Parkinson's disease and levodopa dependency or abuse have been reported. We present a 35-year-old patient with young-onset Parkinson's disease who developed motor complications, levodopa dependency, and drug-induced psychosis after primary treatment with levodopa. Diagnostic criteria and treatment guidelines for this neuropsychiatric disorder are presented as well as a tentative neurobiological answer to the question of why levodopa dependency is observed only in a minority of patients with Parkinson's disease.     

Early combination of bromocriptine and levodopa in the treatment of Parkinson's disease: a 5-year follow-up

Compared with levodopa, long-term bromocriptine treatment of parkinsonian patients for 5 years resulted in fewer fluctuations of disability and peak-dose dyskinesias, but also less improvement in parkinsonian disability. Combination of low-dose bromocriptine and levodopa resulted in a therapeutic response equal to that of levodopa alone but with fewer end-of-dose disturbances and peak-dose dyskinesias. I believe that treatment should begin promptly with a low dose of levodopa, combined with a dopamine agonist such as bromocriptine.     

Does levodopa alter depression and psychopathology in Parkinsonism patients?

Twenty-seven Parkinsonism patients and 31 controls, matched for age and verbal IQ, were tested on an objectively scored personality test (Minnesota Multiphasic Personality Inventory) at the beginning of the patients' levodopa therapy and three months later. Patients, but not the controls, were retested after 15 months of levodopa treatment. The patients, all of whom were intact intellectually, obtained MMPI scores indicating moderate depression before beginning levodopa treatment. There was no test evidence to indicate that levodopa significantly increased or decreased the amount of depression in the patients after three or 15 months of levodopa. The patient group, however, significantly increased their Index of Psychopathology (Ip) score after 15 months of levodopa but not after three months.     

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.     

Inter- and intraindividual pharmacokinetic variations in the treatment of Parkinson's disease]

In the treatment of Parkinson's disease, levodopa, DCI, MAO-B inhibitor, COMT inhibitors, dopamine receptor agonists, amantadine, anticholinergics have been applied and new drugs are being developed. Levodopa is still the golden standard in the treatment of Parkinson's disease. The study on levodopa bioavailability showed 3-4 times differences in individual patients. Drug-food interactions are prominent in levodopa. Low protein food increased levodopa bioavailability and improved no ON or delayed ON in the treatment of Parkinson's disease. Vitamine C or magnesium did not alter the bioavailability of levodopa. The bioavailability of levodopa between the levodopa/carbidioa (100/12.5) group and the levodopa/benserazide (100/25) group was studied in patients with Parkinson's disease by population PK study. C(max) of levodopa in levodeopa/benserazide group was twice as high as in levodopa/carbidopa group. Domperidone, a dopamine receptor antagonist applied as an antiemetic inceases vowel movement. The effect of domperidone on levodopa bioavailability was studied, and the combination of domperidone with levodopa increased AUC of levodopa. Clarythromycin or grape fruit juice inhibits both of CYP3A4 and P-glycoprotein which work on metabolism and absorption of drugs. Coadministration of clarythromycin with ergot alkaloids such as cabergoline or bromocriptine increased the AUC up to 2-3 times. Amantadine is excreted through kidney without being metabolized and renal function is the most important factor in the blood concentration of amantadine. In elder women with the body weight of 50 kg or less, creatinine clearance is less than 50 ml/min even though the serum creatinine is within the normal range. Selegiline is metabolized through CYP2D6 and 3A4. Coadministration of qunidine, cimetidine, maclorides, antifungals, grape fruit juice increase the bioavailability of selegiline and may augment the antiparkinsonian effect.     

Rapid switch from oral antiparkinsonian combination drug therapy to duodenal levodopa infusion

Six patients with Parkinson's disease (PD) with severe motor complications were directly switched from their oral antiparkinsonian combination drug regime to nasoduodenal levodopa infusion without previously recommended transient treatment with levodopa alone. Duodenal levodopa infusion reduced motor complications to a considerable extent. We have shown that a prior change to an oral levodopa monotherapy and a slow titration of duodenal levodopa infusion may be skipped and a direct switch to duodenal levodopa is a safe option. © 2007 Movement Disorder Society     

Levodopa response in early Parkinson's disease

To further characterize the short‐term levodopa response in early PD, we performed a retrospective analysis of the ELLDOPA study which randomized 361 early PD subjects to placebo, levodopa 150, 300, or 600 mg/day. We evaluated change in UPDRS motor scores (UPDRSm) from baseline to weeks 9 and 24, and identified changes in UPDRSm that best discriminated treatment with levodopa from placebo. Linear regressions were used to determine associations between baseline characteristics and changes in UPDRSm. Mean percent improvement in UPDRSm in levodopa‐treated subjects was greater than that for placebo‐treated subjects (27.4% vs. 5.8% at 9 weeks, P < 0.001 and 26.2% vs. 4.0% at 24 weeks, P < 0.001). UPDRSm change at 9 weeks ranged from –92.9% (improvement) to 85.7% (worsening) for levodopa and –86.7% to 160% for placebo, and at 24 weeks ranged from –100.0% to 242.9% for levodopa and –87.5% to 112.5% for placebo. UPDRSm improvements of 22.0% at 9 weeks and 23.8% at 24 weeks best discriminated treatment with levodopa 300 mg/day (a common initial maintenance dosage in clinical practice) from placebo. Significant associations were not observed between baseline subject characteristics and magnitude of response from baseline to week 24. We conclude that although levodopa treatment significantly improved PD signs when compared with placebo, there was a wide range and considerable overlap in clinical responses to levodopa and placebo. A substantial proportion of subjects with early PD did not experience a robust response to levodopa. An improvement in UPDRSm of ～22% best discriminated levodopa treatment from placebo. © 2009 Movement Disorder Society     

L-tryptophan in the treatment of levodopa induced psychiatric disorders

Nine patients with levodopa induced psychiatric side effects were treated with L-Tryptophan in a single blind controlled study. In all patients levodopa therapy was continued and no sedative agents were given. In 8 patients all psychiatric side effects cleared within 48 hours, and without reoccurrence of these symptoms on an 8 month follow up. Only one patient did not respond to the treatment, but this patient proved to have a psychotic depression which was unrelated to levodopa therapy. Six patients with levodopa induced psychiatric disorders were used as control subjects and were not treated with L-Tryptophan. In these patients mental changes subsided only after levodopa had been discontinued for a period of 2 to 8 weeks. The rationale for treatment with L-Tryptophan is based on the findings of decreased serotonin content of the brain after levodopa treatment. This was documented by animal studies and reflected by changes in the spinal fluid concentration of 5-hydroxyindolacetic acid before and after L-Tryptophan treatment. This study confirms the results described by Dr. Birkmayer who treated levodopa induced psychosis first in 1972 in this manner.     

Optimization of use of levodopa in Parkinson's disease: role of levodopa-carbidopa-entacapone combination

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.