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1.
Eur J Clin Pharmacol ; 68(11): 1493-9, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22527346

ABSTRACT

PURPOSE: To investigate the association between adverse reactions to catechol-O-methyltransferase (COMT) inhibitors and the UDP-glucuronosyltransferase 1A9 genotypes UGT1A9*1b and UGT1A9*3a, which were previously identified in individual cases of COMT inhibitor-induced toxicity. METHODS: The study included 52 Parkinson's disease (PD) patients on COMT inhibitors without evidence of adverse reactions and 11 PD patients who had been withdrawn from COMT inhibitors due to adverse reactions. UGT1A9*1b was identified by direct sequencing of the PCR amplification of the gene and UGT1A9*3a was assayed by real-time PCR. RESULTS: The frequency of the *3a/*3a and *1/*3a genotype variants was 45.5 % in subjects with adverse reactions and 21.1 % in subjects without adverse reactions [overall UGT1A9*3a allele frequency 27.3 vs. 11.5 %, P = 0.087; odds ratio (OR) 2.87, 95 % confidence interval (CI) 0.94-8.77]. The frequency of genotype combinations leading to low glucuronosyltransferase activity (*3a/*3a irrespective of *1b or *1/*3a and *1/*1b) was 5.8 % in subjects without adverse reactions and 36.4 % in subjects with adverse reactions (P = 0.014; OR 9.33, 95 % CI 1.71-50.78). CONCLUSIONS: In PD patients UDP-glucuronosyltransferase 1A9 genotypes are associated with adverse reactions to COMT inhibitors, leading to treatment withdrawal. UDP-glucuronosyltransferase 1A9 genotyping may be a screening and/or diagnostic test to assist individualized treatments with COMT inhibitors.


Subject(s)
Antiparkinson Agents/adverse effects , Catechol O-Methyltransferase Inhibitors , Enzyme Inhibitors/adverse effects , Glucuronosyltransferase/genetics , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Alleles , Antiparkinson Agents/therapeutic use , Cohort Studies , Down-Regulation , Enzyme Inhibitors/therapeutic use , Female , Gene Frequency , Genetic Association Studies , Glucuronosyltransferase/metabolism , Hospitals, University , Humans , Italy , Male , Parkinson Disease/metabolism , Real-Time Polymerase Chain Reaction , Retrospective Studies , UDP-Glucuronosyltransferase 1A9
2.
Mov Disord ; 27(2): 227-35, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21997192

ABSTRACT

Abnormal postures of the trunk are a typical feature of Parkinson's disease (PD). These include Pisa syndrome (PS), a tonic lateral flexion of the trunk associated with slight rotation along the sagittal plane. In this study we describe clinical, electromyographic (EMG), and radiological features of PS in a group of 20 PD patients. All patients with trunk deviation underwent EMG and radiological (RX and CT scan) investigation. Clinical characteristics of patients with PS were compared with a control group of PD patients without trunk deviation. PD patients with PS showed a significantly higher score of disease asymmetry compared with the control group. In the majority of patients with PS, trunk bending was contralateral to the side of symptom onset. EMG showed abnormal tonic hyperactivity on the side of the deviation in the paravertebral thoracic muscles and in the abdominal oblique muscles. CT of the lumbar paraspinal muscles showed muscular atrophy more marked on the side of the deviation, with a craniocaudal gradient. PS may represent a complication of advanced PD in a subgroup of patients who show more marked asymmetry of disease and who have detectable hyperactivity of the dorsal paravertebral muscles on the less affected side. This postural abnormality deserves attention and proper early treatment to prevent comorbidities and pain.


