Continuous Levodopa Delivery with an Intraoral Micropump System: An Open-Label Pharmacokinetics and Clinical Study.

BACKGROUND: Double-blind studies have demonstrated that motor complications in Parkinson's disease (PD) can be reduced with continuous delivery of levodopa. The DopaFuse system is a novel, intraoral micropump that attaches to a retainer and uses a propellant to deliver levodopa/carbidopa (LD/CD) continuously into the mouth. OBJECTIVES: Evaluate the safety, pharmacokinetics, and efficacy of LD/CD delivered via the DopaFuse system compared to treatment with intermittent doses of standard oral LD/CD in PD patients with motor fluctuations. METHODS: This was a 2-week, open-label study (NCT04778176) in 16 PD patients treated with ≥4 levodopa doses/day and experiencing motor fluctuations. On Day 1 (clinic setting) patients received their usual dose of standard LD/CD; DopaFuse therapy was initiated on Day 2, and on Day 3 patients received DopaFuse plus a morning oral LD/CD dose. Patients returned home on Days 4-14 and returned for in-clinic assessment on Day 15. RESULTS: Continuous DopaFuse delivery of LD/CD was associated with reduced variability in plasma levodopa levels compared to oral LD/CD (mean ± SD levodopa Fluctuation Index reduced from 2.15 ± 0.59 on Day1 to 1.50 ± 0.55 on Day 2 (P = 0.0129) and to 1.03 ± 0.53 on Day 3 (P < 0.0001)). This pharmacokinetic improvement translated into significantly reduced OFF time with DopaFuse therapy (reduction of -1.72 ± 0.37 h at Day 15; P = 0.0004) and increased ON time without severe dyskinesias (increase of 1.72 ± 0.37 h at Day 15; P = 0.0004) versus oral LD/CD administration. DopaFuse therapy was not associated with any clinically significant adverse events. CONCLUSIONS: Continuous delivery of LD/CD using the DopaFuse system was associated with significantly less variability in plasma levodopa concentrations and reductions in OFF time compared to treatment with standard oral LD/CD therapy and was well tolerated. © 2024 International Parkinson and Movement Disorder Society.

Therapeutic education for empowerment and engagement in patients with Parkinson's disease: A non-pharmacological, interventional, multicentric, randomized controlled trial.

Background: In 1997 the European Parkinson's Disease Associations launched the Charter for People with Parkinson's disease that stated the right of patients to be informed and trained on the disease, its course, and treatments available. To date, few data analyzed the effectiveness of education program on motor and non-motor symptoms of PD. Objective: The aim of this study was to evaluate the efficacy of an education program as it was a pharmacological treatment, thus choosing as the primary endpoint the change in daily OFF hours, the most widely used outcome in pharmaceutical clinical trials on PD patients with motor fluctuations. Secondary outcomes were change in motor and non-motor symptoms, quality of life and social functioning. The long-term efficacy of the education therapy was also evaluated by analyzing data collected at 12- and 24-weeks follow-up outpatient visits. Methods: One hundred and twenty advanced patients and their caregivers were assigned to the intervention or control group in a single-blind, multicentric, prospective, randomized study evaluating an education program structured in individual and group sessions over a 6-weeks period.At the end of study, the intervention group showed a significant reduction in daily OFF hours compared to control patients (-1.07 ± 0.78 vs. 0.09 ± 0.35, p < 0.0001) and a significant improvement was also reported in most secondary outcomes. Patients retained significant medication adherence and daily OFF hours reduction at 12- and 24-weeks follow-up. Conclusion: The results obtained demonstrated that education programs may translate in a notable improvement in motor fluctuations and non-motor symptoms in advanced PD patients.Clinical Trial Registration:Clinicaltrials.gov, identifier NCT04378127.

An evaluation of the efficacy and value of CVT-301 for the treatment of Parkinson's disease.

Introduction: Levodopa is the most effective drug in the treatment of Parkinson's disease, but its chronic treatment is linked to the occurrence of motor complications with fluctuations of motor performance and dyskinesia. Unpredictable OFF episodes can be severe and disabling and current rescue medications cannot always be used safely. Rescue therapy is characterized by a rapid and predictable ON response and the safety profile of levodopa will represent a major advantage for patients affected by unresponsive OFF episodes.Areas covered: CVT-301 is a new inhaled formulation of LD recently developed as a self-administered treatment for OFF periods. Herein, the pharmacodynamic and pharmacokinetic properties, efficacy, and safety of CVT-301 are reviewed.Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism, and less plasma level variability. It should be noted that the delivery device used has been described as relatively simple to use, but the few steps required to prepare and self-administer the dose can be challenging for PD patients during their OFF state. Additionally, resolution of an OFF episode requires the administration of two capsules of CVT-301, which further complicates the use of the device.

