The CITIMERIVA Study: CITIcoline plus MEmantina plus RIVAstigmine in Older Patients Affected with Alzheimer’s Disease

Clinical Drug Investigation volume 41, pages177–182(2021)Cite this article

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Abstract

Objective

Combined therapy of memantine or acetylcholinesterase inhibitors, with cholinergic precursors such as citicoline, can be effective in Alzheimer’s disease. Indeed, they are able to increase the intrasynaptic levels of acetylcholine more than the single drug. Our aim was to evaluate the efficacy and safety of oral citicoline plus memantine plus rivastigmine in patients with Alzheimer’s disease.

Methods

This was a multi-centric, retrospective case-control study conducted in Italian Centers for Cognitive Impairment and Dementia on consecutive patients aged 65 years or older affected with Alzheimer’s disease. Overall, 104 patients were recruited (27% male, mean age 76.04 ± 4.92 years); 41 (39.42%) treated with citicolin 1000 mg/day given orally + memantine + rivastigmine (Cases) and 63 (60.58%) treated with memantine + rivastigmine (Controls). At baseline (T0), month 6 (T1) and month 12 (T2), cognitive functions were assessed by the Mini Mental State Examination (MMSE), functional dependence by basal Activities (ADL) and Instrumental Activities of Daily Living (IADL), comorbidity by the Cumulative Illness Rating Scale (CIRS), mood by the Geriatric Depression Scale (GDS), and behavioural disturbances by the Neuropsychiatric Inventory (NPI). Adverse events were reported during the study.

Results

The difference in MMSE score was not significant when comparing the two groups at T0, T1 or T2. However, in the case group, the MMSE total score showed a statistically significant difference at T0 versus T1 (13.63 ± 2.46 vs. 14.17 ± 2.24; p = 0.008), and at T0 versus T2 (13.63 ± 2.46 vs. 14.32 ± 2.53; p = 0.002). In the control group, no statistical differences were found at baseline (T0), T1 and T2. ADL, IADL, GDS and NPI total score did not improve during the study in either the case or the control group.

Conclusions

In our study we observed absence of a statistically significant difference between case and control groups for the MMSE total scores. However, in the case group in the MMSE total scores, there was a statistically significant increase between the baseline and the end of the study.

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References

  1. 1.

    Clodomiro A, Gareri P, Puccio G, Frangipane F, Lacava R, Castagna A, Manfredi GL, Colao R, Bruni AC. Somatic comorbidities and Alzheimer’s disease treatment. NeurolSci. 2013;34(9):1581–9.

    Google Scholar 

  2. 2.

    Secades JJ, Frontera G. CDP-choline: pharmacological and clinical review. Methods Find ExpClinPharmacol. 1995;17(suppl B):1–54.

    CAS  Google Scholar 

  3. 3.

    Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005;18(2):CD000269.

    Google Scholar 

  4. 4.

    Hurtado O, Lizasoain I, Moro MÁ. Neuroprotection and recovery: recent data at the bench on citicoline. Stroke. 2011;42(suppl1):S33–5.

    CAS  Article  Google Scholar 

  5. 5.

    Gareri P, Castagna A, Cotroneo AM, Putignano S, De Sarro G, Bruni AC. The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives. ClinInterv Aging. 2015;3(10):1421–9. https://doi.org/10.2147/CIA.S87886.

    Article  Google Scholar 

  6. 6.

    Castagna A, Cotroneo AM, Ruotolo G, Gareri P. The CITIRIVAD study: CITIcoline plus RIVAstigmine in elderly patients affected with dementia study. Clin Drug Investig. 2016;36(12):1059–65.

    CAS  Article  Google Scholar 

  7. 7.

    Gareri P, Castagna A, Cotroneo AM, Putignano D, Conforti R, Santamaria F, et al. The Citicholinage study: citicoline plus cholinesterase inhibitors in aged patients affected with alzheimer’s disease study. J Alzheimer’s Dis. 2017;56:557–65.

    CAS  Article  Google Scholar 

  8. 8.

    Vincent S, Lane R. Rivastigmine in vascular dementia. IntPsychogeriatrics. 2003;15(Suppl 1):201–5.

    Google Scholar 

  9. 9.

    Polinsky RJ. Clinical pharmacology of rivastigmine: a new generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. ClinTher. 1998;20(4):634–47.

    CAS  Google Scholar 

  10. 10.

    Lefèvre G, Buche M, Sedek G, Maton S, Enz A, Lorch U, et al. Similar rivastigmine pharmacokinetics and pharmacodynamics in Japanese and white healthy participants following the application of novel rivastigmine patch. J ClinPharmacol. 2009;49:430–43.

    Google Scholar 

  11. 11.

    Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006;5:160–70.

    CAS  Article  Google Scholar 

  12. 12

    Lipton SA. Pathologically-activated therapeutics for neuroprotection: Mechanism ofNMDA receptor block by memantine and S-nitrosylation. Curr Drug Targets. 2007;8:621–5.

    CAS  Article  Google Scholar 

  13. 13.

    McAllister J, Ghosh S, Berry D, Park M, Sadeghi S, Wang KX, Parker WD, Swerdlow RH. Effects of memantine on mitochondrial function. BiochemPharmacol. 2008;75:956–64.

    CAS  Google Scholar 

  14. 14.

