No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Levodopa-induced skin disorders in patients with Parkinson disease: a systematic literature review approach
Abstract
The use of levodopa for treatment of Parkinson’s disease is a well-established clinical practice. Data about the true incidence and severity of cutaneous complications associated with the use of levodopa are largely lacking. Aim of this review was to evaluate the quality of evidence referring to the skin disorders caused by levodopa treatment for Parkinson’s disease. Thirty of 1084 studies were included; 8 randomized controlled trials and 22 case reports in a total of 2749 patients. Malignant melanoma was the most frequent oral levodopa-related skin disorder followed by allergic cutaneous reactions, alopecia, vitiligo, skin hyperpigmentation, Laugier–Hunziker syndrome, Henoch–Schönlein syndrome, pseudobullous morphea and scleroderma-like illness. Naranjo scores ranged from 2 to 8. Regarding levodopa clinical trials, the most frequent skin complication was peripheral edema, followed by malignant melanoma. Although evidence is not robust, melanoma is the most frequent and possible fatal levodopa-associated skin disorder, while other skin allergic or immunological reactions are less common and reversible. Although levodopa treatment may induce melanogenesis and promote melanomagenesis, existing evidence does not support an association between levodopa therapy and induction or progression of malignant melanoma. The suggested association with melanoma may reflect the well-documented association of Parkinson’s disease with melanoma rather than the exposure to the drug. Nevertheless, until a solid conclusion can be drawn, the use of levodopa in the context of malignant melanoma should be considered with caution. Well-designed prospective studies are needed to determine the cause and effect relationship between levodopa and skin disorders.
... Use of the medication rarely leads to any skin-related manifestations and is otherwise generally well tolerated. Lower extremity edema has been noted in 1-2% of patients across clinical trials [175]. There are also reports of an allergic reaction to levodopa therapy manifesting as a generalized pruritic maculopapular rash that subsequently resolves with discontinuation of levodopa treatment, however, it is thought that this reaction is more likely attributed to yellow dye sometimes used in the medication, particularly the Sinemet 25/100 formulation, rather than levodopa [175][176][177][178]. ...
... Lower extremity edema has been noted in 1-2% of patients across clinical trials [175]. There are also reports of an allergic reaction to levodopa therapy manifesting as a generalized pruritic maculopapular rash that subsequently resolves with discontinuation of levodopa treatment, however, it is thought that this reaction is more likely attributed to yellow dye sometimes used in the medication, particularly the Sinemet 25/100 formulation, rather than levodopa [175][176][177][178]. As stated previously, there is no credible connection between levodopa use and development of melanoma. ...
Parkinson's disease is associated with a variety of dermatologic disorders and the study of skin may provide insights into pathophysiological mechanisms underlying this common neurodegenerative disorder. Skin disorders in patients with Parkinson's disease can be divided into two major groups: 1) non-iatrogenic disorders, including melanoma, seborrheic dermatitis, sweating disorders, bullous pemphigoid, and rosacea, and 2) iatrogenic disorders related either to systemic side effects of antiparkinsonian medications or to the delivery system of antiparkinsonian therapy, including primarily carbidopa/levodopa, rotigotine and other dopamine agonists, amantadine, catechol-O-methyl transferase inhibitors, subcutaneous apomorphine, levodopa/carbidopa intestinal gel, and deep brain stimulation. Recent advances in our understanding of the role of α-synuclein in peripheral tissues, including the skin, and research based on induced pluripotent stem cells derived from skin fibroblasts have made skin an important target for the study of Parkinson's disease pathogenesis, drug discovery, novel stem cell therapies, and diagnostics.
... This result indicates a notable effect of the levodopa-loaded MAP formulation on skin cells, classified as a grade 1 (non-cytotoxic) effect based on predefined cytotoxicity grade levels [41]. Notably, the impact of levodopa on HDFa cells had not been previously documented concerning topical administration, unlike its known induction of skin reactions in oral administration [42]. The observed increase in toxicity aligns with a previously reported study suggesting low cytotoxicity, primarily due to the production of free radical species on HDFa cells [43]. ...
... Bougea et al. reported in a meta-analysis that melanoma is the most common skin disease associated with the use of L-DOPA. This conclusion was made on the basis of a review of clinical cases in which of 32 described patients, 13 were diagnosed with melanoma after taking L-DOPA [64]. However, Olsen et al. showed that L-DOPA had no effect on the risk of malignant melanoma, as indicated by an odds ratio of 1.0 (95% confidence interval, 0.8-1.3) ...
Simple Summary
This article examines the fascinating association between melanoma, a malignant skin cancer, and Parkinson’s disease (PD), a neurodegenerative disorder. Both diseases involve cells that produce melanin, a pigment that provides skin color and protects against UV radiation. This study explores the potential impact of melanin synthesis on these diseases, considering the divergent roles of eumelanin and pheomelanin, melanin types present in both skin and brain cells. Additionally, it investigates the influence of PD treatments, such as L-DOPA, on melanoma risk, although the nature of this relationship remains uncertain. The research aims to provide insights into these intricate connections and their implications for the medical field.
Abstract
A common feature of Parkinson’s disease (PD) and melanoma is their starting points being based on cells capable of converting tyrosine into melanin. Melanocytes produce two types of melanin: eumelanin and pheomelanin. These dyes are designed to protect epidermal cells from the harmful effects of UV radiation. Neurones of the substantia nigra, which degenerate during PD, produce neuromelanin, the physiological role of which is not fully explained. This article discusses the potential role of melanins in the pathogenesis of both diseases. Melanins, due to their ability to accumulate toxic substances, may become their sources over time. The use of glutathione for the synthesis of pheomelanins and neuromelanins may reduce the antioxidant capacity of cells, leading to an excessive synthesis of free radicals. This study also tested the hypothesis that certain drugs used in the treatment of PD (L-DOPA, MAO-B and COMT inhibitors, and amantadine), aimed at increasing dopamine concentration, could potentially contribute to the development of melanoma. The role and properties of melanins should continue to be researched. Whether excessive melanin synthesis or its accumulation in the extracellular space may be factors initiating the development of diseases remains an open question.