Effect of family history, occupation and diet on the risk of Parkinson disease: A case-control study.

BACKGROUND: The aetiology of Parkinson's disease (PD) is still very controversial, with a peculiar lack of established risk factors or protective behavior. METHODS: We carried out a case-control study of 634 idiopathic PD patients admitted from 2011 to 2015 to two hospitals located in central Italy and 532 controls matched by hospital, gender and age (± 5 years). The study questionnaire included questions on host factors, family history, residence, occupation and lifestyle. Odds ratios (ORs) for PD and 95% confidence intervals (CIs) were estimated with logistic regression, adjusting for actual and potential confounders. RESULTS: A lower OR was observed in females (0.74; 95%CI:0.58-0.96), while older age classes showed a constantly increased risk for PD (p<0.005) starting from the class 65-69 years. Subjects who reported a first degree relative affected by PD showed a borderline increase which was more evident in those enrolled in the urban center of Rome (OR = 1.65; 95%CI: 1.09-2.50). Significant reduction of the risk was associated to current smoking (OR = 0.48; 95%CI: 0.24-0.54), and to vegetables consumption (p<0.03), while borderline increases were associated to meat and cold cut consumption. Occupational activities classified according to ISCO-08 categories did not show increased risk, while higher ORs' were found for pilots and physicians. CONCLUSIONS: The results from this study confirmed the higher risk of PD in males and in elderly, and the inverse association with smoking habit. The possible etiological role of familial clustering, dietary habit, and some job tasks is suggested.

The impact of intestinal microbiota on weight loss in Parkinson's disease patients: a pilot study.

Background: There is increasing evidence of the association between microbiome dysfunction and Parkinson's disease (PD). Moreover, some PD patients suffer from unintentional weight loss (WL) which may precede the motor manifestations of the disease. Materials & methods: Gut microbiota profiling by 16S rRNA gene sequencing was performed in PD patients with an unintended WL, in steady weight patients (non-WL [NWL]) and in matched normal subjects. KEGG functional predictions were carried out. Results: Microbiota profiles revealed a dissimilarity between WL and NWL. Moreover, WL pathways were characterized by fatty acid biosynthesis, while NWL by inflammation pathways. Conclusion: The gut microbiota could participate in weight alteration observed in PD by the presence of bacteria involved in weight gain and inflammation, or conversely by bacteria implicated in energy expenditure.

Safety considerations when using non-ergot dopamine agonists to treat Parkinson's disease.

INTRODUCTION: Nonergot dopamine agonists (NEDA) represent an excellent treatment option for Parkinson's disease (PD) patients, in both early and advanced stages of the disease. The post-marketing phase of NEDA has highlighted, though, the occurrence of important long-term adverse events. AREAS COVERED: This review reports recent updates on NEDA adverse events, analyzing neurobiological bases and risk factors of these complications. A literature search has been performed using Medline and reviewing the bibliographies of selected articles. EXPERT OPINION: NEDA represents a very important option in the treatment of PD. Criticisms on their use can be overcome through a better knowledge of these molecules and of the risk factors for adverse events which allow specialists to prevent the occurrence of undesired complications and consent a tailor-based approach. Abbreviations: PD: Parkinson's disease, DA: dopamine agonists, NEDA: non-ergot dopamine agonists, ICD: impulse control disorders, DAWS: dopamine agonist withdrawal syndrome, CYP: Cytochrome P, PK: pharmacokinetic, AUC: area under the curve, HRT: hormone replacement therapy, AV: atrioventricular, HF: heart failure, OH: orthostatic hypotension, RBD: REM behavior disorders, PDP: Parkinson's disease psychosis, DRT: dopamine replacement therapy, DDS: dopamine dysregulation syndrome, MMSE: Mini-Mental state examination, EDS: excessive daytime somnolence.

Clinical and pharmacokinetics equivalence of multiple doses of levodopa benserazide generic formulation vs the originator (Madopar).

