Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1299 2022-10-26 10:39:55 |
2 format -3 word(s) 1296 2022-10-27 04:40:32 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Esumi, S.;  Ushio, S.;  Zamami, Y. Polypharmacy in Older Adults with Alzheimer’s Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/31356 (accessed on 03 July 2024).
Esumi S,  Ushio S,  Zamami Y. Polypharmacy in Older Adults with Alzheimer’s Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/31356. Accessed July 03, 2024.
Esumi, Satoru, Soichiro Ushio, Yoshito Zamami. "Polypharmacy in Older Adults with Alzheimer’s Disease" Encyclopedia, https://encyclopedia.pub/entry/31356 (accessed July 03, 2024).
Esumi, S.,  Ushio, S., & Zamami, Y. (2022, October 26). Polypharmacy in Older Adults with Alzheimer’s Disease. In Encyclopedia. https://encyclopedia.pub/entry/31356
Esumi, Satoru, et al. "Polypharmacy in Older Adults with Alzheimer’s Disease." Encyclopedia. Web. 26 October, 2022.
Polypharmacy in Older Adults with Alzheimer’s Disease
Edit

The number of patients with Alzheimer’s disease is increasing annually. Most of these patients are older adults with comorbid physical illnesses, which means that they are often treated with a combination of medications for the disease they have and those for Alzheimer’s disease. Thus, older adults with Alzheimer’s disease are potentially at risk for polypharmacy. In addition, the drug interactions between Alzheimer’s disease medications and those for the treatment of physical illnesses may reduce their efficacy and increase side effects.

Alzheimer’s disease polypharmacy drug interactions

1. Introduction

It is widely known that the number of older adults with dementia is increasing worldwide. In the United States, the number of people aged 65 years and older was 52 million in 2018 and is predicted to increase to 95 million by 2060, 50 million of which will have dementia by 2050 [1][2]. Similarly, the number of elderly with dementia in Asia is increasing. According to a meta-analysis published in 2014, the prevalence of dementia among patients aged 65 years and older in South Korea is 9.2%, which is higher than that of patients of similar age in Europe, the United States, and other Asian countries [3][4]. Furthermore, the odds ratio for death from dementia and other neurodegenerative diseases is reportedly higher in Korea than that in other countries. In Japan, there were an estimated 3.5 million people with dementia in 2012 (approximately 8% of the global population), and the number of dementia patients is projected to reach 4.9 million by 2034, when the population over 65 years of age reaches its peak [5]. In addition, the cost of informal care for patients with dementia is estimated at approximately $54 billion.
Most patients with Alzheimer’s disease are elderly and have two or more chronic conditions [6][7][8]. For example, a research of Medicare claims data revealed that 67% of beneficiaries over the age of 65 years had two or more chronic diseases [9]. Patients with Alzheimer’s disease and related dementias often have comorbid physical diseases [10]. Considering the barriers to communication and cognitive decline associated with this disease, polypharmacy is more likely to occur in patients with dementia than in the general elderly population [11][12]. According to the currently accepted definition, polypharmacy is defined as taking five or more medications per day, with a prevalence of 30–60% among the elderly (65 years and older) [13][14][15][16][17]. Although in most cases polypharmacy results from prescribing necessary medications to treat diseases in the elderly, there are reports that polypharmacy is associated with adverse outcomes. Inappropriate polypharmacy leads to an increased incidence of falls, frailty, and decreased quality of life [18][19][20][21]. Such adverse events further increase the cost and burden of care for dementia patients.
Patients with dementia have a high incidence of potentially inappropriate medication (PIM), estimated to be 14–74% [22][23][24]. PIMs are medications whose benefits do not exceed the risks associated with taking them, such as adverse events, and are a common cause of adverse drug reactions in the elderly [25][26]. They have been associated with a decreased quality of life, poor nutrition, and depression in nursing home residents with dementia [27][28][29]. According to a survey of PIM use among older adults with dementia in seven European countries, patients with dementia had a high incidence of PIM intake, regardless of severity, even those with mild Alzheimer’s disease [30][31]. Inadequate communication between patients with dementia and healthcare providers triggers a prescription cascade in which healthcare providers misidentify the side effects of drugs as new symptoms and prescribe drugs to treat drug-related problems, thereby triggering polypharmacy [32][33][34]. In other words, prescribing additional drugs for adverse reactions to PIM may lead to polypharmacy, which is associated with many more adverse events, greater healthcare utilisation, and even mortality [35][36].