... [25] Malignant melanoma and peripheral edema are seen to be associated with Levodopa+ Carbidopa and angioedema is rare. [26] Causality assessment of ADRs is based on temporal relationship, previous knowledge, results of dechallenge, and rechallenge. This is very relevant as many etiological factors can produce the same cutaneous reaction. ...
Background: Cutaneous adverse drug reactions (CADRs) range from mild-to-severe types and occasionally can become fatal. Hence, these incur additional financial burden both to patients and community. Aim and Objective: The aim of the study was to describe the characteristics of CADRs reported to ADR monitoring center (AMC) of a tertiary care center. Materials and Methods: CADRs reported to the AMC over a period of 2 ½ years were retrospectively studied. This study mainly focused on affected age group, gender, various pattern of CADRs, the group and name of drugs causing CADRs, and severity and causality assessment. Results: CADRs contributed 31.6% of the total ADRs reported to the AMC. Among these, 51.7% were females and 40% were of 51-60 years age group. About 37.9% of CADRs were pruritus. Antibacterial drugs were the most common cause of CADRs and beta-lactam antibiotics were responsible for 30% of CADRs. Stevens Johnson syndrome (SJS) constituted 4.9% of CADRs and 20% of this was due to Paracetamol. Drugs were withdrawn in 89% of cases and 85% cases recovered. On causality assessment, 94% were of probable category. Conclusion: Pruritus was the most commonly observed CADR and antibacterial drugs were the most common cause. Beta lactam antibiotic was the most frequent antibacterial drug to cause CADRs. The most common serious CADR was SJS and Paracetamol was the most frequent culprit drug.
... Although the iatrogenic relationship between melanoma and brain cancer and levodopa remains speculative [19,20] levodopa is thought to affect tumour generation by inducing cellular oxidative stress [21][22][23]. An alternative explanation for such close associations between PD and cancer risks might be confounded by environmental factors such as lifestyle (cigarette smoking, coffee and alcohol consumption). ...
Background
Increasing evidence suggests significant associations between Parkinson’s disease (PD) and cancer risks. We conducted an updated review of studies that examined the risks of various cancer among PD patients and how this differed when cancer preceded PD diagnosis or PD diagnosis preceded cancer.
Methods
Four databases were searched for studies that examined the association between PD and incidence of cancer from database inception to June 4th, 2021. Three independent reviewers screened the articles for eligibility and extracted study data. Pooled relative risk (RRs) with 95% confidence interval (CI) were calculated using random-effects model.
Results
Forty studies involving 11 case-control studies, 2 nested case-control studies, 22 cohort studies and 5 cross-sectional studies were included. Compared to controls, PD patients had lower risks of lung cancer and genitourinary cancers, gastrointestinal cancers and haematological cancers. Conversely, higher risks of melanoma and brain cancer were noted among PD patients. No association was found between PD and risk of female cancers. Subgroup analysis found negative associations between PD patients and risks of colon cancer, rectal cancer and non-Hodgkin lymphoma.
Conclusion
Findings from our meta-analysis suggest PD patients had lower risks of lung cancer, genitourinary cancers, gastrointestinal cancers and haematological cancer and increased risks of melanoma and brain cancer. Future research to understand the underlying mechanisms between PD and cancers are warranted.
... By that time, there was a widespread fear that this therapy could cause melanoma, as L-DOPA is a substrate in melanin synthesis. An iatrogenic relationship between melanoma and L-DOPA treatment has not been proven [33][34][35]. Currently, the more frequent occurrence of melanoma in patients with idiopathic PD (IPD) is beyond doubt [19,28,31,36,37]. ...
Epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson's disease (PD) patients. However, some neoplasms are associated with a higher risk of occurrence in PD patients. Both pathologies share some common biological pathways. Although the etiologies of PD and cancer are multifactorial, some factors associated with PD, such as α-synuclein aggregation; mutations of PINK1, PARKIN, and DJ-1; mitochondrial dysfunction; and oxidative stress can also be involved in cancer proliferation or cancer suppression. The main protein associated with PD, i.e., α-synuclein, can be involved in some types of neoplastic formations. On the other hand, however, its downregulation has been found in the other cancers. PINK1 can act as oncogenic or a tumor suppressor. PARKIN dysfunction may lead to some cancers' growth, and its expression may be associated with some tumors' suppression. DJ-1 mutation is involved in PD pathogenesis, but its increased expression was found in some neoplasms, such as melanoma or breast, lung, colorectal, uterine, hepatocellular, and nasopharyngeal cancers. Both mitochondrial dysfunction and oxidative stress are involved in PD and cancer development. The aim of this review is to summarize the possible associations between PD and carcinogenesis.
Parkinson’s Disease (PD) is a prevalent movement disorder among the population with more than 10 million living with PD worldwide. L-DOPA has been a drug of choice in the treatment of PD for a long time due to its potential to cross the blood-brain barrier. However, prolonged use of synthetic L-DOPA also exerted toxicities in the patients. A significant number of research studies have been documented for a promising future of using natural L-DOPA resources for the management of PD or perhaps delaying the onset of PD. This review will highlight the potential of some of the natural L-DOPA sources and neuroprotective agents used in PD management.
Dear Editor, Levodopa, an amino acid precursor of dopamine and melanin, has been widely used to treat patients with Parkinson disease. Although the incidence of levodopa‐induced cutaneous adverse reactions has not been fully evaluated, recent studies have revealed that melanocyte‐associated skin adverse reaction is the most common.¹ Cases of darkening of white hair following levodopa therapy for Parkinson disease have been reported.² Notably, in vitro studies have revealed the protective effect of levodopa on neuronal cells.³ Therefore, we speculated that levodopa may exert a protective effect on melanocytes and could prevent vitiligo development.