AIMS: While several generic preparations of levodopa/carbidopa and levodopa/benserazide (LBD) are currently available, pharmacokinetic (PK) equivalence and therapeutic equivalence studies with levodopa generics are not available in Italy. Lack of data on generic formulations is a critical factor for their limited use in this country and often lead patients to refuse the generic version of the branded drug. METHODS: An experimental, 2-centre, randomized, double-blind, 2-sequence, noninferiority cross-over study was designed to evaluate both the PK equivalence and clinical equivalence of multiple doses of the generic preparation of LDB, Teva Italia, compared to the originator (Madopar). Forty-three out-patients with a diagnosis of idiopathic Parkinson's disease on LDB, were recruited and randomly assigned to 1 of 2 study sequences: generic-originator or originator-generic. Clinical evaluations were performed at the end of each study period. A PK study with an LDB fixed dose (100 + 25 mg) was performed in a subpopulation of 14 subjects. RESULTS: Clinical data showed a reduction of 0.49 and 1.54 in the mean UPDRS III scores for the LDB and the originator, respectively. The 95% CIs [-2.21: 0.11] of the mean difference original vs LDB are smaller than the clinically significant difference of 3 UPDRS III points, supporting the conclusion that the treatment with LDB is not inferior to the originator. No statistically significant differences were found with respect to area under the curve to last dose, half-life, maximum concentration, time to maximum concentration and last observed concentration. CONCLUSION: These findings prove the therapeutic clinical equivalence as well the PK equivalence of the generic LDB and the originator (Madopar).

Are All Dopamine Agonists Essentially the Same?

Dopamine agonists (DAs) represent an excellent treatment option for patients with Parkinson's disease, in both the early and advanced stages of the disease, improving motor symptoms, lowering the incidence of motor complications, and addressing several non-motor symptoms. Indeed, each of these compounds have different pharmacokinetic and pharmacodynamic properties, resulting in a unique efficacy and safety profile. Comorbidities, prominent non-motor symptoms and individual subjects' clinical characteristics should guide the choice of a specific DA, allowing better management of the patient by optimizing the DA benefit/risk ratio. In this article we discuss brain distribution of dopamine receptors and their role in each of the dopaminergic pathways, the pharmacological profile of non-ergoline DAs and class-related adverse effects, as reported from post-marketing studies.

Continuous versus intermittent oral administration of levodopa in Parkinson's disease patients with motor fluctuations: A pharmacokinetics, safety, and efficacy study.

BACKGROUND: Laboratory and clinical evidence indicate that continous delivery of levodopa is associated with reduced motor complications compared to standard intermittent levodopa. OBJECTIVE: To assess the pharmacokinetics and efficacy of continuous oral delivery of l-dopa/carbidopa in PD patients with motor fluctuations. METHODS: Eighteen PD patients with motor fluctuations were enrolled in an open-label study comparing pharmacokinetics and efficacy measures between standard intermittent oral l-dopa/carbidopa and "continuous" oral l-dopa/carbidopa. Continuous treatment was operationally defined as sips of an l-dopa dispersion at 5- to 10-minute intervals. On day 1, patients received their usual oral l-dopa/carbidopa doses. On day 2, patients received l-dopa/carbidopa dose by "continuous" oral administration. On day 3, patients received a single dose of oral l-dopa/carbidopa followed by continuous administration of l-dopa/carbidopa. Each study period was 8 hours, and the total l-dopa/carbidopa dose administered was the same on each day. Analyses of variability were primarily-based samples drawn between 4 and 8 hours when subjects were in a relative steady state. RESULTS: There was less variability in plasma l-dopa concentration with continuous versus intermittent oral l-dopa/carbidopa treatment (fluctuation index was 0.99 ± 0.09 vs. 1.38 ± 0.12 [P < 0.001] and coefficient of variation was 0.35 ± 0.03 vs. 0.49 ± 0.04 [P < 0.001]). Mean OFF time was decreased by 43% (P < 0.001) with continuous oral l-dopa therapy. No safety or tolerability issues were observed. CONCLUSIONS: Continuous oral delivery of l-dopa/carbidopa was associated with less plasma variability and reduced off time in comparison to standard intermittent oral l-dopa/carbidopa therapy. © 2019 International Parkinson and Movement Disorder Society.

Pharmacokinetic drug evaluation of CVT-301 for the treatment of Parkinson's disease.

INTRODUCTION: Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients. Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed. Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability. List of Abbreviations: PD: Parkinson's disease; LD: Levodopa; CD: Carbidopa; AADC: aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS: Unified Parkinson's Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffuse lung CO ; tmax: time to maximum concentration.

Istradefylline for the treatment of Parkinson's disease: is it a promising strategy?