Subject(s)
Muscle, Skeletal/physiopathology , Parkinson Disease/complications , Posture/physiology , Torsion Abnormality , Aged , Atrophy/etiology , Electromyography , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective Studies , Spinal Cord/diagnostic imaging , Spinal Cord/pathology , Tomography, X-Ray Computed , Torsion Abnormality/diagnostic imaging , Torsion Abnormality/etiology , Torsion Abnormality/pathology
3.
Funct Neurol ; 26(2): 87-95, 2011.
Article in English | MEDLINE | ID: mdl-21729590

ABSTRACT

This paper traces the development of research and healthcare models in the field of cerebrovascular disorders at the C. Mondino National Institute of Neurology in Pavia, Italy. It starts with a description of the original experiences of Ottorino Rossi and his thesis on atherosclerosis which date back to the beginning of the last century; it then illustrates the connections between his seminal essay and the future directions followed by research in this institute, through to the development of one of the first stroke units in Italy. In this context, we examine a large range of scientific approaches, many related to cerebrovascular diseases (such as headaches) and autonomic disorders, and some of their biological and physiological markers. The originality of an approach also based on tools of advanced technology, including information technology, is emphasised, as is the importance of passion and perseverance in the pursuit of extraordinary results in what is an extremely complex and difficult field.


Subject(s)
Cerebrovascular Disorders/history , Cerebrovascular Disorders/therapy , Neurology , Autonomic Nervous System Diseases/history , Autonomic Nervous System Diseases/therapy , History, 19th Century , History, 20th Century , History, 21st Century , Humans , Italy , Neurology/history , Neurology/methods , Neurology/organization & administration
4.
Mov Disord ; 26(3): 442-8, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21462260

ABSTRACT

BACKGROUND: Pain is one of the major nonmotor symptoms of Parkinson's disease. We hypothesized that Parkinson's disease patients could show an early diffuse abnormal processing of the nociceptive inputs also in the absence of clinical pain syndrome and that this could represent the physiopathological substrate to explain the high incidence of diffuse pain symptoms. MATERIALS AND METHODS: We used the temporal summation threshold of the nociceptive withdrawal reflex and the related pain sensation to evaluate the facilitation in pain processing at spinal level. Fifteen (7 Women; 8 Men; mean age 63.0 ± 9.1) Parkinson's disease patients without clinical pain and 12 (6 Women, 6 Men; mean age 61.2 ± 4.2) healthy subjects were recruited. Parkinson's disease group has been subdivided into two subgroups, 7 early-stage Parkinson's disease patients with unilateral signs (Hoehn and Yahr stage 1) and 8 patients in a more advanced stage of the disease showing bilateral parkinsonian signs (Hoehn and Yahr stages 2 and 2.5), both "on" and "off" treatments with levodopa. RESULTS: A significant facilitation in temporal summation of pain (reduced temporal summation threshold and increased painful sensation) was found in Parkinson's disease patients when compared with controls. This facilitation is more evident in Parkinson's disease with bilateral signs and on the side more affected in Parkinson's disease with unilateral signs. Levodopa administration failed to significantly modify the neurophysiological abnormalities; however, a slight improvement has been detected. CONCLUSIONS: The increased gain in pain processing at spinal level in Parkinson's disease patients could be a consequence of the degenerative phenomena involving supraspinal projections implicated in the modulation of pain processing and could make Parkinson's disease patients more predisposed to develop a pain condition.


Subject(s)
Pain Threshold/physiology , Pain/etiology , Pain/pathology , Parkinson Disease/complications , Spinal Cord/physiopathology , Adult , Aged , Antiparkinson Agents/therapeutic use , Disability Evaluation , Female , Humans , Levodopa/therapeutic use , Male , Middle Aged , Pain/drug therapy , Pain Measurement , Pain Threshold/drug effects , Parkinson Disease/drug therapy , Physical Stimulation , Psychophysics/methods , Reflex/physiology , Severity of Illness Index
5.
Headache ; 50(10): 1587-96, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20807249

