Dopaminergic agonists in Parkinson's disease.

BACKGROUND: Non-ergoline dopamine agonists (DA) are effective treatments for Parkinson's disease (PD). This review presents the pharmacology, evidence of efficacy and safety profile of pramipexole, ropinirole, and rotigotine, and practical recommendations are given regarding their use in clinical practice. RESULTS: Extended-release formulations of pramipexole and ropinirole and transdermal continuous delivery rotigotine patches are currently available; these may contribute to stabilising of plasma levels. In early PD, the three drugs significantly improve disability scales, delay time to dyskinesia and allow a later introduction of levodopa. In late PD they reduced total 'off'-time, improved Unified Parkinson's Disease Rating Scale (UPDRS) in both 'on' and 'off' state and allowed a reduction in total levodopa dosage. A significant improvement in quality of life scales has also been demonstrated. Extended-release formulations have proved to be non-inferior to the immediate release formulations and are better tolerated (ropinirole). Despite a generally good safety profile, serious adverse events, such as impulse control disorder and sleep attacks, need to be routinely monitored. Although combination therapy has not been addressed in scientific literature, certain combinations, such as apomorphine and another DA, may be helpful. Switching from one DA to another is feasible and safe, although in the first days an overlap of dopaminergic side effects may occur. When treatment with DA is stopped abruptly, dopamine withdrawal syndrome may present. Suspending any DA, especially pramipexole, has been linked to onset of apathy, which may be severe. CONCLUSIONS: New non-ergotine DAs are a valuable option for the treatment of both early and late PD. Despite their good safety profile, serious adverse effects may appear; these effects may have a pathoplastic effect on the course of PD and need to be monitored.

Classifying risk factors for dyskinesia in Parkinson's disease.

BACKGROUND: Currently there is no classification of risk factors applicable to an individual patient with Parkinson's disease for the development of dyskinesia. METHODS: We conducted literature search to identify and classifying risk factors into groups - (a) intrinsic vs extrinsic and (b) modifiable vs non-modifiable. RESULTS: Younger age, young age of onset and severity of PD are major intrinsic non-modifiable risk factors for dyskinesia, female gender is another factor but not independent of other factors. Genetic expression and plasticity may determine pre-disposition to age of onset of PD and dyskinesia, these are currently non-modifiable factors arising due to an interaction of intrinsic and extrinsic factors. Lower initial body weight and weight loss during the course of the disease increase the risk of dyskinesia. Levodopa dose per kilogram body weight is a more significant risk factor than absolute levodopa dose. Early use of longer acting non-levodopa (i.e. dopamine agonists) medications delays the onset of dyskinesia. Interaction between body weight, levodopa dose and mode and duration of drug delivery is a significant modifiable factor. CONCLUSION: Dyskinesia in PD arises as a consequence of the interaction of intrinsic versus extrinsic and modifiable versus non-modifiable factors. Identification and manipulation of modifiable factors for an individual patient may reduce the risk and burden of dyskinesia. Adjustment of levodopa dose according to body weight during the course of the disease seems to be a significant modifiable risk factor for dyskinesia.

Efficacy and safety of pallidal stimulation in primary dystonia: results of the Spanish multicentric study.

BACKGROUND: Dystonia is a complex clinical syndrome originated by a wide range of aetiologies. The diagnosis of dystonia is made after the evaluation of aetiological, phenomenological and genetic factors. Medications, except in patients with dopa-responsive dystonia, are of limited efficacy. Botulinum toxin injections are not applicable to patients with generalised dystonia, since many muscular groups contribute to disability. Clinical studies in children and adults with primary generalised dystonia (PGD) have reported beneficial effects of bilateral GPi deep brain stimulation (DBS) in both motor symptoms and disability produced by dystonia as well as a favourable impact of DBS in the health-related quality of life (HRQoL). Some clinical aspects of GPi stimulation in primary dystonia still remain controversial such as the influence of disease duration or age at onset in determining the postoperative clinical outcome. RESULTS: The authors report the results of a multicentric study designed to assess the tolerability and clinical effects of bilateral pallidal DBS on motor impairment, functional disability, quality of life, pain and mood in patients with medically refractory primary generalised or segmental dystonia.

A global view of Parkinson's disease pathogenesis: implications for natural history and neuroprotection.

Neuroprotection in PD remains the most important goal of current research. Most of presently used strategies are directed at interfering with signalling pathways involved in neuronal death. However, the influence of compensatory alterations in neurotransmitter receptors and related signalling pathways, as well as the role of aging and associated lesions, are not taken into consideration. Their progressive failure might contribute to the appearance and/or progression of the disease. Thus, early restoration of basal ganglia physiology will support the compensatory events and delay the irreversible modification of circuitry that characterizes the clinical progression of PD. Enhancing neuronal plasticity and avoiding the negative effects of aging and associated lesions might help the remaining neural circuits to compensate for lost or broken circuits and improve overall network performance and neurological function. These modulating factors represent potential targets for therapeutic intervention resulting in lasting clinical benefit for the patient. The concept of neuroprotection should be modified, shifting the focus from neurons that are lost to those that survive.