INTRODUCTION: Istradefylline (ISD) is a new drug developed for the treatment of Parkinson's disease (PD). It is an adenosine receptor A2A antagonists that will represent an important option for patients with advanced PD where it has been demonstrated efficacy in decreasing daily OFF time and is well tolerated. ISD has been marketed in Japan since May 2013. Areas covered: The objective of this review is to summarize evidences emerged from clinical studies that have demonstrated the efficacy of ISD in advanced parkinsonian patients. It will then focus on the potential role in treating non-motor symptoms (NMS) and cognitive decline, which heavily affect quality of life for PD patients. Its putative role as neuroprotective agent will also be discussed. Expert opinion: ISD might represent an alternative option for patients with advanced PD. The reduction of OFF time highlighted in pivotal trials is comparable to that obtained with different levodopa adjunct therapies. The low profile of side effects makes ISD a more suitable drug for advanced patients whose illness is complicated by depression or cognitive impairment. Future studies are warranted to investigate the possible effects of this drug to delay the occurrence of dyskinesia and to impact significantly on NMS.

Non motor symptoms in progressive supranuclear palsy: prevalence and severity.

NMSs have been extensively studied in PD patients but not in other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP). The primary objective of this study was to analyze the frequency, severity and the type of non-motor symptoms (NMS) in PSP patients using the non-motor symptoms scale (NMSS). The secondary objective was to differentiate NMS between PSP and Parkinson's disease (PD). We enrolled in this cross-sectional study 50 consecutive PSP and 100 matched Parkinson's disease (PD) patients, in the proportion PSP/PD = 1/2, matched in age, sex, and disease duration. Motor and Non Motor symptoms (different scales for each disease) were evaluated at baseline using PSP scale, SCOPA Motor, Montreal Cognitive Assessment (MOCA), HADS, Hamilton, and Non Motor Symptom scale (NMSS). Comparative analysis was done using chi-squared test, Mann-Whitney test and Fisher's exact test. Fifty PSP (56% female) and 100 PD (59% female) patients completed the study protocol and were included for statistical analysis. The NMSS total domains score in the PSP group was 77.58 ± 42.95 (range 14-163) with NMS burden grade: 4, very severe, and the in the PD group was 41.97 ± 35.45 (range: 0-215) with NMS burden grade: 3, severe. The comparative analysis showed that NMS total score (p < 0.0001), Sleep/Fatigue (p = 0.0007), Mood/Apathy (p = 0.0001), Gastrointestinal (p < 0.0001), and Urinary dysfunction (p = 0.0001) domains were significantly more severe in PSP patients than in PD. This observational study reports that NMSs are very frequent in PSP patients hence the higher burden of NMS in PSP specifically related to mood/apathy, attention/memory, gastrointestinal, urinary disturbances compared to PD.

Constipation in Parkinson's Disease.

Constipation is one of the main and disabling nonmotor symptoms in Parkinson's disease (PD), with a prevalence ranging from 24.6% to 63% according to the different diagnostic criteria used to define chronic constipation. Constipation is currently recognized as a risk factor of PD in relation to the number of evacuation per week and its severity. Moreover, several studies have demonstrated that constipation may precede the occurrence of motor symptoms underlying an earlier involvement of the enteric nervous system and the dorsal motor nucleus of the vagus in the α-synuclein pathology. In PD, constipation is mainly due to slower colonic transit or puborectalis dyssynergia, but the concomitant use of antiparkinsonian, pain, and antidepressant medications may worsen it. An accurate diagnosis and an adequate treatment of constipation it is pivotal to prevent complications such as intestinal occlusion and to ensure an optimal clinical response to levodopa.

Advances in dopamine receptor agonists for the treatment of Parkinson's disease.

INTRODUCTION: Dopamine agonists (DA) are a class of agents which directly stimulate dopamine receptors mimicking the endogenous neurotransmitter dopamine. At first used as adjunctive therapy in the advanced phases of the disease, over the years a significant role was found for DA monotherapy as a first approach in the initial stage of Parkinson's disease (PD). Several reviews have already reported efficacy and safety of DA in PD and differences between DA and levodopa. Therefore the objective of this review is to gather recent updates in DA therapy. A thorough knowledge of recent literature evidences, would help clinician in the management of treatment with DA. AREAS COVERED: Our review investigates recent updates on DA therapy, the role of these compounds in controlling non-motor symptoms (NMS) as well as new formulations under clinical evaluation and newly emerged post-marketing safety considerations. A literature search has been performed using Medline and reviewing the bibliographies of selected articles. EXPERT OPINION: DA represents a very important option in the treatment of PD, even though there are still some criticisms and unmet needs. A better knowledge of dopamine receptors could lead to identification of new compounds able to better balance clinical efficacy and side effects.

