ADMET considerations for restless leg syndrome drug treatments

Expert Opinion on Drug Metabolism and Toxicology

Volumn 8, Issue 10, 2012, Pages 1247-1261

  De Biase, Stefano ^a,b,c   Merlino, Giovanni ^a   Lorenzut, Simone ^a,b,c   Valente, Mariarosaria ^a,b,c   Gigli, Gian Luigi ^a,b,c  

^a SANTA MARIA DELLA MISERICORDIA UNIVERSITY HOSPITAL   (Italy)

^b UNIVERSITY OF UDINE   (Italy)

^c UNIVERSITY OF UDINE   (Italy)

Author keywords

Absorption; Augmentation; Distribution; Dopamine; Elimination; Gabapentin enacarbil; Iron; Levodopa; Metabolism; Periodic leg movements; Pharmacokinetic; Pramipexole; Pregabalin; Restless legs syndrome; Ropinirole; Rotigotine; Tolerance; Toxicology

Indexed keywords

ANTACID AGENT; ANTICONVULSIVE AGENT; BENSERAZIDE; CABERGOLINE; CARBIDOPA; CIMETIDINE; CIPROFLOXACIN; DOMPERIDONE; DOPA DECARBOXYLASE INHIBITOR; DOPAMINE RECEPTOR STIMULATING AGENT; FERROUS SULFATE; FLUVOXAMINE; GABAPENTIN; GABAPENTIN ENACARBIL; IRON; LEVODOPA; MEXILETINE; MONOAMINE OXIDASE INHIBITOR; MUSCARINIC RECEPTOR BLOCKING AGENT; NORFLOXACIN; OMEPRAZOLE; PERGOLIDE; PLACEBO; PRAMIPEXOLE; RANITIDINE; ROPINIROLE; ROTIGOTINE; TRICYCLIC ANTIDEPRESSANT AGENT; UNINDEXED DRUG; VERAPAMIL;

ABNORMAL VISION; APPLICATION SITE REACTION; ASTHENIA; CHRONIC KIDNEY DISEASE; CONFUSION; CONSTIPATION; DIZZINESS; DRUG ABSORPTION; DRUG ANTAGONISM; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG CONTRAINDICATION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG FORMULATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENTIATION; DRUG RELEASE; DRUG SAFETY; DRUG STRUCTURE; ERYTHEMA; FATIGUE; HALLUCINATION; HEADACHE; HEART ARRHYTHMIA; HUMAN; INSOMNIA; IRON DEFICIENCY; LUNG FIBROSIS; MAXIMUM PLASMA CONCENTRATION; MENTAL DISEASE; NAUSEA; NEUROPATHIC PAIN; ORTHOSTATIC HYPERTENSION; PERIPHERAL NEUROPATHY; PLEUROPULMONARY FIBROSIS; PRURITUS; RESTLESS LEGS SYNDROME; REVIEW; RHINOPHARYNGITIS; SKIN MANIFESTATION; SMOKING; SOMNOLENCE; TOXICOLOGY; UNSPECIFIED SIDE EFFECT; VOMITING;

AMINES; ANTICONVULSANTS; BENZOTHIAZOLES; CARBAMATES; CYCLOHEXANECARBOXYLIC ACIDS; DOPAMINE AGENTS; DOPAMINE AGONISTS; ERGOLINES; GAMMA-AMINOBUTYRIC ACID; HUMANS; INDOLES; LEVODOPA; NEURALGIA; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RESTLESS LEGS SYNDROME; TETRAHYDRONAPHTHALENES; THIOPHENES; TREATMENT OUTCOME;

EID: 84866504077     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2012.708023     Document Type: Review

References (111)