ABSTRACT

OBJECTIVE: The aim of the present study was to evaluate a possible involvement of 2 polymorphisms of the serotonin 5HT2A receptor gene (A-1438G and C516T) as risk factors for medication overuse headache (MOH) and whether the presence of these polymorphic variants might determine differences within MOH patients in monthly drug consumption. BACKGROUND: Despite a growing scientific interest in the mechanisms underlying the pathophysiology of MOH, few studies have focused on the role of genetics in the development of the disease, as well as on the genetic determinants of the inter-individual variability in the number of drug doses taken per month. METHODS: Our study was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Genotype-specific risks were estimated as odds ratios with associated 95% confidence intervals by unconditional logistic regression and adjusted for age and gender. A stepwise multiple linear regression analysis was employed to identify significant predictors of the number of drug doses taken per month. RESULTS: No significant association was found between 5HT2A A and 1438G and C516T gene polymorphisms and MOH risk. In contrast, a higher consumption of monthly drug doses was observed among 516T 5HT2A carriers (median 50, range 13-120) compared to 516CC patients (median 30, range 12-128) (Mann-Whitney U-test, P = .018). In the stepwise multiple regression analysis, C516T 5HT2A polymorphism (P = .018) and class of overused drug (P = .047) emerged as significant, independent predictors of the monthly drug consumption in MOH patients. CONCLUSIONS: Although our results do not support a major role of the A-1438G and C516T polymorphic variants of the 5HT2A gene in the susceptibility of MOH, our findings support an influence of the C516T polymorphism on the number of symptomatic drug doses taken and, possibly, on the drug-seeking behavior in these patients.


Subject(s)
Headache Disorders, Secondary/genetics , Receptor, Serotonin, 5-HT2A/genetics , Adolescent , Adult , Aged , Alleles , DNA/genetics , Drug-Seeking Behavior , Female , Gene Frequency , Genetic Variation , Genotype , Headache Disorders, Secondary/psychology , Humans , Italy/epidemiology , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Young Adult
6.
Clin Neuropharmacol ; 33(2): 61-6, 2010.
Article in English | MEDLINE | ID: mdl-19935405

ABSTRACT

INTRODUCTION: Slow gastric emptying decreasing levodopa (LD) bioavailability contributes to motor fluctuations in Parkinson disease (PD). Melevodopa (LD methylester), ensuring rapid duodenal absorption, has been proposed as rescue therapy for afternoon off periods. OBJECTIVE: To assess daily motor fluctuations by multiple administrations of Sirio (Chiesi Farmaceutici SpA, Parma, Italy) (melevodopa/carbidopa) in PD patients. PATIENTS AND METHODS: In this open-label naturalistic study, 75 PD patients (group A) completely switched standard LD (Sinemet or Madopar) with Sirio at an equivalent dosage (800-1000 mg/d). One hundred nineteen PD patients (group B) partially replaced their standard LD (Sinemet) with Sirio at an equivalent dosage (400-500 mg/d) while continuing Stalevo 100. In both groups, the observational period lasted 6 months. Assessments included an on/off diary, the Unified Parkinson's Disease Rating Scale (motor examination [UPDRS II] and activities of daily living [UPDRS III]), the dyskinesia scale, and an adverse event profile. RESULTS: Group A showed a significant reduction of afternoon off hours at 6 months (P < 0.05). Forty-five patients (69%) reported a subjective early onset of on motor response. Twelve patients (18.5%) reported its shorter duration. The dyskinesia scale score remained unchanged. Ten patients (13.3%) discontinued melevodopa for gastric intolerance. Group B showed at 6 months a significant reduction of total hours of daily off periods (P < 0.05), particularly in the morning (P < 0.01) and afternoon (P < 0.05). Seventy subjects (59%) expressed positive judgment on quickness of onset of on motor response. The dyskinesia scale score was unchanged. No significant adverse events were reported. CONCLUSIONS: Switching PD patients with motor fluctuations to melevodopa, particularly in the presence of entacapone, could optimize critical periods of the day such as the morning delay on and afternoon off periods.


Subject(s)
Carbidopa/therapeutic use , Catechols/therapeutic use , Dyskinesias/drug therapy , Levodopa/analogs & derivatives , Parkinson Disease/drug therapy , Aged , Carbidopa/adverse effects , Drug Combinations , Drug Therapy, Combination , Female , Humans , Levodopa/adverse effects , Levodopa/therapeutic use , Male , Patient Satisfaction , Time Factors
7.
Parkinsonism Relat Disord ; 15(9): 703-5, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19482505

ABSTRACT

Mutations in the Grb10-interacting GYF protein 2 (GIGYF2) gene, within the PARK11 locus, have been nominated as a cause of Parkinson's disease in Italian and French populations. By sequencing the whole GIGYF2 coding region in forty-six probands (thirty-seven Italians) with familial Parkinson's disease compatible with an autosomal dominant inheritance, we identified no mutations. Our data add to a growing body of evidence suggesting that GIGYF2 mutations are not a frequent cause of PD.