Adjuvant therapies for Parkinson's disease: critical evaluation of safinamide.

Safinamide (SAF) is a new drug developed for the treatment of Parkinson's disease (PD). It is a benzylamino derivative with multiple mechanisms of action and antiparkinsonian, anticonvulsant, and neuroprotective properties. SAF inhibits monoamine oxidase B and dopamine reuptake and glutamate release, blocks voltage-dependent sodium channels, and modulates calcium channels. Although the antiparkinsonian effect can be ascribed in part to the inhibition of the monoamine oxidase B, which is complete at 50 mg, the enhanced benefit seen at the 100 mg dose is probably due to nondopaminergic mechanisms. SAF will represent an important option for patients with both early and advanced PD. In early PD patients, the addition of SAF to dopamine agonists may be an effective treatment strategy to improve motor function, prolong the use of dopamine agonists, and/or delay the introduction of levodopa. In advanced parkinsonian patients, SAF has been demonstrated to significantly increase on time with no, or nontroublesome dyskinesias. All studies performed have demonstrated its efficacy in benefiting both short-term and long-term quality-of-life outcomes in both early and advanced PD patients. SAF has been investigated in long-term (24 months), double-blind, placebo-controlled studies, where it showed a very good safety profile. SAF has not been studied in de novo PD patients, and its potential positive effect on dyskinesia deserves further dedicated studies.

Rasagiline for the treatment of Parkinson's disease: an update.

INTRODUCTION: Rasagiline is a potent, selective, irreversible Monoamine Oxidase-B (MAO-B) inhibitor, developed to prolong the action of dopamine in the brain. It has been demonstrated that rasagiline can improve motor and some non-motor symptoms (NMS) in both early and advanced Parkinson's disease (PD) patients, and it also exhibits neuroprotective and antiapoptotic properties. AREAS COVERED: The objective of this review, performed by a Medline search on the most recent papers investigating the therapeutic effects of rasagiline, is to describe the role of rasagiline in the schedule of treatment of early and advanced PD patients. It will then focus on its role in treating NMS, fatigue, early morning off and cognitive decline, which heavily affect quality of life for PD patients. EXPERT OPINION: Rasagiline is an efficacious, well-tolerated, easy to use drug. The drug has been extensively studied and has proven its efficacy in monotherapy and in combination with any other antiparkinsonian therapy. It proved to be efficacious in reducing 'off' time and in improving early morning 'off' but also some NMS, thus enhancing the therapeutic approach to PD.

L-Dopa Pharmacokinetic Profile with Effervescent Melevodopa/Carbidopa versus Standard-Release Levodopa/Carbidopa Tablets in Parkinson's Disease: A Randomised Study.

Objectives. To characterize the pharmacokinetic profile of levodopa (L-dopa) and carbidopa after repeated doses of the effervescent tablet of melevodopa/carbidopa (V1512; Sirio) compared with standard-release L-dopa/carbidopa in patients with fluctuating Parkinson's disease. Few studies assessed the pharmacokinetics of carbidopa to date. Methods. This was a single-centre, randomized, double-blind, double-dummy, two-period crossover study. Patients received V1512 (melevodopa 100 mg/carbidopa 25 mg) or L-dopa 100 mg/carbidopa 25 mg, 7 doses over 24 hours (Cohort 1), 4 doses over 12 hours (Cohort 2), or 2 doses over 12 hours in combination with entacapone 200 mg (Cohort 3). Pharmacokinetic parameters included area under the plasma-concentration time curve (AUC), maximum plasma concentration (C max), and time to C max (t max). Results. Twenty-five patients received at least one dose of study medication. L-dopa absorption tended to be quicker and pharmacokinetic parameters less variable after V1512 versus L-dopa/carbidopa, both over time and between patients. Accumulation of L-dopa in plasma was less noticeable with V1512. Carbidopa exposure and interpatient variability was lower when V1512 or L-dopa/carbidopa was given in combination with entacapone. Both treatments were well tolerated. Conclusions. V1512 provides a more reliable L-dopa pharmacokinetic profile versus standard-release L-dopa/carbidopa, with less drug accumulation and less variability. This trial is registered with ClinicalTrials.gov NCT00491998.