We conducted a nationwide, population‐based, case–control study to investigate the association between levodopa use and vitiligo development using the Korean National Health Insurance (NHI) claims database. We first identified all patients with vitiligo aged ≥ 40 years who met a physician at least four times between January 2007 and December 2017 with a diagnosis of vitiligo (vitiligo group). The control individuals had no history of vitiligo and were propensity score matched for age, sex and insurance type. We identified levodopa use in both groups before the first visit date when vitiligo was diagnosed (in the vitiligo group) and conducted conditional logistic regression analyses to explore the association of levodopa use and vitiligo development. All analyses were conducted using SAS software (version 9·4; SAS Institute, Cary, NC, USA). This study was approved by the institutional review board of St Vincent’s Hospital (VC17ZESI0090).
Parkinson's disease (PD) is a neurodegenerative disorder associated with the death of dopaminergic neurons within the substantia nigra of the brain. Melanoma is a cancer of melanocytes, pigmented cells that give rise to skin tone, hair, and eye color. Although these two diseases fundamentally differ, with PD leading to cell degeneration and melanoma leading to cell proliferation, epidemiological evidence has revealed a reciprocal relationship where patients with PD are more susceptible to melanoma and patients with melanoma are more susceptible to PD. The hallmark pathology observed in PD brains is intracellular inclusions, of which the primary component is proteinaceous α-synuclein (α-syn) amyloid fibrils. α-Syn also has been detected in cultured melanoma cells and tissues derived from patients with melanoma, where an inverse correlation exists between α-syn expression and pigmentation. Although this has led to the prevailing hypothesis that α-syn inhibits enzymes involved in melanin biosynthesis, we recently reported an alternative hypothesis in which α-syn interacts with and modulates the aggregation of Pmel17, a functional amyloid that serves as a scaffold for melanin biosynthesis. In this perspective, we review the literature describing the epidemiological and molecular connections between PD and melanoma, presenting both the prevailing hypothesis and our amyloid-centric hypothesis. We offer our views of the essential questions that remain unanswered to motivate future investigations. Understanding the behavior of α-syn in melanoma could not only provide novel approaches for treating melanoma but also could reveal insights into the role of α-syn in PD. © 2021 International Parkinson and Movement Disorder Society.
Parkinson disease (PD) is well recognized by its motor features of bradykinesia, tremor, rigidity, and gait and balance difficulties. However, PD is also characterized by a myriad of nonmotor symptoms, which may occur even before motor symptoms, early in the course of disease, and throughout the advancing disease. These nonmotor symptoms span multiple different systems, invoke multiple different neurotransmitters, and require multiple strategies for treatment including pharmacologic and nonpharmacologic interventions and, often, multiple different disciplines. This article discusses symptoms, assessments, and therapeutics for the nonmotor symptoms of PD including those affecting mood, cognition, behavior, sleep, autonomic function, and sensory systems.
Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, depletion of dopamine in the striatum and the presence of Lewy bodies. Cancer is uncontrolled growth of cells in the body and migration of these cells from their site of origin to other parts of the body. PD and cancer are two opposite diseases, one arising from cell proliferation and the other from cell degeneration. This fundamental difference is consistent with inverse comorbidity between most cancers and neurodegenerative diseases. However, a positive association of PD and melanoma has been reported which has recently become of significant interest. A link between PD and cancer has been supported by many epidemiological studies, most of which show that PD patients have a lower risk of developing most cancers than the general population. However, the mechanisms underlying this epidemiological observation are not known. In this review we focus on epidemiological studies correlating PD and melanoma and the possible mechanisms underlying the co-occurrence of the two diseases. We explore possible explanations for the important observations that more PD patients develop melanoma that would otherwise be expected and vice-versa.
Background:
D-Decarboxylase inhibitors, such as carbidopa or benserazide, have been used as adjunct therapy in Parkinson disease shortly after levodopa synthesis in the 1960s. These compounds increase intracerebral drug concentration and decrease adverse effects by blocking peripheral conversion to dopamine. Skin rash as part of an allergic reaction was previously described in subjects who were using levodopa in combination with carbidopa or benserazide; however, etiology was never clear. Allergic reactions to carbidopa have not previously been reported.
Methods:
We report a case of a 77-year-old woman with a diagnosis of idiopathic Parkinson disease, who developed autonomic and dermatological signs: conjunctival injection, rhinorrhea, excessive sweating, hypertension, and pruritic generalized rash, among others, immediately after carbidopa/levodopa administration regardless of the manufacturer. Treatment with dexamethasone combined with chloropyramine hydrochloride resulted in complete resolution of the hypersensitivity reaction each time it presented. The autonomic and dermatological manifestations did not reappear after treatment was replaced with benserazide/levodopa.
Conclusions:
To the best of our knowledge, this is the first case report of an allergic reaction specific to carbidopa. Our case highlights the importance of identifying the source of a hypersensitivity drug response, whether it is caused by the active component or by the excipients.
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, characterized by a symptom triad comprising resting tremor, rigidity, and akinesia. In addition, non-motor symptoms of PD are well recognized and often precede the overt motor manifestations. Cutaneous manifestations as markers of PD have long been discussed, and cumulative evidence shows an increased prevalence of certain dermatological disorders in PD. Seborrheic dermatitis is considered to occur as a premotor feature of PD referable to dysregulation of the autonomic nervous system. Also, an increased risk of melanoma has been observed in PD. Light hair color is a known risk factor for melanoma, and interestingly the risk of PD is found to be significantly higher in individuals with light hair color and particularly with red hair. Furthermore, several studies have reported a high prevalence of PD in patients with bullous pemphigoid. Moreover, a 2-fold increase in risk of new-onset PD has been observed in patients with rosacea. Besides the association between PD and various dermatological disorders, the skin may be useful in the diagnosis of PD. Early PD pathology is found not only in the brain but also in extra-neuronal tissues. Thus, the protein α-synuclein, which is genetically associated with PD, is present not only in the CNS but also in the skin. Hence, higher values of α-synuclein have been observed in the skin of patients with PD. Furthermore, an increased risk of PD has been found in the Cys/Cys genotype, which is associated with red hair color. In this review, we summarize the current evidence of the association between PD and dermatological disorders, the cutaneous adverse effects of neurological medications, and describe the potential of skin protein expression and biomarkers in identification of risk and diagnosis of PD.