Subject(s)
Carrier Proteins/genetics , Parkinson Disease/genetics , Adult , Aged , Humans , Middle Aged , Mutation , Pedigree
8.
Parkinsonism Relat Disord ; 15(9): 675-81, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19398215

ABSTRACT

Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious therapeutic option in the treatment of advanced Parkinson's disease (PD). The procedure may be however associated with functional impairment of different types and intensity. In this paper we describe the functional impairments detected in a group of 34 subjects with PD who were submitted to DBS. These patients belonged to a cohort of 75 consecutive PD patients who underwent the surgical procedure. The rehabilitation program included physiotherapy exercises for recovery/maintenance of the range of motion, active exercises, exercises for coordination and proprioception, and walking training based on the use of sensory cues, with daily sessions for a period of 4-8 weeks. The motor examination section of unified Parkinson's disease rating scale (UPDRS-ME) and the functional independence measure (FIM) scores showed a consistent and significant improvement in the patients' motor performances. The reported findings suggest that rehabilitation may play an important role in the correction of specific functional impairments caused by or associated with DBS in PD.


Subject(s)
Deep Brain Stimulation/adverse effects , Parkinson Disease/rehabilitation , Parkinson Disease/therapy , Subthalamic Nucleus/physiology , Cognition Disorders/etiology , Cognition Disorders/rehabilitation , Deglutition Disorders/etiology , Deglutition Disorders/rehabilitation , Exercise Therapy , Female , Humans , Male , Middle Aged , Movement Disorders/etiology , Movement Disorders/rehabilitation , Pain/etiology , Pain/rehabilitation , Pilot Projects , Postural Balance , Speech Disorders/etiology , Speech Disorders/rehabilitation
9.
Clin Neuropharmacol ; 32(3): 133-9, 2009.
Article in English | MEDLINE | ID: mdl-18978486

ABSTRACT

Long-term treatment of Parkinson disease (PD) is frequently associated with l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs). L-DOPA-induced dyskinesias are likely due to changes in the signal transduction pathways, at the striatal level, related to pulsatile stimulation of dopamine receptors. We investigated whether markers of this phenomenon can also be detected peripherally. We analyzed mRNA expression for D5 (D1-like) and D3 (D2-like) receptors and levels of second messengers, such as cAMP and free intracellular Ca2+ ([Ca2+]i), in peripheral blood lymphocytes of PD patients with (LID+) or without LIDs (LID-). Patients with PD showed depressed [Ca2+]i rise in response to mitogen-induced activation. The defect was more pronounced in LID+ (-33% with respect to healthy controls) than in LID- patients (-20%). Peripheral blood lymphocyte levels of cAMP were decreased in both LID+ (3.8 +/- 2.9 pmol/10 cells) and LID- patients (4.2 +/- 2.4 pmol/10(6) cells), with respect to controls (6 +/- 2.6 pmol/10(6) cells). No differences were found in dopamine receptor mRNA expression. Our results demonstrate that second messenger levels are altered in the peripheral blood lymphocytes of PD patients treated with dopaminergic agents and that patients with LIDs show further alterations in the regulation of [Ca2+]i homeostasis. This may represent a distinctive trait of patients prone to develop dyskinetic movements.


Subject(s)
Akathisia, Drug-Induced/etiology , Antiparkinson Agents/adverse effects , Calcium/metabolism , Homeostasis/drug effects , Levodopa/adverse effects , Parkinson Disease/metabolism , Aged , Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology , Case-Control Studies , Cyclic AMP/metabolism , Female , Humans , Ionophores/pharmacology , Lactones/pharmacology , Lymphocytes/drug effects , Lymphocytes/metabolism , Male , Middle Aged , Mitogens/pharmacology , Parkinson Disease/drug therapy , Phytohemagglutinins/pharmacology , RNA, Messenger/metabolism , Receptors, Dopamine D3/genetics , Receptors, Dopamine D3/metabolism , Receptors, Dopamine D5/genetics , Receptors, Dopamine D5/metabolism , Sesquiterpenes/pharmacology
10.
Arch Neurol ; 65(9): 1191-4, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18779422

ABSTRACT

OBJECTIVE: To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls. DESIGN: Case-control study. PATIENTS AND METHODS: Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects. RESULTS: The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy. CONCLUSION: These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.


