Skip to main content
Log in

Safety and Tolerability of Pharmacotherapies for Parkinson’s Disease in Geriatric Patients

  • Review Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Parkinson’s disease is a chronic neurodegenerative movement disorder affecting people mainly beyond their 50s. Geriatric patients with Parkinson’s disease experience a specific profile of comorbidities. Multimorbidity and resulting polypharmacotherapy are frequent at this age. Comorbid diseases, widely spread, involve arterial hypertension, ischemic heart disease, heart failure, atrial fibrillation, polyneuropathy, diabetes mellitus, cerebrovascular disease, sarcopenia, and frailty. Following years of drug development, levodopa is still the most effective drug for the treatment of motor symptoms. However, a wide range of other drugs are available with specific effects, contraindications, and complications. The treatment of geriatric patients with Parkinson’s disease is challenging and requires the cooperation of multidisciplinary teams. A careful assessment of a patient’s Parkinson’s disease symptoms, comorbidities, medication, vital signs, and resources is crucial for an effective and safe therapy. Laboratory tests can assist in the identification of contraindications for specific treatments. Identifying potentially inadequate drugs from prescription lists can lead to a better targeted treatment for geriatric patients with Parkinson’s disease. Future research should help develop a more evidence-based therapy of geriatric patients with Parkinson’s disease. For this purpose, randomized controlled trials of geriatric patients are urgently needed. An international register concerning issues of safer drug application and monitoring could help to implement a better treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. de Lau LML, Breteler MMB. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–35.

    Article  PubMed  Google Scholar 

  2. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348:1356–64.

    Article  CAS  PubMed  Google Scholar 

  3. Politis M, Wu K, Molloy S, Bain PG, Chaudhuri KR, Piccini P. Parkinson’s disease symptoms: the patients perspective. Mov Disord. 2010;25:1646–51.

    Article  PubMed  Google Scholar 

  4. Forsaa EB, Larsen JP, Wentzel-Larsen T, Herlofson K, Alves G. Predictors and course of health-related quality of life in Parkinson’s disease. Mov Disord. 2008;23:1420–7.

    Article  PubMed  Google Scholar 

  5. Soh S-E, Morris ME, McGinley JL. Determinants of health-related quality of life in Parkinson’s disease: a systematic review. Parkinsonism Relat Disord. 2011;17:1–9.

    Article  PubMed  Google Scholar 

  6. Klietz M, Tulke A, Müschen LH, Paracka L, Schrader C, Dressler DW, et al. Impaired quality of life and need for palliative care in a German cohort of advanced Parkinson’s disease patients. Front Neurol. 2018;9:120.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kempster PA, O’Sullivan SS, Holton JL, Revesz T, Lees AJ. Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study. Brain. 2010;133:1755–62.

    Article  PubMed  Google Scholar 

  8. Muller-Rebstein S, Trenkwalder C, Oertel WH, Culmsee C, Eckermann G, Höglinger GU. Pharmacotherapy of Parkinson’s disease: aspects of drug safety. Nervenarzt. 2017;88:888–94.

    Article  CAS  PubMed  Google Scholar 

  9. Giugni JC, Okun MS. Treatment of advanced Parkinsonʼs disease. Curr Opin Neurol. 2014;27:450–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lingor P, Csoti I, Koschel J, Schrader C, Winkler C, Wolz M, et al. The geriatric patient with Parkinson’s disease: a neurological challenge. Fortschr Neurol Psychiatry. 2016;84(Suppl. 1):S41–7.

    Google Scholar 

  11. Jakovljevic M, Ostojic L. Comorbidity and multimorbidity in medicine today: challenges and opportunities for bringing separated branches of medicine closer to each other. Psychiatr Danub. 2013;25(Suppl. 1):18–28.

    PubMed  Google Scholar 

  12. Dodel R. Multimorbidity: concept, epidemiology and treatment. Nervenarzt. 2014;85:401–8.

    Article  CAS  PubMed  Google Scholar 

  13. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380:37–43.

    Article  PubMed  Google Scholar 

  14. Hou JG, Wu LJ, Moore S, Ward C, York M, Atassi F, et al. Assessment of appropriate medication administration for hospitalized patients with Parkinson’s disease. Parkinsonism Relat Disord. 2012;18:377–81.

    Article  PubMed  Google Scholar 

  15. McLean G, Hindle JV, Guthrie B, Mercer SW. Co-morbidity and polypharmacy in Parkinson’s disease: insights from a large Scottish primary care database. BMC Neurol. 2017;17:126.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Choi J, Ahn A, Kim S, Won CW. Global prevalence of physical frailty by Fried’s criteria in community-dwelling elderly with national population-based surveys. J Am Med Dir Assoc. 2015;16:548–50.

    Article  PubMed  Google Scholar 

  17. Santos-Eggimann B, Cuenoud P, Spagnoli J, Junod J. Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. J Gerontol A Biol Sci Med Sci. 2009;64:675–81.

    Article  PubMed  Google Scholar 

  18. Peball M, Mahlknecht P, Werkmann M, Marini K, Murr F, Herzmann H, et al. Prevalence and associated factors of sarcopenia and frailty in Parkinson’s disease: a cross-sectional study. Gerontology. 2018. https://doi.org/10.1159/000492572 (Epub ahead of print).

    Article  PubMed  Google Scholar 

  19. Riedel O, Dodel R, Deuschl G, Förstl H, Henn F, Heuser I, et al. Dementia and depression determine care dependency in Parkinson’s disease: analysis of 1,449 outpatients receiving nursing care in Germany. Nervenarzt. 2011;82:1012–9.

    Article  CAS  PubMed  Google Scholar 

  20. Riedel O, Dodel R, Deuschl G, Klotsche J, Förstl H, Heuser I, et al. Depression and care-dependency in Parkinson’s disease: results from a nationwide study of 1449 outpatients. Parkinsonism Relat Disord. 2012;18:598–601.

    Article  CAS  PubMed  Google Scholar 

  21. Leibson CL, Maraganore DM, Bower JH, Ransom JE, O’Brien PC, Rocca WA. Comorbid conditions associated with Parkinson’s disease: a population-based study. Mov Disord. 2005;21:446–55.

    Article  Google Scholar 

  22. Tönges L, Bartig D, Muhlack S, Jost W, Gold R, Krogias C. Characteristics and dynamics of inpatient treatment of patients with Parkinson’s disease in Germany: analysis of 1.5 million patient cases from 2010 to 2015. Nervenarzt. 2018;2018(16):552.

    Google Scholar 

  23. Müller-Rebstein S, Trenkwalder C, Ebentheuer J, Oertel WH, Culmsee C, Höglinger GU. Drug safety analysis in a real-life cohort of Parkinson’s disease patients with polypharmacy. CNS Drugs. 2018;31:1093–102.

    Article  CAS  Google Scholar 

  24. Balzer-Geldsetzer M, Ferreira J, Odin P, Bloem BR, Meissner WG, Lorenzl S, et al. Study protocol: Care of Late-Stage Parkinsonism (CLaSP): a longitudinal cohort study. BMC Neurol. 2018;18:185.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zesiewicz TA, Strom JA, Borenstein AR, Hauser RA, Cimino CR, Fontanet HL, et al. Heart failure in Parkinson’s disease: analysis of the United States Medicare current beneficiary survey. Parkinsonism Relat Disord. 2004;10:417–20.