Background
Parkinson’s Disease is a progressive neurodegenerative disease, characterized by symptoms of motor impairment, resulting from the loss of dopaminergic neurons in the midbrain, however non-neuronal symptoms are also common. Although great advances have been made in the pathogenic understanding of Parkinson’s Disease in the nervous system, little is known about the molecular alterations occurring in other non-neuronal organ systems. In addition, a higher rate of melanoma and non-melanoma skin cancer has been observed in the Parkinson’s Disease population, indicating crosstalk between these diseases.
Methods
To understand the molecular pathogenesis and gene expression alterations of Parkinson’s Disease in peripheral tissues, and in order to explore the possible link between skin cancer and neurodegeneration, whole transcriptomic profiling of patients’ skin was performed. Skin biopsies from 12 patients and matched controls were collected, and processed with high-throughput RNA-sequencing analysis.
Results
This analysis resulted in a large collection of over 1000 differentially expressed genes, among which clear biological and functional networks could be distinguished. The central functional processes altered in patients skin can be grouped into six broad categories: impaired cellular metabolism and mitochondrial dysfunction, defective protein metabolism, disturbed skin homeostasis, dysfunctional nuclear processes, altered signalling and tumour pathways, as well as disordered immune regulation.
Conclusions
These results demonstrate that the molecular alterations leading to neurodegeneration in the CNS are systemic and manifest also in peripheral tissues, thereby indicating the presence of “skin-brain” crosstalk in Parkinson’s Disease. In addition, the extensive homeostatic imbalance and basal stress can lead to increased susceptibility to external and internal mutagenic hazards in these patients, and thus provide a possible molecular link for the crosstalk between skin cancer and Parkinson’s Disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-016-0784-z) contains supplementary material, which is available to authorized users.
Objectives:
The objectives of this study were to present procedure- and device-associated adverse events (AEs) identified with long-term drug delivery via percutaneous endoscopic gastrojejunostomy (PEG-J). Levodopa-carbidopa intestinal gel (LCIG, also known in US as carbidopa-levodopa enteral suspension, CLES) is continuously infused directly to the proximal small intestine via PEG-J in patients with advanced Parkinson's disease (PD) to overcome slow and erratic gastric emptying and treat motor fluctuations that are not adequately controlled by oral or other pharmacological therapy.
Methods:
An independent adjudication committee of three experienced (>25 years each) gastroenterologists reviewed gastrointestinal procedure- and device-associated AEs reported for PD patients (total n=395) enrolled in phase 3 LCIG studies. The rate, clinical significance, and causality of the procedure/device events were determined.
Results:
The patient median exposure to PEG-J at the data cutoff was 480 days. Procedure- and device-associated serious AEs (SAEs) occurred in 67 (17%) patients. A total of 42% of SAEs occurred during the first 4 weeks following PEG-J placement. SAEs of major clinical significance with the highest procedural incidence were peritonitis (1.5%), pneumonia (1.5%), and abdominal pain (1.3%). The most common non-serious procedure- and device-associated AEs were abdominal pain (31%), post-operative wound infection (20%), and procedural pain (23%). In all, 17 (4.3%) patients discontinued treatment owing to an AE.
Conclusions:
In conclusion, incidences of PEG-J AEs with the LCIG delivery system and PEG-J longevity were compared favorably with ranges described in the PEG/PEG-J literature. A low discontinuation rate in this study suggests acceptable procedural outcomes and AE rates in PD patients treated with this PEG-J drug delivery system.
Systematic reviews and meta-analyses have become increasingly important in health care. Clinicians read them to keep up to date with their field [1],[2], and they are often used as a starting point for developing clinical practice guidelines. Granting agencies may require a systematic review to ensure there is justification for further research [3], and some health care journals are moving in this direction [4]. As with all research, the value of a systematic review depends on what was done, what was found, and the clarity of reporting. As with other publications, the reporting quality of systematic reviews varies, limiting readers' ability to assess the strengths and weaknesses of those reviews.
Several early studies evaluated the quality of review reports. In 1987, Mulrow examined 50 review articles published in four leading medical journals in 1985 and 1986 and found that none met all eight explicit scientific criteria, such as a quality assessment of included studies [5]. In 1987, Sacks and colleagues [6] evaluated the adequacy of reporting of 83 meta-analyses on 23 characteristics in six domains. Reporting was generally poor; between one and 14 characteristics were adequately reported (mean = 7.7; standard deviation = 2.7). A 1996 update of this study found little improvement [7].
In 1996, to address the suboptimal reporting of meta-analyses, an international group developed a guidance called the QUOROM Statement (QUality Of Reporting Of Meta-analyses), which focused on the reporting of meta-analyses of randomized controlled trials [8]. In this article, we summarize a revision of these guidelines, renamed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), which have been updated to address several conceptual and practical advances in the science of systematic reviews (Box 1).
Box 1: Conceptual Issues in the Evolution from QUOROM to PRISMA
Completing a Systematic Review Is an Iterative Process
The conduct of a systematic review depends heavily on the scope and quality of included studies: thus systematic reviewers may need to modify their original review protocol during its conduct. Any systematic review reporting guideline should recommend that such changes can be reported and explained without suggesting that they are inappropriate. The PRISMA Statement (Items 5, 11, 16, and 23) acknowledges this iterative process. Aside from Cochrane reviews, all of which should have a protocol, only about 10% of systematic reviewers report working from a protocol [22]. Without a protocol that is publicly accessible, it is difficult to judge between appropriate and inappropriate modifications.
Objective:
To assess the association between Parkinson's disease (PD) and melanoma via systematic review and meta-analysis.
Methods:
Comprehensive search in PubMed, Web of Science, Embase and four China databases (SinoMed, WanFang data, CNKI and VIP database) of epidemiologic evidences on PD and melanoma published before April 30, 2015. Studies which reported risk estimates of melanoma among PD patients or risk estimates of PD in patients with melanoma were included. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated by random-effects models. Heterogeneity across studies was assessed using Cochran Q and I(2) statistics. Subgroup analyses and sensitivity analyses were conducted to evaluate sources of heterogeneity. Subgroup analyses were done according to temporal relationship, geographic region and gender respectively. We assessed publication bias using the Begg and Egger test. In addition, study appraisal was done using a scale for observational studies to ensure the quality of evidence.