Subject(s)
Pain/physiopathology , Parkinson Disease/physiopathology , Aged , Case-Control Studies , Female , Humans , Male , Middle Aged , Motor Skills/physiology , Pain/complications , Pain/diagnosis , Parkinson Disease/complications , Parkinson Disease/diagnosis
11.
Parkinsonism Relat Disord ; 14 Suppl 2: S124-9, 2008.
Article in English | MEDLINE | ID: mdl-18595767

ABSTRACT

The investigation of pathogenic and pathophysiological mechanisms of Parkinson's disease relies on experimental models reproducing, in the animal, the pathological and behavioural features of the disease. Despite the availability of innovative models, 6-hydroxydopamine (6-OHDA) remains the most widely used tool to induce a nigrostriatal lesion in the animal (rat). This is due to (1) the relatively low complexity and cost of the procedure, (2) the fact that the 6-OHDA-induced lesion is highly reproducible, and (3) the versatility of the procedure, which can yield varying degrees of nigrostriatal lesions that develop with different temporal profiles, depending on the site chosen for the toxin injection.


Subject(s)
Adrenergic Agents/toxicity , Oxidopamine/toxicity , Parkinson Disease/etiology , Animals , Disease Models, Animal , Humans , Parkinson Disease/pathology , Parkinson Disease/physiopathology
12.
Eur J Pharmacol ; 580(1-2): 43-7, 2008 Feb 02.
Article in English | MEDLINE | ID: mdl-18035351

ABSTRACT

Triptans mediate vasoconstriction of meningeal vessels via stimulation of vascular 5-hydroxytryptamine (5-HT)(1B) receptors. These drugs are recommended for acute treatment in patients with moderate-to-severe migraine attacks and in those patients with mild-to-moderate headache that are not controlled adequately by other agents. Yet, approximately 25% of all migraine users and 40% of all attacks do not respond to triptan treatment. Among the hypothesis to explain this is the possibility that genetic single nucleotide polymorphisms that alter the receptor, for example changing the transcriptional rate and therefore the amount of target protein might change the clinical response to these drugs. In the present contribution, we therefore decided to evaluate whether single nucleotide polymorphisms on the 5-HT(1B) gene might contribute to inter-individual variability in clinical responses to triptans. Two polymorphisms in the promoter region of the 5-HT(1B) receptor (T-261G and A-161T) and the synonymous variation G861C in the coding region were genotyped by restriction fragment length polymorphism in 105 migraine patients. In our sample population, 71% of patients responded to triptans. Allelic and diplotype frequencies were not significantly different between responders and non-responders. On the other hand, extrapolation of in vitro data on promoter activity would suggest that patients with higher copy number of receptors respond slightly better. Our data therefore do not support the involvement of 5-HT(1B) single nucleotide polymorphisms in mediating the inter-individual variability to triptans.


Subject(s)
Migraine with Aura/drug therapy , Migraine without Aura/drug therapy , Polymorphism, Single Nucleotide , Receptor, Serotonin, 5-HT1B/drug effects , Serotonin Receptor Agonists/pharmacology , Tryptamines/pharmacology , Adult , Aged , Alleles , Female , Gene Frequency , Haplotypes , Humans , Male , Middle Aged , Migraine with Aura/genetics , Migraine without Aura/genetics , Open Reading Frames , Polymorphism, Restriction Fragment Length , Promoter Regions, Genetic , Receptor, Serotonin, 5-HT1B/genetics , Receptor, Serotonin, 5-HT1B/metabolism
13.
Funct Neurol ; 22(2): 75-9, 2007.
Article in English | MEDLINE | ID: mdl-17637209

ABSTRACT

This paper looks at the use of magnetic resonance spectroscopy (MRS) for diagnostic and research purposes in Parkinson's disease and parkinsonian syndromes. The review considers both proton MRS (1H MRS) and phosphorus MRS (31 P MRS) studies. MRS is useful for diagnostic purposes, helping to differentiate Parkinson's disease from other parkinsonian syndromes. Even more usefully, MRS can be used for non invasive in vivo human research.