1. International classification of sleep disorders. Diagnostic and coding manual. 2nd edition. American Academy of Sleep Medicine; Westchester, IL: 2005
2. Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol 2005;4:465-75 (Pubitemid 40982457)
3. Provini F, Vetrugno R, Meletti S, et al. Motor pattern of periodic limb movements during sleep. Neurology 2001;57:300-4 (Pubitemid 32667365)
4. Allen RP, Earley CJ. Restless legs syndrome: A review of clinical and pathophysiologic features. J Clin Neurophysiol 2001;18:128-47 (Pubitemid 32549908)
5. Merlino G, Valente M, Serafini A, Gigli GL. Restless legs syndrome: Diagnosis, epidemiology, classification and consequences. Neurol Sci 2007;28(Suppl 1):37-46
6. Nomura T, Inoue Y, Kusumi M, et al. Prevalence of restless legs syndrome in a rural community in Japan. Mov Disord 2008;23:2363-9
7. Allen RP, Earley CJ. Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset. Sleep Med 2000;1:11-19
8. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of RLS identifies common variants in three genomic regions. Nat Genet 2007;39:1000-6 (Pubitemid 47185185)
9. Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000;54:1698-700 (Pubitemid 30226823)
10. Gigli GL, Adorati M, Dolso P, et al. Restless legs syndrome in end-stage renal disease. Sleep Med 2004;5:309-15 (Pubitemid 38684229)
11. Merlino G, Fratticci L, Valente M, et al. Association of restless legs syndrome in type 2 diabetes: A case-control study. Sleep 2007;30:866-71 (Pubitemid 47044818)
12. Manconi M, Ferini-Strambi L, Filippi M, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: The REMS study. Sleep 2008;31:944-52 (Pubitemid 351956933)
13. Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome and pregnancy. Neurology 2004;63:1065-9 (Pubitemid 39287916)
14. O'Keeffe ST. Secondary causes of restless legs syndrome in older people. Age Ageing 2005;34:349-52 (Pubitemid 41511315)
15. Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286-92 (Pubitemid 40989594)
16. Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther 2004;26:925-35 (Pubitemid 38943041)
17. Oertel WH, Trenkwalder C, Zucconi M, et al. State of the art in restless legs syndrome therapy: Practice recommendations for treating restless legs syndrome. Mov Disord 2007;22(Suppl 18):466-75
18. Earley CJ, Allen RP, Beard JL, Connor Jr. Insight into the pathophysiology of restless legs syndrome. J Neurosci Res 2000;62:623-8
19. Deleu D, Northway MG, Hanssens Y. Clinical Pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease. Clin Pharmacokinet 2002;41:261-309 (Pubitemid 34533757)
20. Katzung G. Basic & clinical pharmacology. McGraw-Hill; New York, US:2007
21. Wade DN, Mearrick PT, Morris JL. Active transport of L-dopa in the intestine. Nature 1973;242:463-5
22. Sharpless NS, Muenter MD, Tyce GM, Owen CA Jr. 3-Methoxy-4- hydroxyphenylalanine (3-O-methyldopa) in plasma during oral L-dopa therapy of patients with Parkinson's disease. Clin Chim Acta 1972;37:359-69
23. Shindler JS, Finnerty GT, Towlson K, et al. Domperidone and levodopa in Parkinson's disease. Br J Clin Pharmacol 1984;18:959-62 (Pubitemid 15190537)
24. Pfeiffer RF. Antiparkinsonian agents: Drug interactions of clinical significance. Drug Saf 1996;14:343-54
25. Guilleminault C, Cetel M, Philip P. Dopaminergic treatment of restless legs and rebound phenomenon. Neurology 1993;43:445 (Pubitemid 23060290)
26. Comella CL. Restless legs syndrome: Treatment with dopaminergic agents. Neurology 2002;58(Suppl 1):87-92
27. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19:205-13 (Pubitemid 26138225)
28. Garcia-Borreguero D. Augmentation: Understanding a key feature of RLS. Sleep Med 2004;5:5-6 (Pubitemid 38145704)
29. Vignatelli L, Billiard M, Clarenbach P, et al. EFNS guidelines on management of restless drugs syndrome and periodic limb movement disorder in sleep. Eur J Neurol 2006;13:1049-65 (Pubitemid 44434310)
30. Trenkwalder C, Collado Seidel V, Kazenwadel J, et al. One-year treatment with standard and sustained-release levodopa: Appropriate long-term treatment of restless legs syndrome? Mov Disord 2003;18:1184-9 (Pubitemid 37336945)