A systems medicine clinical platform for understanding and managing non- communicable diseases.

Non-Communicable Diseases (NCDs) are among the most pressing global health problems of the twenty-first century. Their rising incidence and prevalence is linked to severe morbidity and mortality, and they are putting economic and managerial pressure on healthcare systems around the world. Moreover, NCDs are impeding healthy aging by negatively affecting the quality of life of a growing number of the global population. NCDs result from the interaction of various genetic, environmental and habitual factors, and cluster in complex ways, making the complex identification of resulting phenotypes not only difficult, but also a top research priority. The degree of complexity required to interpret large patient datasets generated by advanced high-throughput functional genomics assays has now increased to the point that novel computational biology approaches are essential to extract information that is relevant to the clinical decision-making process. Consequently, system-level models that interpret the interactions between extensive tissues, cellular and molecular measurements and clinical features are also being created to identify new disease phenotypes, so that disease definition and treatment are optimized, and novel therapeutic targets discovered. Likewise, Systems Medicine (SM) platforms applied to extensively-characterized patients provide a basis for more targeted clinical trials, and represent a promising tool to achieve better prevention and patient care, thereby promoting healthy aging globally. The present paper: (1) reviews the novel systems approaches to NCDs; (2) discusses how to move efficiently from Systems Biology to Systems Medicine; and (3) presents the scientific and clinical background of the San Raffaele Systems Medicine Platform.

Drug safety evaluation of ropinirole prolonged release.

INTRODUCTION: The need for multiple administrations and a difficult titration schedule has always represented a limit in the use of dopamine agonists in the treatment of early Parkinson's disease. To avoid these problems, Ropinirole prolonged release (RPR), a non-ergoline dopamine receptor agonist that can be taken once a day, has been formulated. The prolonged release formulation has higher patient compliance due to a simpler and fastest titration schedule; the once-a-day administration makes this molecule especially suitable for young Parkinsonian patients who are still working and having an active lifestyle. AREAS COVERED: In this paper, we will review ropinirole's mechanism of action including pharmacokinetics and pharmacodynamic data and the results of the main clinical studies in early and advanced PD patients. We will also discuss safety data shown during the experimental phase and after RPR commercialization. This article reviews the use of RPR in early and advanced Parkinsonian patients. Medical literature on the use of RPR in Parkinson's disease was identified using MEDLINE and the reference lists of published articles. EXPERT OPINION: RPR is effective in the treatment of patients with early Parkinson's disease; in advanced Parkinsonian patients, the amount of daily off-time significantly decreases, improving the mean on time. RPR has also demonstrated to be effective in ameliorating the quality of sleep without increasing the occurrence of daily sleepiness and nocturnal psychosis. RPR was generally well tolerated in both early and advanced Parkinsonian patients.

Peripheral blood mononuclear cells from mild cognitive impairment patients show deregulation of Bax and Sod1 mRNAs.

Elevated oxidative stress-induced apoptosis has been found in peripheral cells from patients with Alzheimer's disease (AD). Furthermore, treatment of lymphocytes from AD patients, with Abeta(1-42) and H(2)O(2) results in enhanced apoptosis. Mild cognitive impairment (MCI), a clinical condition between normal aging and AD, shares with AD a similar pattern of peripheral markers of oxidative stress. In this study we investigated spontaneous and H(2)O(2)-induced oxidative stress and apoptosis levels in peripheral blood mononuclear cells (PBMCs) from MCI and AD patients, as well as from Parkinson's disease (PD) patients without cognitive impairment or age-matched healthy control. Sod1 mRNA levels were studied to analyse the anti-oxidative pathway, while Bax and Bcl-2 mRNAs levels and PARP protein cleavage were monitored to study apoptosis. We found that the expression of Sod1 and Bax mRNAs was statistically higher in both MCI and AD patients compared to controls or PD subjects. Since Bcl-2 mRNA level was not different among groups, the Bax/Bcl-2 ratio was statistically higher in AD and MCI patients. PARP cleavage was also enhanced in PBMCs from MCI and AD individuals and this finding was associated with a higher level of spontaneous apoptosis. Interestingly, exposure to H(2)O(2) induced a significant decrease of Bcl-2 mRNA transcript, while Sod1 and Bax mRNAs levels were unchanged in PBMCs derived from MCI and AD patients. In conclusion, our results show that Bax and Sod1 mRNA levels are altered in PBMCs from both MCI and AD patients and indicate these changes as potential biomarkers in the early diagnosis of AD.