Subject(s)
Magnetic Resonance Imaging , Parkinson Disease/diagnosis , Parkinsonian Disorders/diagnosis , Animals , Humans , Magnetic Resonance Spectroscopy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/pathology
14.
Mov Disord ; 22(9): 1239-44, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17566120

ABSTRACT

Chronic constipation is the most frequent symptom of autonomic system involvement in Parkinson's disease (PD). Quite often the symptom is severe and impairs patients' quality of life. The objective of this study is to determine the efficacy and safety of an isosmotic macrogol solution for the treatment of constipation in PD patients, in a double-blind, placebo-controlled study. A total of 57 PD patients with constipation were randomly assigned to receive an isosmotic macrogol electrolyte solution (MC-ES; 29 patients) or placebo (28 patients) for 8 weeks. Treatment efficacy was defined as complete relief of the symptom or a marked improvement of two of the following indicators: stool frequency, straining, stool consistency, use of rectal laxatives as a rescue therapy. The responder rates were significantly higher in the MC-ES group both at the first (4 weeks; P < 0.0003) and at the final evaluation (8 weeks; P < 0.0012). The frequency of bowel movements (P < 0.002) and stool consistency (P < 0.006) were significantly changed in the MC-ES group compared to the placebo group. At the final evaluation, a rectal laxative was used by 2 (12.5%) patients on placebo, whereas no use was recorded in the MC-ES group. Responder rate for straining showed a favorable trend in patients treated with macrogol versus placebo. Unified Parkinson's Disease Rating Scale Part III and Parkinson's Disease Questionnaire (PDQ-39) did not show any significant modification in either group during the 8-week treatment period. The results of this placebo-controlled study show the efficacy of MC-ES in the treatment of constipation in PD. MC-ES was well-tolerated and did not affect the course of PD.


Subject(s)
Constipation/drug therapy , Polyethylene Glycols/therapeutic use , Surface-Active Agents/therapeutic use , Aged , Chi-Square Distribution , Constipation/etiology , Double-Blind Method , Female , Humans , Male , Parkinson Disease/complications , Severity of Illness Index , Time Factors
15.
Lancet Neurol ; 6(6): 513-20, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17509486

ABSTRACT

BACKGROUND: Continuous dopaminergic drug delivery is an unmet medical need in advanced Parkinson's disease. The aim of this trial-Clinical Efficacy of Pramipexole And Transdermal Rotigotine in Advanced PD (CLEOPATRA-PD)-was to assess the efficacy of adjunct treatment with rotigotine in comparison with placebo and with pramipexole in levodopa-treated patients with advanced Parkinson's disease and wearing-off type motor fluctuations. METHODS: In this randomised controlled trial, eligible participants were randomly assigned to receive either rotigotine (up to 16 mg/24 h as a transdermal patch), pramipexole (up to 4.5 mg/day orally), or placebo for 6 months. Primary efficacy variables were absolute change in total hours "off" (assessed by home diaries) from baseline to end of study and responder rate (defined as the proportion of patients with >or=30% reduction in absolute off time per day). Analyses were done by intention to treat. This trial is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00244387. FINDINGS: 204 patients were randomly assigned to receive rotigotine, 201 to receive pramipexole, and 101 to receive placebo; 427 (84%) completed the trial. The number of discontinuations in each group was similar; most were for adverse events. The mean dose of rotigotine was 12.95 mg/24 h (SD 3.54), the mean dose of pramipexole was 3.1 mg/day (1.24). Mean absolute change in off time from baseline was -2.5 h (SE 0.20) with rotigotine, -2.8 h (0.20) with pramipexole, and -0.9 h (0.29) with placebo. The absolute change in off time from baseline compared with placebo was -1.58 h (95% CI -2.27 to -0.90; p<0.0001) for rotigotine and -1.94 h (-2.63 to -1.25; p<0.0001) for pramipexole. Responder rates were 67% (134 of 200 patients) for pramipexole, 59.7% (120 of 201 patients) for rotigotine, and 35% (35 of 100 patients) for placebo. INTERPRETATION: In terms of change in absolute off time, rotigotine was non-inferior to pramipexole. Continuous delivery of rotigotine as transdermal patches could offer similar efficacy to oral pramipexole in patients with fluctuating Parkinson's disease over 6 months of treatment.