31. Merlino G, Gigli GL. Sleep-related movement disorders. Neurol Sci 2011. [Epub ahead of print]
32. REQUIP: Prescribing Information. Available from: Http://www. requip.com [Last accessed 11 March 2012]
33. Coldwell MC, Boyfield I, Brown T, et al. Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4 receptors expressed in Chinese hamster ovary cells. Br J Pharmacol 1999;127:1696-702 (Pubitemid 29369006)
34. Jenner P. The rationale for the use of dopamine agonists in Parkinson's disease. Neurology 1995;45(Suppl 3):6-12
35. Tompson DJ, Vearer D. Steady-state pharmacokinetic properties of a 24-hour prolonged-release formulation of ropinirole Results of two randomized studies in patients with Parkinson's disease. Clin Ther 2007;29:2654-66
36. Kushida CA. Ropinirole for the treatment of restless legs syndrome. Neuropsychiatr Dis Treat 2006;2:407-19 (Pubitemid 46321871)
37. Varga LI, Ako-Agugua N, Colasante J, et al. Critical review of ropinirole and pramipexole - putative D(3)-receptor selective agonists - for the treatment of RLS. J Clin Pharm Ther 2009;34:493-505
38. Wynalda MA, Wienkers LC. Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos 1997;25:1211-14 (Pubitemid 27446593)
39. Bloomer JC, Clarke SE, Chenery RJ. An assessment of the potential of ropinirole, a dopamine receptor agonist, to inhibit various human cytochrome P450 enzymes. Br J Pharmacol 1998;124:41
40. Hansen RA, Song L, Moore CG, et al. Effect of ropinirole on sleep outcomes in patients with restless legs syndrome: Meta-analysis of pooled individual patient data from randomized controlled trials. Pharmacotherapy 2009;29:255-62
41. Garci'a-Borreguero D, H€ogl B, Ferini-Strambi L, et al. Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom disease): Results from a prospective, multicenter study over 66 weeks. Mov Disord 2012;27:277-83
42. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinson's disease. Arch Neurol 2005;62:1377-81 (Pubitemid 41352054)
43. Voon V, Schoerling A, Wenzel S, et al. Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome. BMC Neurol 2011;11:117
44. Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev 2005;9:185-200 (Pubitemid 40694186)
45. MIRAPEX: Prescribing Information. Available from: Http://www. mirapexer. com [Last accessed 16 March 2012]
46. Kvernmo T, Härtter S, Burger E. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther 2006;28:1065-78 (Pubitemid 44374749)
47. Wright CE, Sisson TL, Ichhpurani AK, Peters GR. Steady-state pharmacokinetic properties of pramipexole in healthy volunteers. J Clin Pharmacol 1997;37:520-5 (Pubitemid 27265653)
48. Bennett JP Jr, Piercey MF. Pramipexole: A new dopamine agonist for the treatment of Parkinson's disease. J Neurol Sci 1999;163:25-31 (Pubitemid 29155411)
49. Merlino G, Serafini A, Robiony F, et al. Clinical experience with pramipexole in the treatment of restless legs syndrome. Expert Opin Drug Metab Toxicol 2008;4:225-35 (Pubitemid 351308419)
50. Wynalda MA, Wienkers LC. Assessment of potential interactions between dopamine receptor agonists and various humas cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos 1997;25:1211-14 (Pubitemid 27446593)
51. Wright CE, Grasela TH, Phillips L. The population pharmacokinetics of pramipexole in Parkinson's disease patients. Clin Pharmacol Ther 1997;61:182 (Pubitemid 127791431)
52. Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67:1034-9 (Pubitemid 44454599)
53. Quickfall J, Suchowersky P. Pathological gambling associated with dopamine agonist use in restless legs syndrome. Parkinsonism Relat Disord 2007;13:535-6 (Pubitemid 350110554)
54. Ferini-Strambi L. Restless legs syndrome augmentation and pramipexole treatment. Sleep Med 2002;3:23-5
55. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: An extended study. Sleep 2003;26:819-21 (Pubitemid 39610626)
56. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011;12:440-4