[Neuroprotection in Parkinson's disease: analysis though group of experts' methodology]. / Neuroprotección en la enfermedad de Parkinson: análisis a través de la metodología de informadores clave.

INTRODUCTION: Currently used antiparkinsonian drugs neither stop nor slow-down the progressive nature of the disease. The final phase of PD is characterized by the presence of symptoms and signs resistant to dopaminergic agents, such as depression, dementia, freezing and falls. Therefore, it is urgent to develop therapies able to positively modify this outcome. Despite neuroprotection is a research priority in PD, no effective strategies have been found so far. METHOD: A key informants study was conducted. A group of experts in PD fulfilled a questionnaire of 10 questions to explore the most important topics related to neuroprotection. Afterwards a consensus about the current situation of neuroprotection in PD was established and future directions of development were suggested. RESULTS: Most of the answers emphasized the need of new concepts, the limitations of animal models and the difficulties in the difficulties in demonstrating a neuroprotective effects in humans owing to a lack of biomarkers. Some of the experts believe that we are already exerting a disease modifying effect. CONCLUSIONS: The concept of neuroprotection should be widened. Animal models should be improved. A reliable biomarker to start neuroprotective therapies long before the appearance of motor symptoms and to evaluate the neuroprotective effect of any therapy should be urgently developed.

[If I were to wake up clumsy and shaking (10 years later)]. / Si me despertara torpe y con temblor... (10 años después).

The diagnosis and treatment of early Parkinson's disease (PD) has undergone considerable changes in the last 10 years. Identification of genes responsible for familial forms of the disease as well as the possibility of detecting dopaminergic dysfunction before the appearance of motor symptoms has opened up the possibility of presymptomatic diagnosis. The concept of PD is changing. Therapeutic strategies are quite different. Several studies support the recommendation of not delaying the onset of dopaminergic therapies. Nonetheless, neuroprotection still has not been totally demonstrated and this continues to be an objective of priority.

[Spinal cord compression due to a epidural lipoma]. / Compresión medular por lipoma epidural dorsal.

INTRODUCTION: The spinal extradural space is normally occupied by adipose tissue and a venous plexus, so it should be not surprising that lipomas arise and reach sufficient size to compress symptomatically the spinal cord. Nevertheless, the spinal epidural lipomas are rare and benign tumours may present as a progressive spinal cord compression syndrome. Magnetic resonance imaging is useful in demonstrating the full extent and characteristics of these lesions, the severity of cord compression and the location in the canal. Usually, the lesion is amenable to total surgical extirpation and the functional prognosis is good. Histopathologically the tumour consists of a mature adipose cells matrix intermixed with vascular endothelial channels, that is the reason why it is also named angiolipomas. CASE REPORT: A 47 year-old woman complained of dorsal and bilateral submamarian pain lasting two years and progressive loss of sensibility and weakness in her legs. Following magnetic resonance studies a posterior spinal cord compression by an extradural tumour at T3-T7 levels was observed. She was operated on and we found an extradural yellow tumour easily to dissect and it was completely removed. One year later she is asymptomatic. CONCLUSIONS: Spinal epidural lipoma is a benign tumour which initially presents itself with local or radicular pain accompanied by progressive spinal cord compression syndrome. The choice treatment is laminectomy and total excision. Probably, this is one of the easiest tumours to remove of the spinal canal and a source of satisfaction because a complete recovery can usually be achieved.

Potential applications of nanotechnologies to Parkinson's disease therapy.

Nanotechnology will play a key role in developing new diagnostic and therapeutic tools. Nanotechnologies use engineered materials with the smallest functional organization on the nanometre scale in at least one dimension. Some aspects of the material can be manipulated resulting in new functional properties. Nanotechnology could provide devices to limit and reverse neuropathological disease states, to support and promote functional regeneration of damaged neurons, to provide neuroprotection and to facilitate the delivery of drugs and small molecules across the blood-brain barrier. All of them are relevant to improve current therapy of Parkinson's disease (PD).

[Rasagiline in Parkinson's disease]. / Rasagilina en la enfermedad de Parkinson.

Rasagiline is a selective and irreversible monoamine oxidase-B inhibitor. It is not metabolized to amphetamine derivatives. It has been shown to be safe and efficacious as monotherapy in early PD, as well as adjuvant therapy in levodopa-treated patients with mild motor complications. Rasagiline can be used with other antiparkinsonian drugs. Tolerance is good even in aged patients. Posology is simple and convenient (once a day). Its early use seems to improve the outcome of parkinsonian patients. Furthermore, a potential neuroprotective effect has been suggested in experimental studies. Results of the ADAGIO study are awaited with interest. Therefore, rasagiline is especially well suited as to be used as the initial treatment of PD.

[Onset of dopaminergic therapy in Parkinson's disease: six good reasons not to delay it]. / Inicio de la terapia dopaminérgica en la enfermedad de Parkinson: seis buenas razones para no retrasarlo.