Results:
We identified 24 eligible studies on PD and melanoma with a total number of 292,275 PD patients: the pooled OR was 1.83 (95 % CI 1.46-2.30) overall, subgroup analyses by temporal relationship showed that risk of melanoma after PD diagnosis was significantly higher (OR 2.43, 95 % CI 1.77-3.32), but not before the diagnosis of PD (OR 1.09, 95 % CI 0.78-1.54). Subgroup analysis by geographic region showed that increased risk of melanoma in PD was found both in Europe (OR 1.44, 95 % CI 1.22-1.70) and in North America (OR 2.64, 95 % CI 1.63-4.28). Gender-specific subgroup analyses did not show difference between men (OR 1.64, 95 % CI 1.27-2.13) and women (OR 1.38, 95 % CI 1.04-1.82) in the risk of melanoma. In addition, we found the risk of non-melanoma skin cancers in PD was slightly higher (OR 1.20, 95 % CI 1.11-1.29) than general population. It was impossible to evaluate the association between PD and melanoma according to use of levodopa or gene polymorphism via meta-analysis since few observational or cohort studies have focused on it.
Conclusions:
An association between PD and melanoma was confirmed. Most of the evidences were of high quality, and the conclusion was robust. Further research is needed to explore the mechanisms underlying this relationship.
Background:
IPX066 is an oral, extended-release, capsule formulation of carbidopa-levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations.
Methods:
We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson's disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov, number NCT00974974.
Findings:
Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-levodopa (mean 3·6 doses per day [SD 0·7]) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-levodopa (mean 5·0 doses per day [1·2]). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-levodopa and 29·79% (15·81) for immediate-release carbidopa-levodopa (mean difference -5·97, 95% CI -9·05 to -2·89; p<0·0001). Extended-release carbidopa-levodopa reduced daily off-time by, on average, an extra -1·17 h (95% CI -1·69 to -0·66; p<0·0001) compared with immediate-release carbidopa-levodopa. During dose conversion with extended-release carbidopa-levodopa, 23 (5%) of 450 patients withdrew because of adverse events and 13 (3%) withdrew because of a lack of efficacy. In the maintenance period, the most common adverse events were insomnia (seven [3%] of 201 patients allocated extended-release carbidopa-levodopa vs two [1%] of 192 patients allocated immediate-release carbidopa-levodopa), nausea (six [3%] vs three [2%]), and falls (six [3%] vs four [2%]).
Interpretation:
Extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency.
Funding:
Impax Laboratories.
To assess the epidemiologic evidence on melanoma in relation to Parkinson disease (PD) via systematic review and meta-analysis.
Epidemiologic studies on melanoma and PD were searched using PubMed, Web of Science, Scoups, and Embase (1965 through June 2010). Eligible studies were those that reported risk estimates of melanoma among patients with PD or vice versa. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models.
We identified 12 eligible publications on melanoma and PD: 8 had fewer than 10 cases with both PD and melanoma, and 7 provided gender-specific results. The pooled OR was 2.11 (95% CI 1.26-3.54) overall, 2.04 (1.55-2.69) for men, and 1.52 (0.85-2.75) for women. Analyses by temporal relationship found that melanoma occurrence was significantly higher after the diagnosis of PD (OR 3.61, 95% CI 1.49-8.77), but not before PD diagnosis (OR 1.07, 95% CI 0.62-1.84). Further analyses revealed that the lack of significance in the latter analysis was due to one study, which when excluded resulted in a significant association (OR 1.44, 95% CI 1.06-1.96). We also analyzed nonmelanoma skin cancers in relation to PD and found no significant relationship (OR 1.11, 95% CI 0.94-1.30).
Collective epidemiologic evidence supports an association of PD with melanoma. Further research is needed to examine the nature and mechanisms of this relationship.
This is a case report of a patient with parkinsonism on levodopa therapy who developed a lid margin melanoma. The possible association is discussed.
The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between-raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance-corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between-raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within-raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between-raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between-raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance.
To evaluate the use of levodopa therapy in patients with Parkinson's disease and malignant melanoma.
A MEDLINE search (January 1966-September 1999) of English-language articles was conducted. Key search terms included levodopa, melanoma, and Parkinson's disease; 34 case reports were identified.
Carbidopa/levodopa continues to be a mainstay in the treatment of Parkinson's disease. Since the late 1970s, a warning has appeared in the prescribing literature for levodopa regarding the risk of activating malignant melanoma. An evaluation was conducted of the case reports in which a causal relationship between levodopa and melanoma was suggested.
There is an unlikely association between levodopa and induction or exacerbation of malignant melanoma.
In the field of movement disorders, areas that have seen important advances in 2016 include the pathogenesis of Parkinson disease involving extra-CNS alpha-synuclein pathology, treatment of hyperkinetic disorders with novel dopamine-depleting drugs, and MRI-guided ultrasound surgery for the treatment of essential tremor.
The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson's disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated-α-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins involved in melanomagenesis. Conversely, genes associated with CMM, affect PD risk. PD/CMM targeted cells share the neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. This article is protected by copyright. All rights reserved.
Importance:
The pathogenesis of rosacea is unclear, but increased matrix metalloproteinase target tissue activity appears to play an important role. Parkinson disease and other neurodegenerative disorders also display increased matrix metalloproteinase activity that contribute to neuronal loss.
Objective:
To investigate the risk of incident (new-onset) Parkinson disease in patients with rosacea.
Design, setting, and participants:
A nationwide cohort study of the Danish population was conducted using individual-level linkage of administrative registers. All Danish citizens 18 years or older from January 1, 1997, to December 31, 2011 (N = 5 472 745), were included. Data analysis was conducted from June 26 to July 27, 2015.
Main outcomes and measures:
The main outcome was a diagnosis of Parkinson disease. Incidence rates (IRs) per 10 000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, medication, and comorbidity were estimated by Poisson regression models.