57. NEUPRO: Prescribing Information. Available from: Http://www. neupro.com [Last accessed 19 March 2012]
58. Merlino G, Serafini A, Robiony F, et al. Restless legs syndrome: Differential diagnosis and management with rotigotine. Neuropsychiatr Dis Treat 2009;5:67-80
59. CawelloW,Wolff HM, MeulingWJ, et al. Transdermal administration of radiolabelled [14C]-rotigotine by a patch formulation. A mass balance trial. Clin Pharmacokinet 2007;46:851-7 (Pubitemid 47443309)
60. Braun M, Cawello W, Poole K, et al. Steady-state pharmacokinetics of rotigotine in patients with early-stage Parkinson's disease. Eur J Neurol 2005;12(Suppl 2):96
61. Malik M, Andreas JO, Hnatkova K, et al. Thorough QT/QTc study in patients with advanced Parkinson's disease: Cardiac safety of rotigotine. Clin Pharmacol Ther 2008;84:595-603
62. Serafini A, Lorenzut S, Gigli GL, et al. The use of rotigotine in the treatment of restless legs syndrome. Ther Adv Neurol Disord 2010;3:241-8
63. Swart PJ, Oelen WE, Bruins AP, et al. Determination of the dopamine D2 agonist N-0923 and its major metabolites in perfused rat livers by HPLC-UV-atmospheric pressure ionization mass spectrometry. J Anal Toxicol 1994;18:71-7
64. Boroojerdi B, Wolff HM, Braun M, Scheller DK. Rotigotine transdermal patch for the treatment of Parkinson's disease and restless legs syndrome. Drugs Today (Barc) 2010;46:483-505
65. Elshoff JP, Cawello W, Horstmann R, et al. Transdermal rotigotine results in suitable pharmacokinetic properties for various patients subpopulations. Mov Disord 2009;24(Suppl 1):262
66. Cawello W, Ahrweiler S, Sulowicz W, et al. Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function. Br J Clin Pharmacol 2012;73:46-54
67. Oertel WH, Benes H, Garcia-Borreguero D, et al. One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome. Sleep Med 2008;9:865-73
68. Garcia-Borreguero D, Ferini-Strambi L, Kohnen R. Augmentation in the therapy of restless legs syndrome with transdermal rotigotine: A retrospective systematic analysis of two large double-blind 6-month trials. Eur J Neurol 2008;15(Suppl 3):110
69. Benes H, Garcia-Borreguero D, Allen R, et al. Augmentation in long-term therapy of the restless legs syndrome with transdermal rotigotine - a retrospective systematic analysis of two large open-label 1-year trials. Mov Disord 2009;24(Suppl 1):438
70. Oertel W, Trenkwalder C, Benes H, et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: A 5-year open-label extension study. Lancet Neurol 2011;10:710-20
71. Trenkwalder C, Benes H, Grote L, et al. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: Results from a multi-center, randomized, active controlled trial. Mov Disord 2007;22:696-703 (Pubitemid 46800141)
72. Trenkwalder C, Hundemer HP, Lledo A, et al. Efficacy of pergolide in treatment of restless legs syndrome: The PEARLS Study. Neurology 2004;62:1391-7 (Pubitemid 38526054)
73. Yaltho T, Ondo W. The use of gabapentin enacarbil in the treatment of restless legs syndrome. Ther Adv Neurol Disord 2010;3:269-75
74. HORIZANT: Prescribing Information. Available from: Http://www. horizant. com [Last accessed 26 March 2012]
75. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: An evidence-based review and implications for clinical practice. Mov Disord 2008;23:2267-302
76. Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res 1993;10:276-81 (Pubitemid 23041744)
77. Cundy KC, Annamalai T, Bu L, et al. XP13512 [(+/-)-1-([(a- isobutanoyloxyethoxy) carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality and colonic absorption compared with gabapentin in rats and monkeys. J Pharmacol ExpTher 2004;311:324-33 (Pubitemid 39287812)
78. Cundy KC, Sastry S, Luo W, et al. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J Clin Pharmacol 2008;48:1378-88
79. Agarwal P, Griffith A, Costantino HR, Vaish N. Gabapentin enacarbil - clinical efficacy in restless legs syndrome. Neuropsychiatr Dis Treat 2010;6:151-8
80. Lal R, Sukbuntherng J, Luo W, et al. Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. Clin Ther 2012;34:201-13