Subject(s)
Antiparkinson Agents/therapeutic use , Benzothiazoles/therapeutic use , Dopamine Agonists/administration & dosage , Parkinson Disease/drug therapy , Tetrahydronaphthalenes/administration & dosage , Thiophenes/administration & dosage , Administration, Cutaneous , Aged , Double-Blind Method , Female , Humans , Male , Middle Aged , Placebos , Pramipexole , Severity of Illness Index , Treatment Outcome
16.
Mov Disord ; 21(12): 2240-3, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17029278

ABSTRACT

Currently, the best treatment option for idiopathic cervical dystonia (ICD) is injection of botulinum toxin (BTX) into the affected muscles, whereas rehabilitative approaches have given disappointing results. We evaluated whether the association of an ad hoc rehabilitative program may improve the clinical efficacy of BTX treatment in a single-center, cross-over, controlled study. Forty patients with ICD were randomly assigned to two different treatment groups: (1) BTX type A (BTX-A) plus a specific program of physical therapy (BTX-PT) or (2) BTX-A alone (BTX-0). Patients in the BTX-PT group showed a longer duration of the clinical benefit (118.8 vs. 99.1 days) and needed a lower dose of BTX at reinjection (284.5 vs. 325.5 units). In addition, they showed more marked reductions in their disability in activities of daily living (-9.7 vs. -4.85 points) and subjective pain (-13.35 vs. 6.95 points) scores. Association of BTX-A therapy with a specific program of physical therapy may improve ICD treatment outcome.


Subject(s)
Botulinum Toxins, Type A/therapeutic use , Neuromuscular Agents/therapeutic use , Physical Therapy Specialty/methods , Torticollis/drug therapy , Torticollis/rehabilitation , Activities of Daily Living , Aged , Analysis of Variance , Cross-Over Studies , Double-Blind Method , Electromyography/methods , Female , Humans , Injections, Intramuscular , Male , Middle Aged , Pain Measurement , Time Factors , Treatment Outcome
17.
Parkinsonism Relat Disord ; 12(4): 195-204, 2006 May.
Article in English | MEDLINE | ID: mdl-16621660

ABSTRACT

Parkinson's disease (PD) patients have a ninefold increased risk of recurring falls compared to healthy controls. The risk of falling due to cardiovascular dysautonomia (CVD) is not quantifiable. But, CVD is an integral part of the disease and at least 20% of PD patients suffer from orthostatic hypotension, an expression of CVD. One way to reduce falls due to CVD in PD patients could be to give adequate information on the relationship between falling risks and cardiovascular dysautonomia to patients and their caregivers. Moreover, drugs given for PD might contribute to OH and we propose that education and non-pharmacological strategies for its treatment might be preferable, especially because of the low efficacy of drugs available for the treatment of OH and the frailty of elderly PD patients.


Subject(s)
Accidental Falls , Autonomic Nervous System Diseases/complications , Autonomic Nervous System Diseases/etiology , Cardiovascular Diseases/complications , Cardiovascular Diseases/etiology , Parkinson Disease/complications , Accidental Falls/statistics & numerical data , Autonomic Nervous System Diseases/physiopathology , Cardiovascular Diseases/physiopathology , Humans , Postural Balance/physiology , Risk
18.
Eur J Hum Genet ; 14(3): 322-31, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16333314

ABSTRACT

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.