Results:
A total of 5 404 692 individuals were included in the reference population; of these, 22 387 individuals (9812 [43.8%] women; mean [SD] age at diagnosis, 75.9 [10.2] years) received a diagnosis of Parkinson disease during the study period and 68 053 individuals (45 712 [67.2%] women; mean age, 42.2 [16.5] years) were registered as having rosacea. The IRs of Parkinson disease per 10 000 person-years were 3.54 (95% CI, 3.49-3.59) in the reference population and 7.62 (95% CI, 6.78-8.57) in patients with rosacea. The adjusted IRR of Parkinson disease was 1.71 (95%, CI 1.52-1.92) in patients with rosacea compared with the reference population. There was a 2-fold increased risk of Parkinson disease in patients classified as having ocular rosacea (adjusted IRR, 2.03 [95% CI, 1.67-2.48]), and tetracycline therapy appeared to reduce the risk of Parkinson disease (adjusted IRR, 0.98 [95% CI, 0.97-0.99]).
Conclusions and relevance:
Rosacea constitutes an independent risk factor for Parkinson disease. This association could be due to shared pathogenic mechanisms involving elevated matrix metalloproteinase activity. The clinical consequences of this association require further study.
CALM-PD (Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease) is a randomized, multicenter, double-blind, controlled clinical trial designed to compare the policy of initial treatment of pramipex ole with the policy of initial treatment with levodopa in early, symptomatic Parkinson's disease with regard to the development of dopamineragic motor complications. At 22 American and Canadian sites, 301 eligible subjects requiring antiparkinsonian therapy to treat emerging disability were enrolled in CALM-PD and randomized to (i) active pramipexole and placebo levodopa or (ii) placebo pramipexole and active levodopa. Subjects are being evaluated systematically at regular intervals during a 23.5-month period to determine if and when dopaminergic motor complications (wearing off, dyskinesias, "on-off " effects) occur. In addition, quality-of-life outcomes, economic outcomes, and functional imaging outcomes are being assessed in standard fashion with [I-123]beta-CIT and SPECT imaging throughout the trial. The study design contains many provisions to approximate routine clinical practice and to produce data about clinical effectiveness, tolerability, and cost to facilitate the evidence-based practice of neurology.
Parkinson's disease is highly heterogeneous in early clinical features and later outcomes. This makes classifying subgroups of PD relevant to clinical research and practice, particularly if they are prognostically relevant. Subgroups have been defined both on the basis of motor and nonmotor features, and subgroups have been determined either empirically, based on clinical observation, or using data-driven analytic techniques. Previous studies have examined both the overall number and the nature of nonmotor symptoms and signs in tremor-dominant compared with non-tremor-dominant subtypes, and longitudinal studies identify nonmotor symptoms as important markers of prognosis and important defining features of PD subtypes. Autonomic features seem to preferentially affect individuals with non-tremor-dominant PD subtype early in the disease. Later in the disease cognitive disturbance distinguishes this phenotype. Pathological and neuroimaging studies provide substantial evidence for fundamental biological differences between tremor-dominant and postural instability gait disorder/akinetic-rigid subtypes. Biomarker studies point toward non-tremor-dominant PD as representing more advanced and diffuse neurodegeneration than tremor-dominant PD, encompassing dopaminergic and nondopaminergic as well as synuclein and nonsynuclein (Abeta) pathologies. This aligns with clinical studies that find a higher burden of nonmotor symptoms in non-tremor-dominant PD. The mounting evidence for the relevance of nonmotor features in PD subtypes behooves us to begin to investigate the biological underpinnings of subtypes defined by both motor and nonmotor features. This may be challenging, as PD subtypes are unlikely to be distinct nonoverlapping entities but are more likely to represent typical phenotypes within a multidimensional spectrum resulting from variable contributions of a number of simultaneous pathological processes. © 2016 International Parkinson and Movement Disorder Society.
Background:
An association between melanoma and Parkinson disease (PD) has been hinted at in the neurology and oncology literature since the 1970s after the initiation of levodopa (L-DOPA) therapy for PD. Given that L-DOPA is a substrate in melanin synthesis, there existed a concern that this therapy might cause melanoma.
Objective:
The objective was to research possible etiological links to explain the connection between PD and melanoma.
Methods:
A PubMed and Google Scholar literature search was performed using access provided by the University of Minnesota biomedical library.
Results:
Patients with PD have an overall decreased risk of cancer diagnoses. However, breast cancer and melanoma have an uncharacteristically high rate of co-occurrence with PD. Family history of melanoma and lighter hair and skin color confer a higher risk of developing PD, and having a first-degree relative with either disease conveys a significantly increased risk of developing the other. Other possible connections that have been explored include pigmentation genes in neural-derived cells, pesticides, MC1R polymorphisms, and abnormal cellular autophagy.
Conclusion:
Although a link between PD and melanoma exists, the etiology of this link continues to be elusive. Both PD and melanoma are likely multifactorial diseases involving genetic and environmental risk factors.
CALM-PD (Comparison of the agonist pramipexole with levodopa on motor complications of Parkinson's disease) is a randomized, multicenter, double- blind, controlled clinical trial designed to compare the policy of initial treatment of pramipexole with the policy of initial treatment with levodopa in early, symptomatic Parkinson's disease with regard to the development of dopaminergic motor complications. At 22 American and Canadian sites, 301 eligible subjects requiring antiparkinsonian therapy to treat emerging disability were enrolled in CALM-PD and randomized to (i) active pramipexole and placebo levodopa or (ii) placebo pramipexole and active levodopa. Subjects are being evaluated systematically at regular intervals during a 23.5-month period to determine if and when dopaminergic motor complications (wearing off, dyskinesias, 'on-off' effects) occur. In addition, quality-of- life outcomes, economic outcomes, and functional imaging outcomes are being assessed in standard fashion with [123I]β-CIT and SPECT imaging throughout the trial. The study design contains many provisions to approximate routine clinical practice and to produce data about clinical effectiveness, tolerability, and cost to facilitate the evidence-based practice of neurology.