    Article  CAS  PubMed  Google Scholar 

  26. Santiago JA, Bottero V, Potashkin JA. Biological and clinical implications of comorbidities in Parkinson’s disease. Front Aging Neurosci. 2017;9:394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lai S-W, Lin C-L, Liao K-F, Chang-Ou K-C. Increased risk of Parkinson’s disease in cataract patients: a population-based cohort study. Parkinsonism Relat Disord. 2015;21:68–71.

    Article  PubMed  Google Scholar 

  28. Jellinger KA. Prevalence of cerebrovascular lesions in Parkinson’s disease: a postmortem study. Acta Neuropathol. 2003;105:415–9.

    PubMed  Google Scholar 

  29. Hong CT, Hu H-H, Chan L, Bai C-H. Prevalent cerebrovascular and cardiovascular disease in people with Parkinson’s disease: a meta-analysis. Clin Epidemiol. 2018;10:1147–54.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ebersbach G, Sojer M, Muller J, Ransmayr G, Wenning G, Poewe W. Dysequilibrium in idiopathic Parkinson disease: the effect of cerebrovascular comorbidity. Nervenarzt. 2002;73:162–5.

    Article  CAS  PubMed  Google Scholar 

  31. Kotagal V, Albin RL, Muller MLTM, Koeppe RA, Studenski S, Frey KA, et al. Advanced age, cardiovascular risk burden, and Timed Up and Go Test performance in Parkinson disease. J Gerontol A Biol Sci Med Sci. 2014;69:1569–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J. Type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care. 2007;30:842–7.

    Article  PubMed  Google Scholar 

  33. Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli G. Clinical features of Parkinson disease when onset of diabetes came first: a case–control study. Neurology. 2012;78:1507–11.

    Article  CAS  PubMed  Google Scholar 

  34. Kotagal V, Albin RL, Müller MLTM, Koeppe RA, Frey KA, Bohnen NI. Diabetes is associated with postural instability and gait difficulty in Parkinson disease. Parkinsonism Relat Disord. 2013;19:522–6.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bohnen NI, Kotagal V, Müller MLTM, Koeppe RA, Scott PJH, Albin RL, et al. Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease. Parkinsonism Relat Disord. 2014;20:1394–8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Metta V, Sanchez TC, Padmakumar C. Osteoporosis: a hidden nonmotor face of Parkinson’s disease. Int Rev Neurobiol. 2017;134:877–90.

    Article  PubMed  Google Scholar 

  37. Deng Q, Zhou X, Chen J, Pan M, Gao H, Zhou J, et al. Lower hemoglobin levels in patients with Parkinson’s disease are associated with disease severity and iron metabolism. Brain Res. 2017;1655:145–51.

    Article  CAS  PubMed  Google Scholar 

  38. Wielinski CL, Erickson-Davis C, Wichmann R, Walde-Douglas M, Parashos SA. Falls and injuries resulting from falls among patients with Parkinson’s disease and other parkinsonian syndromes. Mov Disord. 2005;20:410–5.

    Article  PubMed  Google Scholar 

  39. Huang Y-F, Cherng Y-G, Hsu SPC, Yeh C-C, Chou Y-C, Wu C-H, et al. Risk and adverse outcomes of fractures in patients with Parkinson’s disease: two nationwide studies. Osteoporos Int. 2015;26:1723–32.

    Article  PubMed  Google Scholar 

  40. Abbott A. Levodopa: the story so far. Nature. 2010;466:S6–7.

    Article  CAS  PubMed  Google Scholar 

  41. Hornykiewicz O. Dopamine miracle: from brain homogenate to dopamine replacement. Mov Disord. 2002;17:501–8.

    Article  PubMed  Google Scholar 

  42. Hauser RA. Levodopa: past, present, and future. Eur Neurol. 2009;62:1–8.

    Article  CAS  PubMed  Google Scholar 

  43. Nutt JG, Fellman JH. Pharmacokinetics of levodopa. Clin Neuropharmacol. 1984;7:35–49.

    Article  CAS  PubMed  Google Scholar 

  44. Cedarbaum JM. Clinical pharmacokinetics of anti-parkinsonian drugs. Clin Pharmacokinet. 1987;13:141–78.

    Article  CAS  PubMed  Google Scholar 

  45. Wood LD. Clinical review and treatment of select adverse effects of dopamine receptor agonists in Parkinson’s disease. Drugs Aging. 2010;27:295–310.

    Article  CAS  PubMed  Google Scholar 

  46. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16:448–58.

    Article  CAS  PubMed  Google Scholar 

  47. Schrag A, Ben-Shlomo Y, Quinn N. How common are complications of Parkinson’s disease? J Neurol. 2002;249:419–23.

    Article  PubMed  Google Scholar 

  48. Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial earlier vs later l-DOPA. Arch Neurol. 1999;56:529–35.

    Article  CAS  PubMed  Google Scholar 

  49. Olanow CW, Obeso JA, Stocchi F. Drug insight: continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Nat Clin Pract Neurol. 2006;2:382–92.

    Article  CAS  PubMed  Google Scholar 

  50. Blanchet PJ, Grondin R, Bedard PJ, Shiosaki K, Britton DR. Dopamine D1 receptor desensitization profile in MPTP-lesioned primates. Eur J Pharmacol. 1996;309:13–20.

    Article  CAS  PubMed  Google Scholar 

  51. Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol. 2006;5:677–87.

    Article  CAS  PubMed  Google Scholar 

  52. Keber U, Klietz M, Carlsson T, Oertel WH, Weihe E, Schafer MKH, et al. Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice. Neurosciene. 2015;298:302–17.

    Article  CAS  Google Scholar 

  53. Klietz M, Keber U, Carlsson T, Chiu W-H, Höglinger GU, Weihe E, et al. l-DOPA-induced dyskinesia is associated with a deficient numerical downregulation of striatal tyrosine hydroxylase mRNA-expressing neurons. Neuroscience. 2016;331:120–33.

    Article  CAS  PubMed  Google Scholar 

  54. Kadastik-Eerme L, Taba N, Asser T, Taba P. Factors associated with motor complications in Parkinson’s disease. Brain Behav. 2017;7:e00837.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Othman AA, Dutta S. Population pharmacokinetics of levodopa in subjects with advanced Parkinson’s disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets. Br J Clin Pharmacol. 2014;78:94–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Stocchi F, Vacca L, Stirpe P, Torti M. Pharmacokinetic drug evaluation of CVT-301 for the treatment of Parkinson’s disease. Expert Opin Drug Metab Toxicol. 2018;14:1189–95.

    Article  CAS  PubMed  Google Scholar 

  57. Stampanoni Bassi M, Sancesario A, Morace R, Centonze D, Iezzi E. Cannabinoids in Parkinson’s disease. Cannabis Cannabinoid Res. 2017;2:21–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Weintraub D, Chiang C, Kim HM, Wilkinson J, Marras C, Stanislawski B, et al. Association of antipsychotic use with mortality risk in patients with Parkinson disease. JAMA Neurol. 2016;73:535–41.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Weintraub D, Chiang C, Kim HM, Wilkinson J, Marras C, Stanislawski B, et al. Antipsychotic use and physical morbidity in Parkinson disease. Am J Geriatr Psychiatry. 2017;25:697–705.

    Article  PubMed  Google Scholar 

  60. Divac N, Prostran M, Jakovcevski I, Cerovac N. Second-generation antipsychotics and extrapyramidal adverse effects. BioMed Res Int. 2014;2014:656370.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Fredericks D, Norton JC, Atchison C, Schoenhaus R, Pill MW. Parkinson’s disease and Parkinsons disease psychosis: a perspective on the challenges, treatments, and economic burden. Am J Manag Care. 2017;23:S83–92.