Determining the point at which drug therapy with a dopaminergic agent should begin in a patient with early Parkinson disease is controversial. The current trend favors not indicating any drug until functional disability is present. However, the evolution demonstrated by patients included in different clinical trials indicates that delaying dopaminergic treatment is associated with worst outcome. In addition, there are other experimental and clinical data that support this idea. On the other side of the argument is the possibility that early use of drugs may inducing adverse effects in non-disabled patients.

Pharmacological treatment of Parkinson's disease: life beyond dopamine D2/D3 receptors?

Parkinson's disease (PD) is a multisystemic disorder in which several neurotransmitters other than dopamine are affected. Drugs acting on non-dopaminergic systems are envisaged as promising agents to treat PD and levodopa-induced dyskinesias (LID). However, compounds targeting glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed in human studies showing negative, inconsistent or unsatisfactory results. Most of these drugs had been tested previously in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, as well as in the classic 6-hydroxydopamine-lesioned rat model. These failures raise several questions and concerns about the true reliability of animal studies, the adequacy of the working hypotheses and design of clinical trials, the validity of tools in current use to evaluate a particular effect, and the selectivity of the drugs used. More importantly, observed discrepancies between the results in models and patients, could challenge the validity of current ideas about the pathophysiology of parkinsonism and LID.

Should levodopa dose be reduced when switched to stalevo?

The addition of entacapone to levodopa-carbidopa (LC) or the switch from LC to a tablet containing levodopa-carbidopa-entacapone (LCE) improves the wearing-off phenomenon, increases the 'on' time and decreases the 'off' time, but the appearance or exacerbation of dyskinesias is the more frequent side-effect. Thus, a reduction of the total levodopa dosage would be recommended. However, this could result in a lack of efficacy against the wearing-off. We report on the results of a clinical trial conducted to determine the best way in terms of efficacy, tolerability and safety of switching from LC to LCE in patients with Parkinson's disease (PD) and end of dose wearing-off. 39 patients with PD and wearing-off without or with mild dyskinesias were randomly assigned to either a group receiving the same LC dosage or to a group in which the total LC amount was reduced by 15-25%. Four weeks after the change, both groups showed an increase in daily 'on' time and a reduction in the daily time spent in 'off'. Two patients in each group experienced an increase in basal dyskinesias. No differences in clinical assessment between groups were found. Tolerance was excellent. This study suggests that switching from LC to LCE in patients with mild-to-moderate wearing-off can be done safely with or without reducing the total LD amount, but in the clinical setting it would be more practical to keep the dosage of LC unchanged unless severe dyskinesias are present.

Classical Parkinson disease versus Parkinson complex--reflections against staging and in favour of heterogeneity.

Pathological studies have prompted the idea that Parkinson disease (PD) is a multisystem disorder, which starts far away from the nigrostriatal dopamine system and it goes through a long pre-clinical period. Evidence from epidemiological research, functional imaging, olfaction and sleep studies provides support to this hypothesis. Accordingly, PD is seen as an homogeneous disease which sequentially affects different neural structures leading to a well-defined clinical picture. This concept, recently named PD complex, has deep theoretical and practical implications which raise some concerns. This report shows the concept of classical PD as opposed to PD complex. Although the relevance of the central argument concerning the PD complex concept is admitted, it needs to be fully proved before premature conclusions are drawn. In contrast, the notion of classical and clinically significant PD can explain many of the well-characterized pathological and clinical features of the disease and it gives support to the idea that the magic word in PD is variability.

Severe stuttering and motor tics responsive to cocaine.

Developmental stuttering and tics share many clinical and therapeutical aspects. Dopaminergic neurotransmission seems to be involved in the pathophysiology of both, tics and stuttering. We report on a patient with severe stuttering and mild facial tics which were dramatically improved by cocaine, challenging previous reports.

[Treatment of Parkinson disease: therapeutic reserve of the dopaminergic agonist]. / Tratamiento de la enfermedad de Parkinson: reserva terapéutica de los agonistas dopaminérgicos.

Parkinson's disease (PD) is a neurodegenerative, chronic and progressive disease whose evolutive course changed significantly after the introduction of levodopa. However, no antiparkinsonian drug has been able to stop the progression of PD. Thus, as the years have passed, greater drug doses have been necessary, either alone or in different combinations. Therefore, it is useful to have drugs with a wide threshold between effective dose and maximum tolerated dose. The concept of therapeutic reserve (TR) can be considered equivalent to therapeutic index or therapeutic window and could be defined as the difference between the dose needed to achieve an optimum therapeutic response at a given time and the dose that causes adverse events (maximum recommended dose or "ceiling dose"). This difference indicates the threshold that makes it possible to use higher doses as the disease advances to maintain an optimum clinical effect without the appearance of adverse events. This concept is important in the case of dopaminergic agonists whose efficacy seems to be similar in the daily clinical practice. Although there are no direct comparative studies, the analysis of the results of different studies suggests that the TR of ropinirole is superior to that of other dopaminergic agonists. The first effective dose, defined as an improvement superior to 30 % is observed with 9 mg/day in 75 % of the patients while the maximum recommended dose is 24 mg/day. This threshold is less with other dopamine agonists.