Background:
Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa compared with placebo or entacapone in patients with Parkinson's disease and motor fluctuations.
Methods:
We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinson's disease with end-of-dose motor fluctuations. Patients aged 30-83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14-15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov, NCT01568073.
Findings:
Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was -56·0 min (SE 13·4; 95% CI -82·3 to -29·7) for placebo, -96·3 min (13·4; -122·6 to -70·0) for entacapone, -91·3 min (13·5; -117·7 to -64·8) for opicapone 5 mg, -85·9 min (13·7; -112·8 to -59·1) for opicapone 25 mg, and -116·8 min (14·0; -144·2 to -89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline -60·8 min, 95% CI -97·2 to -24·4; p=0·0015) and non-inferior to entacapone (-26·2 min, -63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group.
Interpretation:
The addition of opicapone 50 mg to levodopa treatment in patients with Parkinson's disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit.
Funding:
BIAL.
Motor complications are a major source of disability for patients with advanced Parkinson’s disease. Surgical therapies provide benefit to some, but these treatments are expensive and associated with adverse effects. Current research indicates that motor complications are associated with abnormal, intermittent, pulsatile stimulation of denervated dopamine receptors using short acting dopaminergic agents such as levodopa. Retrospective studies suggest that the use of longer‐acting more continuous dopaminergic therapies can improve both motor fluctuations and dyskinesia. We performed a prospective, long‐term (4‐year) trial comparing patients randomized to receive subcutaneous infusion of the dopamine agonist lisuride versus conventional therapy with oral levodopa and dopamine agonists. We demonstrate that patients receiving lisuride infusions experienced a significant reduction in both motor fluctuations and dyskinesia compared with patients receiving standard dopaminergic therapies. Benefits persisted for the 4‐year duration of the study. Mean Unified Parkinson’s Disease Rating Scale scores in ‘ON’ and ‘OFF’ states did not significantly change between baseline and 4 years for patients in the lisuride group, but deteriorated in patients in the levodopa group. This study indicates that continuous lisuride infusion can be beneficial for patients with advanced Parkinson’s disease and reverse established motor fluctuations and dyskinesia.
The concept that the skin is a mirror of Parkinson's disease dates to the start of the last century. Despite dermatological disorders being recognised as a common non-motor symptom of Parkinson's disease, they are often overlooked. This article reviews the various skin disorders seen in Parkinson's disease and addresses the other dermatological questions that are frequently raised by those attending Parkinson's disease clinics.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
• Malignant melanoma derives from melanocytic cells that possess the special biochemical pathway for the conversion of levodopa to melanin. Levodopa is widely employed in the treatment of Parkinson's disease, and several patients receiving levodopa have been observed to have acquired melanomas, raising concern about a possible relationship between this drug and the tumor. We encountered a 74-year-old woman in whom three distinct primary melanomas developed after she had been receiving long-term therapy with levodopa and a decarboxylase inhibitor. These lesions could be distinguished histologically from epidermotropic metastatic melanoma. Although the association between levodopa and melanoma is tenuous, careful monitoring of pigmentary changes in patients receiving levodopa is advised.
(Arch Dermatol 116:1041-1044, 1980)
Background: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. Objective: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. Design: A double-blind, randomized, comparative clinical trial. Setting: Forty-four sites in the United States and Canada. Patients: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. Intervention: Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. Main Outcome Measure: Change from baseline in total daily TTON as measured using home diaries. Results: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. Conclusion: Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.
Background
Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube.
Methods
In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994.
Findings
From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference −1·91 h [95% CI −3·05 to −0·76]; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 [95% CI 0·56 to 3·17]; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube.
Interpretation
Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study.
Funding
AbbVie.
The images are from a 74-year-old man with Par-kinson's disease (PD) 1 year before (A) and 2 years after levodopa treatment (B,C), which clearly demonstrate his white hair turning dark gray. The patient has a 2-year history of PD. L-dopa/carbi-dopa was administered at doses up to 400 mg/day with clinical benefit. Ten months after administration of L-dopa, his wife began to notice repigmen-tation of his hair. Thereafter, his white hair further turned dark gray. There have been two reports describing darkening of white hair and beard subsequent to levodopa therapy in patients with PD. 1,2 How L-dopa affects melanin synthesis is controversial. However, because L-dopa serves as a precursor of the common metabolic pathways of dopamine and melanin, 3 it may stimulate melanin synthesis, possibly contributing to darkening of white hair. References 1. Grainger KM. Pigmentation in Parkinson's disease treated with lev-odopa.
The Cochrane Handbook for Systematic Reviews of Interventions (the Handbook) has undergone a substantial update, and Version 5 of the Handbook is now available online at www.cochrane-handbook.org and in RevMan 5. In addition, for the first time, the Handbook will soon be available as a printed volume, published by Wiley-Blackwell. We are anticipating release of this at the Colloquium in Freiburg. Version 5 of the Handbook describes the new methods available in RevMan 5, as well as containing extensive guidance on all aspects of Cochrane review methodology. It has a new structure, with 22 chapters divided into three parts. Part 1, relevant to all reviews, introduces Cochrane reviews, covering their planning and preparation, and their maintenance and updating, and ends with a guide to the contents of a Cochrane protocol and review. Part 2, relevant to all reviews, provides general methodological guidance on preparing reviews, covering question development, eligibility criteria, searching, collecting data, within-study bias (including completion of the Risk of Bias table), analysing data, reporting bias, presenting and interpreting results (including Summary of Findings tables). Part 3 addresses special topics that will be relevant to some, but not all, reviews, including particular considerations in addressing adverse effects, meta-analysis with non-standard study designs and using individual participant data. This part has new chapters on incorporating economic evaluations, non-randomized studies, qualitative research, patient-reported outcomes in reviews, prospective meta-analysis, reviews in health promotion and public health, and the new review type of overviews of reviews.
Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease.
There is growing evidence in the scientific literature for shared risk and overlapping disease mechanisms in the development of cancer and Parkinson disease (PD). This association has recently been highlighted with respect to melanoma and PD. Therefore, we review and discuss the literature concerning this unexplained link. A striking overlap is observed in the tyrosine and L-dopa biosynthetic pathways suggesting a common disease mechanism associated with these 2 heterogeneous disorders that warrants further investigation.