    PubMed  Google Scholar 

  62. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294:1934–43.

    Article  CAS  PubMed  Google Scholar 

  63. Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, et al. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of Parkinson’s disease psychosis. Neuropsychopharmacology. 2010;35:881–92.

    Article  CAS  PubMed  Google Scholar 

  64. Riederer P, Laux G. MAO-inhibitors in Parkinson’s disease. Exp Neurobiol. 2011;20:1–17.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Schapira AHV. Monoamine oxidase B inhibitors for the treatment of Parkinson’s disease: a review of symptomatic and potential disease-modifying effects. CNS Drugs. 2011;25:1061–71.

    Article  CAS  PubMed  Google Scholar 

  66. Cereda E, Cilia R, Canesi M, Tesei S, Mariani CB, Zecchinelli AL, et al. Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case–control study. J Neurol. 2017;264:1254–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kumagai T, Nagayama H, Ota T, Nishiyama Y, Mishina M, Ueda M. Sex differences in the pharmacokinetics of levodopa in elderly patients with Parkinson disease. Clin Neuropharmacol. 2014;37:173–6.

    Article  CAS  PubMed  Google Scholar 

  68. Nagayama H, Ueda M, Kumagai T, Tsukamoto K, Nishiyama Y, Nishimura S, et al. Influence of ageing on the pharmacokinetics of levodopa in elderly patients with Parkinson’s disease. Parkinsonism Relat Disord. 2011;17:150–2.

    Article  PubMed  Google Scholar 

  69. Kanis JA, Cooper C, Rizzoli R, Reginster J-Y. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2019;30:3–44.

    Article  CAS  PubMed  Google Scholar 

  70. van den Bos F, Speelman AD, Samson M, Munneke M, Bloem BR, Verhaar HJJ. Parkinson’s disease and osteoporosis. Age Ageing. 2013;42:156–62.

    Article  PubMed  Google Scholar 

  71. Yasui K, Nakaso K, Kowa H, Takeshima T, Nakashima K. Levodopa-induced hyperhomocysteinaemia in Parkinson’s disease. Acta Neurol Scand. 2003;108:66–7.

    Article  CAS  PubMed  Google Scholar 

  72. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015;14:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Szadejko K, Dziewiatowski K, Szabat K, Robowski P, Schinwelski M, Sitek E, et al. Polyneuropathy in levodopa-treated Parkinson’s patients. J Neurol Sci. 2016;371:36–41.

    Article  CAS  PubMed  Google Scholar 

  74. Loens S, Chorbadzhieva E, Kleimann A, Dressler D, Schrader C. Effects of levodopa/carbidopa intestinal gel versus oral levodopa/carbidopa on B vitamin levels and neuropathy. Brain Behav. 2017;7:e00698.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Velseboer DC, de Haan RJ, Wieling W, Goldstein DS, de Bie RMA. Prevalence of orthostatic hypotension in Parkinson’s disease: a systematic review and meta-analysis. Parkinsonism Relat Disord. 2011;17:724–9.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Ferrer-Gila T, Rizea C. Orthostatic hypotension in the elderly. Rev Neurol. 2013;56:337–43.

    PubMed  Google Scholar 

  77. Jost WH, Augustis S. Severity of orthostatic hypotension in the course of Parkinson’s disease: no correlation with the duration of the disease. Parkinsonism Relat Disord. 2015;21:314–6.

    Article  PubMed  Google Scholar 

  78. Noack C, Schroeder C, Heusser K, Lipp A. Cardiovascular effects of levodopa in Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:815–8.

    Article  Google Scholar 

  79. Kondo M, Ueda Y, Makino M, Nakajima K. Worsened orthostatic hypotension due to levodopa administration in a case of Parkinson’s disease. Nihon Ronen Igakkai Zasshi. 2000;37:255–8.

    Article  CAS  PubMed  Google Scholar 

  80. Merola A, Sawyer RP, Artusi CA, Suri R, Berndt Z, Lopez-Castellanos JR, et al. Orthostatic hypotension in Parkinson disease: impact on health care utilization. Parkinsonism Relat Disord. 2018;47:45–9.

    Article  PubMed  Google Scholar 

  81. Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Curr Treat Options Neurol. 2018;20:54.

    Article  PubMed  Google Scholar 

  82. Doi H, Sakakibara R, Sato M, Masaka T, Kishi M, Tateno A, et al. Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease. J Neurol Sci. 2012;319:86–8.

    Article  CAS  PubMed  Google Scholar 

  83. Muller T, Erdmann C, Bremen D, Schmidt WE, Muhlack S, Woitalla D, et al. Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients. Clin Neuropharmacol. 2006;29:61–7.

    Article  PubMed  Google Scholar 

  84. Heetun ZS, Quigley EMM. Gastroparesis and Parkinson’s disease: a systematic review. Parkinsonism Relat Disord. 2012;18:433–40.

    Article  PubMed  Google Scholar 

  85. Greene RJ, Hall AD, Hider RC. The interaction of orally administered iron with levodopa and methyldopa therapy. J Pharm Pharmacol. 1990;42:502–4.

    Article  CAS  PubMed  Google Scholar 

  86. Campbell NR, Hasinoff B. Ferrous sulfate reduces levodopa bioavailability: chelation as a possible mechanism. Clin Pharmacol Ther. 1989;45:220–5.

    Article  CAS  PubMed  Google Scholar 

  87. Deleu D, Jacob P, Chand P, Sarre S, Colwell A. Effects of caffeine on levodopa pharmacokinetics and pharmacodynamics in Parkinson disease. Neurology. 2006;67:897–9.

    Article  CAS  PubMed  Google Scholar 

  88. Robertson DR, Higginson I, Macklin BS, Renwick AG, Waller DG, George CF. The influence of protein containing meals on the pharmacokinetics of levodopa in healthy volunteers. Br J Clin Pharmacol. 1991;31:413–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Simon N, Gantcheva R, Bruguerolle B, Viallet F. The effects of a normal protein diet on levodopa plasma kinetics in advanced Parkinson’s disease. Parkinsonism Relat Disord. 2004;10:137–42.

    Article  PubMed  Google Scholar 

  90. Hubble JP. Long-term studies of dopamine agonists. Neurology. 2002;58:S42–50.

    Article  CAS  PubMed  Google Scholar 

  91. Jenner P. Pharmacology of dopamine agonists in the treatment of Parkinson’s disease. Neurology. 2002;58(4 Suppl. 1):S1–8.

    Article  CAS  PubMed  Google Scholar 

  92. Piercey MF. Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson’s disease. Clin Neuropharmacol. 1998;21:141–51.

    CAS  PubMed  Google Scholar 

  93. Chen JJ, Swope DM, Dashtipour K, Lyons KE. Transdermal rotigotine: a clinically innovative dopamine-receptor agonist for the management of Parkinson’s disease. Pharmacotherapy. 2009;29:1452–67.

    Article  CAS  PubMed  Google Scholar 

  94. Tulloch IF. Pharmacologic profile of ropinirole: a nonergoline dopamine agonist. Neurology. 1997;49(1 Suppl. 1):S58–62.

    Article  CAS  PubMed  Google Scholar 

  95. Hagell P, Odin P. Apomorphine in the treatment of Parkinson’s disease. J Neurosci Nurs. 2001;33(21–34):37–8.

    Google Scholar 

  96. Stacy M, Silver D. Apomorphine for the acute treatment of “off” episodes in Parkinson’s disease. Parkinsonism Relat Disord. 2008;14:85–92.