    Folch J, Busquets B, Ettcheto M, Sanchez-Lopez E, Castro-Torres RD, et al. Memantine for the treatment of dementia: a review on its current and future applications. J Alzheimer’s Dis. 2018;2018:1223–40. https://doi.org/10.3233/JAD-170672.

    CAS  Article  Google Scholar 

  15. 15.

    Gareri P, Cotroneo AM, Orsitto G, Putignano S. The CITIMEM study: A pilot study. Optimizing pharmacological treatment in Dementia. Arch Gerontol Geriatrics. 2020;89:104073.

    CAS  Article  Google Scholar 

  16. 16.

    Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98.

    CAS  Article  Google Scholar 

  17. 17.

    Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA. 1963;185:914–9.

    CAS  Article  Google Scholar 

  18. 18.

    Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9(3):179–86.

    CAS  Article  Google Scholar 

  19. 19.

    Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am GeriatrSoc. 1968;16(5):622–6.

    CAS  Article  Google Scholar 

  20. 20.

    Rinaldi P, Mecocci P, Benedetti C, Ercolani S, Bregnocchi M, Menculini G, et al. Validation of the five-item geriatric depression scale in elderly subjects in three different settings. J Am GeriatrSoc. 2003;51(5):694–8.

    Article  Google Scholar 

  21. 21.

    Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inentory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44:2308–14.

    CAS  Article  Google Scholar 

  22. 22.

    Winslow B, Onysko M, Stob C. Hazlewood K Treatment of Alzheimer’s disease. Am Fam Physician. 2011;570(1404–1412):571.

    Google Scholar 

  23. 23.

    Caltagirone C, Bianchetti A, Di Luca M, Mecocci P, Padovani A, Pirfo E, Scapicchio P, Senin U, Trabucchi M, Musicco M. Guidelines for the treatment ofAlzheimer’s disease from the Italian association of psichogeriatrics. Drugs Aging. 2005;2005:1–26.

    Google Scholar 

  24. 24.

    Piamonte BLC, Espiritu AI, Anlacan VMM. Effects of citicoline as an adjunct treatment for Alzheimer’s disease: a systematic review. J Alzheimer’s Dis. 2020. https://doi.org/10.3233/JAD-200378.

    Article  Google Scholar 

  25. 25.

    Gareri P, Putignano D, Castagna A, Cotroneo AM, De Palo G, Fabbo A, Forgione L, Giacummo A, Lacava R, Marino S, Simone M, Zurlo A, Putignano S. Retrospective study on the benefits of combined Memantine and cholinEsterase inhibitor treatMent in AGEd Patients affected with Alzheimer’s Disease: the MEMAGE study. J Alzheimers Dis. 2014;41(2):633–40. https://doi.org/10.3233/JAD-132735.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank Miss Elisa Manzo for revising the English language. The research was carried out in accordance with national requirements and conforms to the principles embodied in the 1964 Declaration of Helsinki (https://www.wma.net) as well as to the International Ethical Guidelines for Biomedical Research Involving Human Subjects and the International Guidelines for Ethical Review for Epidemiological Studies (https://www.cioms.ch). Patients signed informed consent forms for treatment of their personal data and medical records. The ethics committee approved the study protocol. The authors have no commercial affiliation or other arrangements that could be considered to pose a conflict of interest regarding the submitted article.

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Affiliations

  1. Azienda Sanitaria Provinciale di Catanzaro, Primary Care Departiment, Center for Cognitive Disorders and Dementia, viale Crotone, 88100, Catanzaro, Italy

    Alberto Castagna, Roberto Lacava & Carmen Ruberto

  2. Azienda Sanitaria Locale Napoli 3 sud, Internal and Geriatric Medicine Department, Center for Cognitive Disorders and Dementia, Health District no.51, Pomigliano d’Arco, Naples, Italy

    Ciro Manzo

  3. Azienda Unica Sanitaria Locale di Modena, Geriatric Service, Cognitive Disorders and Dementia Unit, Modena, Italy

    Andrea Fabbo

  4. Azienda Ospedaliera Pugliese-Ciaccio di Catanzaro, Geriatric Unit, Center for Cognitive Disorders and Dementia, Catanzaro, Italy

    Giovanni Ruotolo

Authors
  1. Alberto Castagna
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  2. Ciro Manzo
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  3. Andrea Fabbo
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  4. Roberto Lacava
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  5. Carmen Ruberto
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  6. Giovanni Ruotolo
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Corresponding author

Correspondence to Alberto Castagna.

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Funding

No funding was received for the conduct of this study.

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The authors declare that there are no conflicts of interest.

Ethics approval

The ethics committee approved the study protocol.

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Written informed consent was obtained.

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Author Contributions

Conceptualization, AC, CM and GR; data curation, AC, AF, RL, CR and GR; formal analysis, AC, CM, AF and GR; writing and original draft preparation, AC, CM and GR; writing, review and editing, AC, CM and GR; supervision AC, CM, AF and GR. The final manuscript was seen and approved by all authors.

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Castagna, A., Manzo, C., Fabbo, A. et al. The CITIMERIVA Study: CITIcoline plus MEmantina plus RIVAstigmine in Older Patients Affected with Alzheimer’s Disease. Clin Drug Investig 41, 177–182 (2021). https://doi.org/10.1007/s40261-020-00996-2

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