This study deals with the effects of dopamine (DA), L-dopa, carbidopa and L-dopa/carbidopa on immuno-inflammatory skin reactions in the rat. For this purpose, male Wistar rats immunized with bovine serum albumin in Freund's adjuvant were treated subcutaneously with different doses of DA, L-dopa, carbidopa and L-dopa/carbidopa, for a period of 14 consecutive days or 3 days before skin-testing with BSA. An additional group of rats received 1 injection of a dopamine-related drug 4 hours before and 1 injection 4 hours after skin-testing. Corresponding controls were treated with saline. Arthus and delayed hypersensitivity skin reactions were read at 4 and 24 hours respectively. The results showed that repeated injections of DA, L-dopa and L-dopa/carbidopa significantly suppressed Arthus and delayed reactions. The highest suppression was recorded in rats treated with L-dopa plus carbidopa. Concerning the dose required for immunosuppression it appears that DA was the most effective. Carbidopa did not affect hypersensitivity skin reactions. These results suggest the in vivo relationship between dopamine-related compounds (L-dopa and DA) and immuno-inflammatory reactions. Most probably, L-dopa when is given alone converts into DA and this increase of DA content in periphery depresses immune reactions. However, L-dopa given together with carbidopa (an enzyme which prevents decarboxylation of L-dopa into DA, and enables the penetration of L-dopa into CNS) augments the content of DA in the brain and thus affects immune responses. It appears, therefore, that L-dopa and DA act both peripherally and centrally on immune responsiveness.
A scleroderma-like illness that resembles eosinophilic fasciitis has been recently described in patients who have ingested products containing L-tryptophan. This illness, termed the eosinophilia-myalgia syndrome, belongs in the spectrum of scleroderma disorders. We report a case of scleroderma-like illness with unusual pseudobullous morphea and eosinophilia in a patient receiving L-5-hydroxytryptophan and carbidopa
We describe a patient with long-standing Parkinson's disease who noted that his white hair turned grey and darkened 8 months after the addition of carbidopa to his established levodopa (L-dopa) therapy and 4 months after the introduction of bromocriptine.
Malignant melanoma developed in an apparently benign nevus four months after therapy with levodopa in a patient with Parkinson's disease. This case is reported, and previous reports of this possible causal relationship are reviewed. Although this and previously reported cases are not inconsistent with the unpredictable and variable natural history of malignant melanoma, it seems prudent to clinically monitor pigmentary lesions in patients receiving levodopa therapy. Biopsy specimens of suspicious lesions in these patients should be examined histologically, and if malignancy is found, alternate therapies for treatment of parkinsonism should be considered.
A warning is given on the use of levodopa in patients with known melanomas or with pigmented lesions. Levodopa was administered to 3 patients with Parkinson's disease and known melanomas or pigmented lesions. One had had a 'benign' pigmented nevus for 20 yr, that increased in size during levodopa therapy. Excisional biopsy of the lesion revealed it to be a malignant melanoma. Levodopa was discontinued, and there was no evidence of recurrence. The second patient had had a malignant melanoma excised 1 yr before initiation of levodopa therapy. Two mth after levodopa therapy was begun, signs of an intracerebral tumor, presumably a melanoma, developed, and the patient died. The third patient had had a melanoma excised more than 7 yr (88 mth) before initiation of levodopa therapy. He remains well 2 yr later. In 2 additional cases in the literature, a temporal association was found between initiation of levodopa therapy and growth of melanoma.
Malignant melanoma derives from melanocytic cells that possess the special biochemical pathway for the conversion of levodopa to melanin. Levodopa is widely employed in the treatment of Parkinson's disease, and several patients receiving levodopa have been observed to have acquired melanomas, raising concern about a possible relationship between this drug and the tumor. We encountered a 74-year-old woman in whom three distinct primary melanomas developed after she had been receiving long-term therapy with levodopa and a decarboxylase inhibitor. These lesions could be distinguished histologically from epidermotropic metastatic melanoma. Although the association between levodopa and melanoma is tenuous, careful monitoring of pigmentary changes in patients receiving levodopa is advised.
The incidence of malignant melanoma (MM) is rising. Besides UV radiation, other factors may contribute to this. We describe two patients in whom MM developed during treatment with levodopa. Levodopa has been implicated as an agent that could enhance the development of MM. However, review of the literature does not provide evidence of a definite relationship between treatment with levodopa and the development of MM. Despite this, it is suggested that patients treated with levodopa, particularly those with a history of MM, be observed carefully for changes in or development of new pigmented lesions.
Since we have recently shown that the beta 2-adrenoreceptor (beta 2-AR) expression of selected regions of the hair follicle (HF) epithelium as well as the number of adrenergic nerve fibers in murine skin change in a hair cycle-dependent manner, this has raised the possibility that adrenergic nerves may exert "trophic" functions during HF cycling. To further explore this concept, we have investigated the effect of neuro-pharmacological manipulations on hair growth (anagen) induction in quiescent telogen mouse skin in vivo. Here, we demonstrate that subcutaneous injections of the noradrenaline (NA)-depleting agent guanethidine, or of the neurotoxin 6-hydroxydopamine, but not of the beta 2-AR agonist isoproterenol induce a premature onset of anagen in the lower back skin of C57BL/6 mice. On day 20 after the start of treatment, more than 80% of the guanethidine-treated mice and ca. 65% of the 6-hydroxydopamine-treated (6-OHDA) mice exhibited premature skin darkening and hair growth at the site of drug application, whereas less than one-third of all control animals showed macroscopic signs of anagen development. This was confirmed by histology, demonstrating mature anagen VI HFs only at the immediate site of treatment with guanethidine or 6-OHDA as opposed to resting telogen HFs in the neighboring untreated skin area. This observation further supports the concept that sympathetic nerves are intimately involved in hair growth control and invites one to explore the neuro-pharmacological manipulation of piloneural interactions as a novel therapeutic strategy for the management of hair growth disorders.