    Article  PubMed  Google Scholar 

  97. Kulisevsky J, Pagonabarraga J. Tolerability and safety of ropinirole versus other dopamine agonists and levodopa in the treatment of Parkinson’s disease: meta-analysis of randomized controlled trials. Drug Saf. 2010;33:147–61.

    Article  CAS  PubMed  Google Scholar 

  98. Voon V, Hassan K, Zurowski M, Duff-Canning S, de Souza M, Fox S, et al. Prospective prevalence of pathologic gambling and medication association in Parkinson disease. Neurology. 2006;66:1750–2.

    Article  CAS  PubMed  Google Scholar 

  99. Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology. 2006;67:1254–7.

    Article  CAS  PubMed  Google Scholar 

  100. Weintraub D, Siderowf AD, Potenza MN, Goveas J, Morales KH, Duda JE, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol. 2006;63:969–73.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Bienfait KL, Menza M, Mark MH, Dobkin RD. Impulsive smoking in a patient with Parkinson’s disease treated with dopamine agonists. J Clin Neurosci. 2010;17:539–40.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Ceravolo R, Frosini D, Rossi C, Bonuccelli U. Impulse control disorders in Parkinson’s disease: definition, epidemiology, risk factors, neurobiology and management. Parkinsonism Relat Disord. 2009;15(Suppl. 4):S111–5.

    Article  PubMed  Google Scholar 

  103. Miyasaki JM. Evidence-based initiation of dopaminergic therapy in Parkinson’s disease. J Neurol. 2010;257(Suppl. 2):S309–13.

    Article  CAS  PubMed  Google Scholar 

  104. Antonini A, Chaudhuri KR, Boroojerdi B, Asgharnejad M, Bauer L, Grieger F, et al. Impulse control disorder related behaviours during long-term rotigotine treatment: a post hoc analysis. Eur J Neurol. 2016;23:1556–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Moller JC, Eggert KM, Unger M, Odin P, Chaudhuri KR, Oertel WH. Clinical risk-benefit assessment of dopamine agonists. Eur J Neurol. 2008;15(Suppl. 2):15–23.

    Article  PubMed  Google Scholar 

  106. Paus S, Brecht HM, Koster J, Seeger G, Klockgether T, Wullner U. Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord. 2003;18:659–67.

    Article  PubMed  Google Scholar 

  107. Etminan M, Gill S, Samii A. Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson’s disease: a meta-analysis. Drug Saf. 2003;26:439–44.

    Article  CAS  PubMed  Google Scholar 

  108. Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology. 2001;57:456–62.

    Article  CAS  PubMed  Google Scholar 

  109. Gao X, Chen H, Schwarzschild MA, Ascherio A. A prospective study of bowel movement frequency and risk of Parkinson’s disease. Am J Epidemiol. 2011;174:546–51.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Zhou C-Q, Zhang J-W, Wang M, Peng G-G. Meta-analysis of the efficacy and safety of long-acting non-ergot dopamine agonists in Parkinson’s disease. J Clin Neurosci. 2014;21:1094–101.

    Article  CAS  PubMed  Google Scholar 

  111. Tan EK, Jankovic J. Choosing dopamine agonists in Parkinson’s disease. Clin Neuropharmacol. 2001;24:247–53.

    Article  CAS  PubMed  Google Scholar 

  112. Chaudhuri KR, Pal S, Brefel-Courbon C. ‘Sleep attacks’ or “unintended sleep episodes” occur with dopamine agonists: is this a class effect? Drug Saf. 2002;25:473–83.

    Article  CAS  PubMed  Google Scholar 

  113. Razmy A, Lang AE, Shapiro CM. Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine agonists. Arch. Neurol. 2004;61:97–102.

    Article  PubMed  Google Scholar 

  114. Sprenger FS, Seppi K, Poewe W. Drug safety evaluation of rotigotine. Expert Opin Drug Saf. 2012;11:503–12.

    Article  CAS  PubMed  Google Scholar 

  115. Ishiguro N, Saito A, Yokoyama K, Morikawa M, Igarashi T, Tamai I. Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney. Drug Metab Dispos. 2005;33:495–9.

    Article  CAS  PubMed  Google Scholar 

  116. Knop J, Hoier E, Ebner T, Fromm MF, Muller F. Renal tubular secretion of pramipexole. Eur J Pharm Sci. 2015;79:73–8.

    Article  CAS  PubMed  Google Scholar 

  117. Wu MJ, Ing TS, Soung LS, Daugirdas JT, Hano JE, Gandhi VC. Amantadine hydrochloride pharmacokinetics in patients with impaired renal function. Clin Nephrol. 1982;17:19–23.

    CAS  PubMed  Google Scholar 

  118. Kaye CM, Nicholls B. Clinical pharmacokinetics of ropinirole. Clin Pharmacokinet. 2000;39:243–54.

    Article  CAS  PubMed  Google Scholar 

  119. Bloomer JC, Clarke SE, Chenery RJ. In vitro identification of the P450 enzymes responsible for the metabolism of ropinirole. Drug Metab Dispos. 1997;25:840–4.

    CAS  PubMed  Google Scholar 

  120. Girndt M, Trocchi P, Scheidt-Nave C, Markau S, Stang A. The prevalence of renal failure: results from the German Health Interview and Examination Survey for Adults, 2008–2011 (DEGS1). Dtsch Arztebl Int. 2016;113:85–91.

    PubMed  PubMed Central  Google Scholar 

  121. Schaeffner ES, Ebert N, Delanaye P, Frei U, Gaedeke J, Jakob O, et al. Two novel equations to estimate kidney function in persons aged 70 years or older. Ann Intern Med. 2012;157:471–81.

    Article  PubMed  Google Scholar 

  122. Pellecchia MT, Vitale C, Sabatini M, Longo K, Amboni M, Bonavita V, et al. Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial versus levodopa sustained release. Clin Neuropharmacol. 2004;27:178–81.

    Article  CAS  PubMed  Google Scholar 

  123. Cawello W, Ahrweiler S, Sulowicz W, Szymczakiewicz-Multanowska A, Braun M. Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function. Br J Clin Pharmacol. 2012;73:46–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cieslak KP, Baur O, Verheij J, Bennink RJ, van Gulik TM. Liver function declines with increased age. HPB (Oxford). 2016;18:691–6.

    Article  Google Scholar 

  125. Cawello W, Fichtner A, Boekens H, Braun M. Influence of hepatic impairment on the pharmacokinetics of the dopamine agonist rotigotine. Eur J Drug Metab Pharmacokinet. 2014;39:155–63.

    Article  CAS  PubMed  Google Scholar 

  126. Navacerrada F, Gonzalez-Alonso MR, Alonso-Navarro H, Pilo-de-la-Fuente B, Plaza-Nieto JF, Jimenez-Jimenez FJ. Liver toxicity possibly related with ropinirole use in the treatment of restless legs syndrome. Eur J Neurol. 2011;18:e65.

    Article  CAS  PubMed  Google Scholar 

  127. Dewey RBJ, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol. 2001;58:1385–92.

    Article  PubMed  Google Scholar 

  128. Stibe CM, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet. 1988;1:403–6.

    Article  CAS  PubMed  Google Scholar 

  129. Humphrey SJ, Turman CN, Curry JT, Wheeler GJ. Cardiovascular and electrocardiographic effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious beagle dogs. J Cardiovasc Pharmacol. 2006;47:337–47.