Subject(s)
Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/physiology , Adult , Aged , Alternative Splicing , Amino Acid Sequence , Animals , Disease Progression , Exons , Family Health , Female , Genes, Dominant , Genetic Testing , Genotype , Heterozygote , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Models, Genetic , Molecular Sequence Data , Mutation , Open Reading Frames , Pedigree , Phenotype , Polymorphism, Genetic , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary
19.
Mov Disord ; 20(11): 1439-48, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16028215

ABSTRACT

Psychotic symptoms are the main and the most disabling "nonmotor" complications of Parkinson's disease (PD), the pathophysiology of which is poorly recognized. Polysomnographic studies have shown a relationship between visual hallucinations and rapid eye movement (REM) sleep. The objective of this study is to clarify the relationship between psychotic symptoms and REM sleep behavior disorder (RBD) in PD. In a Parkinson's disease outpatient unit, 289 consecutive subjects with idiopathic PD were administered (in the period from January to December 2002) a multiple-choice questionnaire and structured interview on sleep and mental disorders. RBD was diagnosed in accordance with the minimal diagnostic criteria of the International Classification of Sleep Disorders. Hallucinations and delusional disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. The presence or absence of psychotic symptoms, of RBD, and of daytime sleepiness, as well as motor status, cognitive status, and mood were assessed. Approximately 32% (n = 92) of the subjects presented with psychotic disorders; 30% (n = 86) had experienced hallucinations; 2% (n = 6) had delusions without hallucinations. Sixty-two (72%) hallucinators reported nocturnal hallucinations. A total of 6.6% (n = 19) of the subjects complained of a delusional disorder. There were 26.6% (n = 77) of subjects who presented with RBD: 28 (36%) with onset before and 49 (63%) with onset after PD diagnosis. The presence of RBD was associated with an increased risk of manifesting hallucinations and delusions (odds ratio [OR], 2.73). Other independent clinical factors found to have an effect on psychotic disorders were cognitive impairment (OR, 3.92), disease duration (OR, 2.46), advanced age (OR, 2.34), and severity of motor symptoms (OR, 2.06). These results suggest that RBD is widely associated with psychosis in PD.


Subject(s)
Delusions/physiopathology , Hallucinations/physiopathology , Parkinson Disease/physiopathology , REM Sleep Behavior Disorder/physiopathology , Sleep, REM/physiology , Aged , Analysis of Variance , Chi-Square Distribution , Demography , Female , Humans , Male , Mental Status Schedule/statistics & numerical data , Middle Aged , Parkinson Disease/therapy , Retrospective Studies
20.
BMC Health Serv Res ; 5(1): 26, 2005 Mar 24.
Article in English | MEDLINE | ID: mdl-15790401

ABSTRACT

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disease which at present has no cure, and it usually results in severe disability. The burden of PD increases as the illness progresses, resulting in the extensive utilisation of both health and community services. Knowledge of healthcare use patterns and of their determinants may greatly contribute to improve patient care, however few studies have examined this issue in PD. The present study was devised to describe the type of and reasons for medical healthcare resource use in persons with PD attending a Centre for PD and Movement Disorders, and to examine drug prescriptions issued on such occasions. METHODS: The study was a retrospective, cross-sectional survey in a cohort of ambulatory patients with PD, conducted by means of standard interviews. RESULTS: In the year before the study, 92 (70.8%) of 130 patients used medical healthcare resources: 1/5 of the patients was admitted to hospital, 1/5 to emergency room, 2/5 were visited by a non-neurology specialist, and 1/4 by the GP. Reasons were: nearly 20% programmed hospital admissions and visits, and more than 25% injuries and musculo-skeletal diseases. Other conditions typically occurring in PD (e.g. dementia, diabetes and cardio- and cerebro-vascular disease) were less frequently involved. On such occasions, drugs for PD were occasionally changed, however drug prescriptions for other indications were issued to more than 66% of the patients. CONCLUSION: Several physicians other than the neurologist may take care of PD patients on different occasions, thus emphasising the need for communication between the reference neurologist and other physicians who from time to time may visit the patient.


Subject(s)
Health Services/statistics & numerical data , Parkinson Disease/therapy , Adult , Aged , Antiparkinson Agents/therapeutic use , Comorbidity , Cross-Sectional Studies , Drug Prescriptions/statistics & numerical data , Electric Stimulation Therapy , Female , Hospitalization/statistics & numerical data , Humans , Italy , Levodopa/therapeutic use , Male , Middle Aged , Neurology , Office Visits/statistics & numerical data , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Patient Care Team , Utilization Review
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