81. McLean MJ. Gabapentin. Epilepsia 1995;36:S57-86
82. Lal R, Sukbuntherng J, Luo W, et al. Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: A randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers. Clin Ther 2009;31:1776-86
83. LYRICA: Prescribing Information. Available from: Http://www.lyrica.com [Last accessed 30 March 2012]
84. Bockbrader HN, Radulovic LL, Posvar EL, et al. Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol 2010;50:941-50
85. Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 2010;49:661-9
86. Ohman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: Does a fetal accumulation occur during pregnancy? Epilepsia 2005; 46:1621-4 (Pubitemid 44921936)
87. Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol 2003; 43:277-83 (Pubitemid 36232656)
88. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med 2010;11:512-19
89. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5:385-91
90. Frauscher B, Gschliesser V, Brandauer E, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: Association with ferritin levels. Sleep Med 2009; 10:611-15
91. Gamaldo CE, Earley CJ. Restless legs syndrome: A clinical update. Chest 2006;130:1596-604 (Pubitemid 44786758)
92. Earley CJ. The importance of oral iron therapy in restless legs syndrome. Sleep Med 2009;10:945-6
93. Gisbert JP, Gomollon F. Intravenous iron in inflammatory bowel disease. World J Gastroenterol 2009;15:4666-74
94. Earley CJ, Heckler D, Allen RP. Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome. Sleep Med 2005;6:301-5 (Pubitemid 40867819)
95. Allen RP, Adler CH, Du W, et al. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: A multi-centred, placebo-controlled preliminary clinical trial. Sleep Med 2011;12:906-13
96. Sloand JA, Shelly MA, Feigin A, et al. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis 2004;43:663-70 (Pubitemid 38401881)
97. Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24:1445-52
98. Wang J, O'Reilly B, Venkataraman R, et al. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med 2009; Ahead of print
99. Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale's pharmacology. Churcill Livingstone Elsevier; Philadelphia, US:2007
100. Quilici S, Abrams KR, Nicolas A, et al. Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome. Sleep Med 2008;9:715-26
101. Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: Results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004;75:92-7 (Pubitemid 38091275)
102. Merlino G, Serafini A, Young JJ, et al. Gabapentin enacarbil, a gabapentin prodrug for the treatment of the neurological symptoms associated with disorders such as restless legs syndrome. Curr Opin Investig Drugs 2009;10:91-102
103. Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med 2004;5:9-14 (Pubitemid 38145706)
104. Oertel WH, Trenkwalder C, Zucconi M, et al. State of the art in restless legs syndrome therapy: Practice recommendations for treating restless legs syndrome. Mov Disord 2007;22:466-75
105. Ferini-Strambi L, Manconi M. Treatment of restless legs syndrome. Parkinsonism Relat Disord 2009;4:65-70
106. Montplaisir J, Fantini ML, Desautels A, et al. Long-term treatment with pramipexole in restless legs syndrome. Eur J Neurol 2006;13:1306-11 (Pubitemid 44736640)
107. Garcia-Borreguero D, Grunstein R, Sridhar G, et al. A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome. Sleep Med 2007;8:742-52 (Pubitemid 47553544)
108. Molnar MZ, Novak M,Mucsi I. Management of restless legs syndrome in patients on dialysis. Drugs 2006;66:607-24 (Pubitemid 43671454)
109. de OliveiraMM, Conti CF, Valbuza JS, et al. The pharmacological treatment for uremic restless legs syndrome: Evidencebased review. Mov Disord 2010;25:1335-42
110. Pizza F, Persici E, La Manna G, et al. Family recurrence and oligo-anuria predict uremic restless legs syndrome. Acta Neurol Scand 2011. [Epub ahead of print]
111. Connor JR, Wang XS, Allen RP, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 2009;132:2403-12