    CAS  PubMed  Google Scholar 

  130. Stocchi F, De Pandis MF, Delfino FA, Anselmo T, Frongillo D. Transient atrial fibrillation after subcutaneous apomorphine bolus. Mov Disord. 1996;11:584–5.

    Article  CAS  PubMed  Google Scholar 

  131. Kaminioti AN, Nikitas GT, Terlis AK, Manolis AG, Thomaides T, Panousopoulou AN. Ventricular bigeminy after subcutaneous administration of apomorphine in a patient with refractory Parkinson’s disease: a case report. J Mov Disord. 2013;6:9–12.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Sartori M, Pratt CM, Young JB. Torsade de Pointe. Malignant cardiac arrhythmia induced by amantadine poisoning. Am J Med. 1984;77:388–91.

    Article  CAS  PubMed  Google Scholar 

  133. Schwartz M, Patel M, Kazzi Z, Morgan B. Cardiotoxicity after massive amantadine overdose. J Med Toxicol. 2008;4:173–9.

    Article  PubMed  PubMed Central  Google Scholar 

  134. De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf. 2002;25:263–86.

    Article  PubMed  Google Scholar 

  135. Watanabe Y, Nakamura Y, Cao X, Ohara H, Yamazaki Y, Murayama N, et al. Intravenous administration of apomorphine does NOT induce long QT syndrome: experimental evidence from in vivo canine models. Basic Clin Pharmacol Toxicol. 2015;116:468–75.

    Article  CAS  PubMed  Google Scholar 

  136. Halvorsen KA, Martensen-Larsen O. Apomorphine revived: fortified, prolonged, and improved therapeutical effect. Int J Addict. 1978;13:475–84.

    Article  CAS  PubMed  Google Scholar 

  137. Auffret M, Drapier S, Verin M. The many faces of apomorphine: lessons from the past and challenges for the future. Drugs R D. 2018;18:91–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Rausten DS, Ochs MA. Apomorphine-naloxone controlled rapid emesis. J Am Coll Emerg Phys. 1973;2:44–5.

    Article  Google Scholar 

  139. Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci. 2007;30:194–202.

    Article  CAS  PubMed  Google Scholar 

  140. Muller T. Catechol-O-methyltransferase inhibitors in Parkinson’s disease. Drugs. 2015;75:157–74.

    Article  CAS  PubMed  Google Scholar 

  141. Axelrod J, Tomchick R. Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem. 1958;233:702–5.

    CAS  PubMed  Google Scholar 

  142. Guldberg HC, Marsden CA. Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev. 1975;27:135–206.

    CAS  PubMed  Google Scholar 

  143. Napolitano A, Del Dotto P, Petrozzi L, Dell’Agnello G, Bellini G, Gambaccini G, et al. Pharmacokinetics and pharmacodynamics of l-Dopa after acute and 6-week tolcapone administration in patients with Parkinson’s disease. Clin Neuropharmacol. 1999;22:24–9.

    Article  CAS  PubMed  Google Scholar 

  144. Ruottinen HM, Rinne UK. A double-blind pharmacokinetic and clinical dose-response study of entacapone as an adjuvant to levodopa therapy in advanced Parkinson’s disease. Clin Neuropharmacol. 1996;19:283–96.

    Article  CAS  PubMed  Google Scholar 

  145. Ferreira JJ, Lees A, Rocha J-F, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurol. 2016;15:154–65.

    Article  CAS  Google Scholar 

  146. Factor SA, Molho ES, Feustel PJ, Brown DL, Evans SM. Long-term comparative experience with tolcapone and entacapone in advanced Parkinson’s disease. Clin Neuropharmacol. 2001;24:295–9.

    Article  CAS  PubMed  Google Scholar 

  147. Rocha J-F, Almeida L, Falcao A, Palma PN, Loureiro AI, Pinto R, et al. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. Br J Clin Pharmacol. 2013;76:763–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Davis TL, Roznoski M, Burns RS. Effects of tolcapone in Parkinson’s patients taking l-dihydroxyphenylalanine/carbidopa and selegiline. Mov Disord. 1995;10:349–51.

    Article  CAS  PubMed  Google Scholar 

  149. Kuoppamaki M, Leinonen M, Poewe W. Efficacy and safety of entacapone in levodopa/carbidopa versus levodopa/benserazide treated Parkinson’s disease patients with wearing-off. J Neural Transm (Vienna). 2015;122:1709–14.

    Article  CAS  Google Scholar 

  150. Rodrigues FB, Ferreira JJ. Opicapone for the treatment of Parkinson’s disease. Expert Opin Pharmacother. 2017;18:445–53.

    Article  CAS  PubMed  Google Scholar 

  151. Antonini A, Abbruzzese G, Barone P, Bonuccelli U, Lopiano L, Onofrj M, et al. COMT inhibition with tolcapone in the treatment algorithm of patients with Parkinson’s disease (PD): relevance for motor and non-motor features. Neuropsychiatr Dis Treat. 2008;4:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Suchowersky O, Bailey P, Pourcher E, Bulger L, Facciponte G. Comparison of two dosages of tolcapone added to levodopa in nonfluctuating patients with PD. Clin Neuropharmacol. 2001;24:214–20.

    Article  CAS  PubMed  Google Scholar 

  153. Olanow CW, Watkins PB. Tolcapone: an efficacy and safety review (2007). Clin Neuropharmacol. 2007;30:287–94.

    Article  CAS  PubMed  Google Scholar 

  154. Lees AJ, Ratziu V, Tolosa E, Oertel WH. Safety and tolerability of adjunctive tolcapone treatment in patients with early Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2007;78:944–8.

    Article  CAS  PubMed  Google Scholar 

  155. Unger MM, Reese JP, Oertel WH, Eggert KM. Real-life evaluations of compliance with mandatory drug safety monitoring exemplified with tolcapone in Parkinson’s disease. Eur Neurol. 2008;60:122–6.

    Article  PubMed  Google Scholar 

  156. Heranval A, Lefaucheur R, Fetter D, Rouille A, Le Goff F, Maltete D. Drugs with potential cardiac adverse effects: retrospective study in a large cohort of parkinsonian patients. Rev Neurol (Paris). 2016;172:318–23.

    Article  CAS  Google Scholar 

  157. Van Booven D, Marsh S, McLeod H, Carrillo MW, Sangkuhl K, Klein TE, et al. Cytochrome P450 2C9-CYP2C9. Pharmacogenet Genomics. 2010;20:277–81.

    PubMed  PubMed Central  Google Scholar 

  158. Dingemanse J, Meyerhoff C, Schadrack J. Effect of the catechol-O-methyltransferase inhibitor entacapone on the steady-state pharmacokinetics and pharmacodynamics of warfarin. Br J Clin Pharmacol. 2002;53:485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. European Medicines Agency. Ongentys: EMA assessment report. London, UK: European Medicines Agency; 2016. p. 1–140.

    Google Scholar 

  160. Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos. 2013;34:45–78.

    Article  CAS  PubMed  Google Scholar 

  161. Yu J, Zhou Z, Tay-Sontheimer J, Levy RH, Ragueneau-Majlessi I. Intestinal drug interactions mediated by OATPs: a systematic review of preclinical and clinical findings. J Pharm Sci. 2017;106:2312–25.

    Article  CAS  PubMed  Google Scholar 

  162. Kalgutkar AS, Dalvie DK, Castagnoli NJ, Taylor TJ. Interactions of nitrogen-containing xenobiotics with monoamine oxidase (MAO) isozymes A and B: SAR studies on MAO substrates and inhibitors. Chem Res Toxicol. 2001;14:1139–62.

    Article  CAS  PubMed  Google Scholar 

  163. Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the treatment of Parkinson’s disease. Pharmacotherapy. 2007;27:174S–85S.

    Article  CAS  PubMed  Google Scholar 

  164. Chang Y, Wang L-B, Li D, Lei K, Liu S-Y. Efficacy of rasagiline for the treatment of Parkinson’s disease: an updated meta-analysis. Ann Med. 2017;49:421–34.

    Article  CAS  PubMed  Google Scholar 

  165. Dashtipour K, Chen JJ, Kani C, Bahjri K, Ghamsary M. Clinical outcomes in patients with Parkinson’s disease treated with a monoamine oxidase type-B inhibitor: a cross-sectional, cohort study. Pharmacotherapy. 2015;35:681–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Dezsi L, Vecsei L. Monoamine oxidase B inhibitors in Parkinson’s disease. CNS Neurol Disord Drug Targets. 2017;16:425–39.

    Article  CAS  PubMed  Google Scholar 

  167. Riederer P, Lachenmayer L. Selegiline’s neuroprotective capacity revisited. J Neural Transm (Vienna). 2003;110:1273–8.

    Article  CAS  Google Scholar 

  168. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361:1268–78.

    Article  CAS  PubMed  Google Scholar 

  169. Sadeghian M, Mullali G, Pocock JM, Piers T, Roach A, Smith KJ. Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson’s disease. Neuropathol Appl Neurobiol. 2016;42:423–35.

    Article  CAS  PubMed  Google Scholar 

  170. Hauser RA, Abler V, Eyal E, Eliaz RE. Efficacy of rasagiline in early Parkinson’s disease: a meta-analysis of data from the TEMPO and ADAGIO studies. Int J Neurosci. 2016;126:942–6.

    Article  CAS  PubMed  Google Scholar 

  171. Jenner P, Langston JW. Explaining ADAGIO: a critical review of the biological basis for the clinical effects of rasagiline. Mov Disord. 2011;26:2316–23.

    Article  PubMed  Google Scholar 

  172. Romberg RW, Needleman SB, Snyder JJ, Greedan A. Methamphetamine and amphetamine derived from the metabolism of selegiline. J Forensic Sci. 1995;40:1100–2.

    Article  CAS  PubMed  Google Scholar 

  173. Stocchi F, Torti M. Adjuvant therapies for Parkinson’s disease: critical evaluation of safinamide. Drug Des Dev Ther. 2016;10:609–18.

    Article  CAS  Google Scholar 

  174. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002;59:1937–43.

    Article  Google Scholar 

  175. Elmer L, Schwid S, Eberly S, Goetz C, Fahn S, Kieburtz K, et al. Rasagiline-associated motor improvement in PD occurs without worsening of cognitive and behavioral symptoms. J Neurol Sci. 2006;248:78–83.

    Article  CAS  PubMed  Google Scholar 

  176. Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1993;328:176–83.

    Article  Google Scholar 

  177. Hauser RA, Silver D, Choudhry A, Eyal E, Isaacson S. Randomized, controlled trial of rasagiline as an add-on to dopamine agonists in Parkinson’s disease. Mov Disord. 2014;29:1028–34.

    Article  CAS  PubMed  Google Scholar 

  178. Richard IH, Kurlan R, Tanner C, Factor S, Hubble J, Suchowersky O, et al. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease in Parkinson Study Group. Neurology. 1997;48:1070–7.

    Article  CAS  PubMed  Google Scholar 

  179. Panisset M, Chen JJ, Rhyee SH, Conner J, Mathena J. Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO). Pharmacotherapy. 2014;34:1250–8.

    Article  CAS  PubMed  Google Scholar 

  180. Aboukarr A, Giudice M. Interaction between monoamine oxidase B inhibitors and selective serotonin reuptake inhibitors. Can J Hosp Pharm. 2018;71:196–207.

    PubMed  PubMed Central  Google Scholar 

  181. Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006;43:180–7.

    Article  CAS  PubMed  Google Scholar 

  182. Chen JJ, Swope DM. Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease. J Clin Pharmacol. 2005;45:878–94.

    Article  CAS  PubMed  Google Scholar 

  183. Churchyard A, Mathias CJ, Boonkongchuen P, Lees AJ. Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1997;63:228–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Laine K, Anttila M, Helminen A, Karnani H, Huupponen R. Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids. Br J Clin Pharmacol. 1999;47:249–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Palovaara S, Anttila M, Nyman L, Laine K. Effect of concomitant hormone replacement therapy containing estradiol and levonorgestrel on the pharmacokinetics of selegiline. Eur J Clin Pharmacol. 2002;58:259–63.

    Article  CAS  PubMed  Google Scholar 

  186. Cruz MP. Xadago (Safinamide): a monoamine oxidase B inhibitor for the adjunct treatment of motor symptoms in Parkinson’s disease. P T. 2017;42:622–37.

    PubMed  PubMed Central  Google Scholar 

  187. Finberg JPM. Pharmacology of rasagiline, a new MAO-B inhibitor drug for the treatment of Parkinson’s disease with neuroprotective potential. Rambam Maimonides Med J. 2010;1:e0003.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Chen JJ, Wilkinson JR. The monoamine oxidase type B inhibitor rasagiline in the treatment of Parkinson disease: is tyramine a challenge? J Clin Pharmacol. 2012;52:620–8.

    Article  CAS  PubMed  Google Scholar 

  189. Marquet A, Kupas K, Johne A, Astruc B, Patat A, Krosser S, et al. The effect of safinamide, a novel drug for Parkinson’s disease, on pressor response to oral tyramine: a randomized, double-blind, clinical trial. Clin Pharmacol Ther. 2012;92:450–7.

    CAS  PubMed  Google Scholar 

  190. Anttila M, Sotaniemi EA, Pelkonen O, Rautio A. Marked effect of liver and kidney function on the pharmacokinetics of selegiline. Clin Pharmacol Ther. 2005;77:54–62.

    Article  CAS  PubMed  Google Scholar 

  191. Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008;168:508–13.

    Article  PubMed  Google Scholar 

  192. Aizenberg D, Sigler M, Weizman A, Barak Y. Anticholinergic burden and the risk of falls among elderly psychiatric inpatients: a 4-year case–control study. Int Psychogeriatr. 2002;14:307–10.

    Article  PubMed  Google Scholar 

  193. Ehrt U, Broich K, Larsen JP, Ballard C, Aarsland D. Use of drugs with anticholinergic effect and impact on cognition in Parkinson’s disease: a cohort study. J Neurol Neurosurg Psychiatry. 2010;81:160–5.

    Article  PubMed  Google Scholar 

  194. Crispo JAG, Willis AW, Thibault DP, Fortin Y, Hays HD, McNair DS, et al. Associations between anticholinergic burden and adverse health outcomes in Parkinson disease. PLoS One. 2016;11:e0150621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Vezina P, Mohr E, Grimes D. Deprenyl in Parkinson’s disease: mechanisms, neuroprotective effect, indications and adverse effects. Can J Neurol Sci. 1992;19:142–6.

    Article  CAS  PubMed  Google Scholar 

  196. Glavin GB, Dugani AM, Pinsky C. L-deprenyl attenuates stress ulcer formation in rats. Neurosci Lett. 1986;70:379–81.

    Article  CAS  PubMed  Google Scholar 

  197. Geyer M, Stamenic I, Buhler H, Bertschinger P. Epidemiology of gastrointestinal bleeding in the elderly. Praxis (Bern 1994). 2006;95:757–65.

    Article  CAS  Google Scholar 

  198. Kyaw MH, Chan FKL. Pharmacologic options in the management of upper gastrointestinal bleeding: focus on the elderly. Drugs Aging. 2014;31:349–61.

    Article  CAS  PubMed  Google Scholar 

  199. Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S. Molecular cloning and characterization of the rat NMDA receptor. Nature. 1991;354:31–7.

    Article  CAS  PubMed  Google Scholar 

  200. Faulkner MA. Safety overview of FDA-approved medications for the treatment of the motor symptoms ofParkinson's disease. Expert Opin Drug Saf. 2014;13(8):1055–69. https://doi.org/10.1517/14740338.2014.931369.

    Article  CAS  PubMed  Google Scholar 

  201. Hubsher G, Haider M, Okun MS. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology. 2012;78:1096–9.

    Article  CAS  PubMed  Google Scholar 

  202. Schwab RS, England ACJ, Poskanzer DC, Young RR. Amantadine in the treatment of Parkinson’s disease. JAMA. 1969;208:1168–70.

    Article  CAS  PubMed  Google Scholar 

  203. Mizoguchi K, Yokoo H, Yoshida M, Tanaka T, Tanaka M. Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-d-aspartate antagonism. Brain Res. 1994;662:255–8.

    Article  CAS  PubMed  Google Scholar 

  204. Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, et al. ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID Study): a randomized clinical trial. JAMA Neurol. 2017;74:941–9.

    Article  PubMed  PubMed Central  Google Scholar 

  205. Oertel W, Eggert K, Pahwa R, Tanner CM, Hauser RA, Trenkwalder C, et al. Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov Disord. 2017;32:1701–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Hiraoka M, Hirano Y, Kawano S, Fan Z, Sawanobori T. Amantadine-induced afterpotentials and automaticity in guinea pig ventricular myocytes. Circ Res. 1989;65:880–93.

    Article  CAS  PubMed  Google Scholar 

  207. Manini AF, Raspberry D, Hoffman RS, Nelson LS. QT prolongation and torsades de pointes following overdose of ziprasidone and amantadine. J Med Toxicol. 2007;3:178–81.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Wilson TW, Rajput AH. Amantadine-dyazide interaction. Can Med Assoc J. 1983;129:974–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Akturk IF, Erol MK. Bradyarrhythmias and pacemaker indications in elderly patients. Turk Kardiyol Dern Ars. 2017;45:71–4.

    PubMed  Google Scholar 

  210. Dandamudi S, Slusser J, Mahoney DW, Redfield MM, Rodeheffer RJ, Chen HH. The prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County, Minnesota. J Card Fail. 2014;20:304–9.

    Article  PubMed  PubMed Central  Google Scholar 

  211. Nakata M, Ito S, Shirai W, Hattori T. Severe reversible neurological complications following amantadine treatment in three elderly patients with renal insufficiency. Eur Neurol. 2006;56:59–61.

    Article  PubMed  Google Scholar 

  212. Bleidner WE, Harmon JB, Hewes WE, Lynes TE, Hermann EC. Absorption, distribution and excretion of amantadine hydrochloride. J Pharmacol Exp Ther. 1965;150:484–90.

    CAS  PubMed  Google Scholar 

  213. Ing TS, Rahn AC, Armbruster KF, Oyama JH, Klawans HL. Letter: accumulation of amantadine hydrochloride in renal insufficiency. N Engl J Med. 1974;291:1257.

    CAS  PubMed  Google Scholar 

  214. Stoof JC, Booij J, Drukarch B, Wolters EC. The anti-parkinsonian drug amantadine inhibits the N-methyl-d-aspartic acid-evoked release of acetylcholine from rat neostriatum in a non-competitive way. Eur J Pharmacol. 1992;213:439–43.

    Article  CAS  PubMed  Google Scholar 

  215. Lupp A, Lucking CH, Koch R, Jackisch R, Feuerstein TJ. Inhibitory effects of the antiparkinsonian drugs memantine and amantadine on N-methyl-d-aspartate-evoked acetylcholine release in the rabbit caudate nucleus in vitro. J Pharmacol Exp Ther. 1992;263:717–24.

    CAS  PubMed  Google Scholar 

  216. Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in older persons: advances in diagnosis and treatment. JAMA. 2017;318:1161–74.

    Article  PubMed  PubMed Central  Google Scholar 

  217. Neagoe AD. Delirium with manic and psychotic features associated with amantadine. Gen Hosp Psychiatry. 2013;35(680):e7–8.

    Google Scholar 

  218. Postma JU, Van Tilburg W. Visual hallucinations and delirium during treatment with amantadine (Symmetrel). J Am Geriatr Soc. 1975;23:212–5.

    Article  CAS  PubMed  Google Scholar 

  219. Flaherty JA, Bellur SN. Mental side effects of amantadine therapy: its spectrum and characteristics in a normal population. J Clin Psychiatry. 1981;42:344–5.

    CAS  PubMed  Google Scholar 

  220. Scott JL, Walls RM. QT interval prolongation. J Emerg Med. 1985;3:221–5.

    Article  CAS  PubMed  Google Scholar 

  221. Moreno O, Garcia PT, Sanchez D, Sancho T, Lecumberri B. Cognitive impairment and severe hypocalcemia in a patient with hypoparathyroidism and systemic sclerosis: report of a case. Endocrinol Nutr. 2015;62:356–8.

    Article  PubMed  Google Scholar 

  222. Fujioka S, Fukae J, Ogura H, Mishima T, Yanamoto S, Higuchi M-A, et al. Hospital-based study on emergency admission of patients with Parkinson’s disease. eNeurologicalSci. 2016;4:19–21.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Guneysel O, Onultan O, Onur O. Parkinson’s disease and the frequent reasons for emergency admission. Neuropsychiatr Dis Treat. 2008;4:711–4.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Braga M, Pederzoli M, Antonini A, Beretta F, Crespi V. Reasons for hospitalization in Parkinson’s disease: a case–control study. Parkinsonism Relat Disord. 2014;20:488–92.

    Article  PubMed  Google Scholar 

  225. Begg DP. Disturbances of thirst and fluid balance associated with aging. Physiol Behav. 2017;178:28–34.

    Article  CAS  PubMed  Google Scholar 

  226. Hindle JV. The practical management of cognitive impairment and psychosis in the older Parkinson’s disease patient. J Neural Transm (Vienna). 2013;120:649–53.

    Article  Google Scholar 

  227. Parkers JD, Marsden CD, Price P. Amantadine-induced heart-failure. Lancet. 1977;1:904.

    Article  CAS  PubMed  Google Scholar 

  228. Mokhles MM, Trifiro G, Dieleman JP, Haag MD, van Soest EM, Verhamme KMC, et al. The risk of new onset heart failure associated with dopamine agonist use in Parkinson’s disease. Pharmacol Res. 2012;65:358–64.

    Article  CAS  PubMed  Google Scholar 

  229. Hasenfuss G, Kasper W, Meinertz T, Busch W, Lehmann M, Krause T, et al. Evaluation of long-term oral levodopa therapy in chronic congestive heart failure. Klin Wochenschr. 1987;65:1087–94.

    Article  CAS  PubMed  Google Scholar 

  230. Montastruc JL, Rascol O, Montastruc P. Naloxone or haloperidol but not yohimbine reverse apomorphine-induced respiratory depression. Clin Neuropharmacol. 1992;15:404–7.

    Article  CAS  PubMed  Google Scholar 

  231. Srinivasan M, Lagercrantz H, Yamamoto Y. A possible dopaminergic pathway mediating hypoxic depression in neonatal rabbits. J Appl Physiol. 1985;1989(67):1271–6.

    Google Scholar 

  232. Gibbons CH, Simon DK, Huang M, Tilley B, Aminoff MJ, Bainbridge JL, et al. Autonomic and electrocardiographic findings in Parkinson’s disease. Auton Neurosci. 2017;205:93–8.

    Article  PubMed  PubMed Central  Google Scholar 

  233. Kannankeril PJ, Roden DM. Drug-induced long QT and torsade de pointes: recent advances. Curr Opin Cardiol. 2007;22:39–43.

    Article  PubMed  Google Scholar 

  234. Roden DM. Predicting drug-induced QT prolongation and torsades de pointes. J Physiol. 2016;594:2459–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Jahn K, Kressig RW, Bridenbaugh SA, Brandt T, Schniepp R. Dizziness and unstable gait in old age: etiology, diagnosis and treatment. Dtsch Arztebl Int. 2015;112:387–93.

    PubMed  PubMed Central  Google Scholar 

  236. Hanewinckel R, van Oijen M, Ikram MA, van Doorn PA. The epidemiology and risk factors of chronic polyneuropathy. Eur J Epidemiol. 2016;31:5–20.

    Article  PubMed  Google Scholar 

  237. Nyholm D, Nilsson Remahl AIM, Dizdar N, Constantinescu R, Holmberg B, Jansson R, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology. 2005;64:216–23.

    Article  CAS  PubMed  Google Scholar 

  238. Swanson PD. Drug treatment of Parkinson’s disease: is ‘polypharmacy’ best? J. Neurol Neurosurg Psychiatry. 1994;57:401–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Krause O, Wiese B, Doyle I-M, Kirsch C, Thürmann P, Wilm S, et al. Multidisciplinary intervention to improve medication safety in nursing home residents: protocol of a cluster randomised controlled trial (HIOPP-3-iTBX study). BMC Geriatr. 2019;19:24.

    Article  PubMed  PubMed Central  Google Scholar 

  240. Lange R, Erbguth F. Parkinson’s disease in the elderly. Z Gerontol Geriatr. 2017;50:547–59.

    Article  PubMed  Google Scholar 

  241. Yildirim AB, Kilinc AY. Polypharmacy and drug interactions in elderly patients. Turk Kardiyol Dern Ars. 2017;45:17–21.

    PubMed  Google Scholar 

  242. Moriarty F, Hardy C, Bennett K, Smith SM, Fahey T. Trends and interaction of polypharmacy and potentially inappropriate prescribing in primary care over 15 years in Ireland: a repeated cross-sectional study. BMJ Open. 2015;5:e008656.

    Article  PubMed  PubMed Central  Google Scholar 

  243. Muhic N, Mrhar A, Brvar M. Comparative analysis of three drug–drug interaction screening systems against probable clinically relevant drug–drug interactions: a prospective cohort study. Eur J Clin Pharmacol. 2017;73:875–82.

    Article  CAS  PubMed  Google Scholar 

  244. Somogyi-Vegh A, Nyaka B, Vida RG, Lovasz A, Botz L. Comprehensive evaluation of drug interaction screening programs: discrepancies and concordances. Orv Hetil. 2015;156:720–30.

    Article  PubMed  Google Scholar 

  245. Kheshti R, Aalipour M, Namazi S. A comparison of five common drug–drug interaction software programs regarding accuracy and comprehensiveness. J Res Pharm Pract. 2016;5:257–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Moura CS, Prado NM, Belo NO, Acurcio FA. Evaluation of drug–drug interaction screening software combined with pharmacist intervention. Int J Clin Pharm. 2012;34:547–52.

    Article  PubMed  Google Scholar 

  247. Pazan F, Weiss C, Wehling M. The FORTA (Fit fOR The Aged) List 2015: update of a validated clinical tool for improved pharmacotherapy in the elderly. Drugs Aging. 2016;33:447–9.

    Article  PubMed  Google Scholar 

  248. Kuhn-Thiel AM, Weiss C, Wehling M. Consensus validation of the FORTA (Fit fOR The Aged) List: a clinical tool for increasing the appropriateness of pharmacotherapy in the elderly. Drugs Aging. 2014;31:131–40.

    Article  CAS  PubMed  Google Scholar 

  249. Brown JD, Hutchison LC, Li C, Painter JT, Martin BC. Predictive validity of the Beers and Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions (STOPP) criteria to detect adverse drug events, hospitalizations, and emergency department visits in the United States. J Am Geriatr Soc. 2016;64:22–30.

    Article  PubMed  PubMed Central  Google Scholar 

  250. Hamilton H, Gallagher P, Ryan C, Byrne S, O’Mahony D. Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalized patients. Arch Intern Med. 2011;171:1013–9.

    Article  PubMed  Google Scholar 

  251. Siebert S, Elkeles B, Hempel G, Kruse J, Smollich M. The PRISCUS list in clinical routine: practicability and comparison to international PIM lists. Z Gerontol Geriatr. 2013;46:35–47.

    Article  CAS  PubMed  Google Scholar 

  252. Cooper JA, Cadogan CA, Patterson SM, Kerse N, Bradley MC, Ryan C, et al. Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review. BMJ Open. 2015;5:e009235.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Kim J, Parish AL. Polypharmacy and medication management in older adults. Nurs Clin North Am. 2017;52:457–68.

    Article  PubMed  Google Scholar 

  254. O’Mahony D, O’Ullivan D, Byrne S, O’Connor MN, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44:213–8.

    Article  PubMed  Google Scholar 

  255. Salbu RL, Feuer J. A closer look at the 2015 Beers criteria. J Pharm Pract. 2017;30:419–24.

    Article  PubMed  Google Scholar 

  256. Antimisiaris D, Cutler T. Managing polypharmacy in the 15-minute office visit. Prim Care. 2017;44:413–28.

    Article  PubMed  Google Scholar 

  257. Jansen J, Naganathan V, Carter SM, McLachlan AJ, Nickel B, Irwig L, et al. Too much medicine in older people? Deprescribing through shared decision making. BMJ. 2016;353:i2893.

    Article  PubMed  Google Scholar 

  258. Scott IA, Hilmer SN, Reeve E, Potter K, Le Couteur D, Rigby D, et al. Reducing inappropriate polypharmacy: the process of deprescribing. JAMA Intern Med. 2015;175:827–34.

    Article  PubMed  Google Scholar 

  259. Loffler C, Drewelow E, Paschka SD, Frankenstein M, Eger J, Jatsch L, et al. Optimizing polypharmacy among elderly hospital patients with chronic diseases: study protocol of the cluster randomized controlled POLITE-RCT trial. Implement Sci. 2014;9:151.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the many collaborators and patients for vital and challenging discussions on the pharmacotherapy of Parkinson’s disease.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin Klietz.

Ethics declarations

Funding

No sources of funding were received for the preparation of this article.

Conflict of interest

Martin Klietz, Stephan Greten, Florian Wegner, and Günter U. Höglinger have no conflicts of interest that are directly relevant to the content of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klietz, M., Greten, S., Wegner, F. et al. Safety and Tolerability of Pharmacotherapies for Parkinson’s Disease in Geriatric Patients. Drugs Aging 36, 511–530 (2019). https://doi.org/10.1007/s40266-019-00654-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-019-00654-z

Navigation