2. Polypharmacy in Alzheimer’s Disease Patients

The main symptoms of Alzheimer’s disease, namely memory impairment and behavioural and psychological symptoms, cause great distress to patients with dementia as well as caregivers [37][38]. Cognitive dysfunction in Alzheimer’s disease can be treated with cognitive-improving drugs, such as acetylcholinesterase inhibitors (donepezil) and NMDA-type glutamate receptor antagonists (memantine). Memantine and acetylcholinesterase inhibitors are sometimes used in combination to enhance efficacy; however, cognitive enhancers are generally used as a single medication [39]. Some countries do not have access to insurance coverage for cognitive-improving drugs because their effectiveness is limited [40].
The behavioural and psychological symptoms of dementia (BPSD) are customarily and widely treated symptomatically with psychotropic drugs [41][42]. Because of the wide variety of BPSD, including depression and delusions, the polypharmacy of psychotropic medication is increasing among the elderly, including patients without dementia [43]. The Beers Criteria, published by the American Geriatrics Society recommend avoiding use of more than three central nervous system (CNS)-active drugs, such as antidepressants, antipsychotics, benzodiazepines and “Z-drugs”, because they are associated with the risk of falls and fractures [44]. It is widely known that these drugs can produce falls due to sedation, daytime sleepiness, orthostatic hypotension, and motor disturbances.
Using Medicare claims data, a study examining psychotropic polypharmacy in patients with dementia revealed that 13.9% of older adults with dementia had “psychotropic polypharmacy” (three or more psychotropic medications for 30 or more consecutive days), and 29.4% of them were exposed to five or more psychotropic medications [1]. The drugs most frequently prescribed to patients with psychotropic polypharmacy were antidepressants (92.0% of days in polypharmacy during the study period), followed by antiepileptic drugs (62.1%), antipsychotics (47.1%), benzodiazepines (40.7%), opioids (32.3%), and benzodiazepine receptor agonists (6.0%). Although cognitive-improving drugs were not included, considering that most dementia cases involve Alzheimer’s disease [45], it is assumed that the polypharmacy of CNS-acting drugs is even more serious with the added influence of cognitive-improving drugs.
A cross-sectional analysis using the National Ambulatory Medical Care Survey (NAMCS) showed that the number of medications was significantly higher in the elderly with dementia than in those without, although the number of outpatient visits did not differ based on dementia status [12]. In addition, the mean number of medications expected to be prescribed per visit was higher in patients with dementia when compared by age, sex, and number of comorbidities (standardised). Interestingly, elderly patients with dementia were more likely to be prescribed drugs that act on the CNS, as well as those that act on the gastrointestinal and urological systems and drugs for diabetes, indicating that polypharmacy with all drugs, not just CNS drugs for dementia symptoms, is likely to develop in patients with dementia.
Certain medications frequently included in polypharmacy, such as anticholinergics and sedatives, are associated with an increased risk of hospitalisation and death in patients with dementia [46]. Therefore, it is necessary to prescribe safer drugs and reduce the incidence of polypharmacy in this population [47][48]. The number of prescribed drugs should be reduced to a level consistent with the risk of hospitalisation and death in patients with dementia.

3. Cognitive Impairment Induced by Polypharmacy

Several reports have examined the association between polypharmacy and cognitive dysfunction, where polypharmacy is defined as the use of five or more drugs that are commonly used in clinical practice [9][17]. In a cross-sectional study on the association between polypharmacy and cognitive function and related comorbidities (depression, hypertension, and/or diabetes) in rural America, older adults afflicted with polypharmacy had 3.71 times higher odds of having cognitive impairment than older adults who were not [49]. In addition, even after adjusting for confounding factors using multivariate analysis, the odds of cognitive impairment were 2.86 times higher in patients with polypharmacy, whereas there was no significant association between comorbidities and cognitive impairment. Based on these results, it is considered that polypharmacy is independently associated with cognitive dysfunction. In general, patients with cognitive impairment have poor medication compliance. However, healthcare providers are unable to ascertain whether patients are taking their medications. Polypharmacy is thought to result from the addition of medications after determining that the prescribed medications are ineffective. Several reports have shown a negative correlation between the number of medications prescribed and adherence (i.e., the higher the number of medications, the worse the adherence) [50][51][52][53]. Future large cohort studies are needed to prospectively evaluate whether polypharmacy induces cognitive dysfunction or vice versa.

References

  1. Maust, D.T.; Strominger, J.; Kim, H.M.; Langa, K.M.; Bynum, J.P.W.; Chang, C.-H.; Kales, H.C.; Zivin, K.; Solway, E.; Marcus, S.C. Prevalence of Central Nervous System-Active Polypharmacy among Older Adults with Dementia in the US. JAMA 2021, 325, 952–961.
  2. Hebert, L.E.; Weuve, J.; Scherr, P.A.; Evans, D.A. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 2013, 80, 1778.
  3. Kim, Y.J.; Han, J.W.; So, Y.S.; Seo, J.Y.; Kim, K.Y.; Kim, K.W. Prevalence and trends of dementia in Korea: A systematic review and meta-analysis. J. Korean Med. Sci. 2014, 29, 903–912.
  4. Choi, H.G.; Park, B.; Kim, J.H.; Kim, J.H.; Kwon, M.J.; Kim, M. Causes of Mortality in Korean Patients with Neurodegenerative Dementia. Biomed. Res. Int. 2022, 2022, 3206594.
  5. Kasajima, M.; Eggleston, K.; Kusaka, S.; Matsui, H.; Tanaka, T.; Son, B.K.; Iijima, K.; Goda, K.; Kitsuregawa, M.; Bhattacharya, J.; et al. Projecting prevalence of frailty and dementia and the economic cost of care in Japan from 2016 to 2043: A microsimulation modelling study. Lancet Public Health 2022, 7, e458–e468.
  6. Salisbury, C. Multimorbidity: Redesigning health care for people who use it. Lancet 2012, 380, 7–9.
  7. Marengoni, A.; Angleman, S.; Melis, R.; Mangialasche, F.; Karp, A.; Garmen, A.; Meinow, B.; Fratiglioni, L. Aging with multimorbidity: A systematic review of the literature. Ageing Res. Rev. 2011, 10, 430–439.
  8. Valderas, J.M.; Starfield, B.; Sibbald, B.; Salisbury, C.; Roland, M. Defining comorbidity: Implications for understanding health and health services. Ann. Fam. Med. 2009, 7, 357–363.
  9. Fried, T.R.; O’Leary, J.; Towle, V.; Goldstein, M.K.; Trentalange, M.; Martin, D.K. Health outcomes associated with polypharmacy in community-dwelling older adults: A systematic review. J. Am. Geriatr. Soc. 2014, 62, 2261–2272.
  10. Clague, F.; Mercer, S.W.; Mclean, G.; Reynish, E.; Guthrie, B. Comorbidity and polypharmacy in people with dementia: Insights from a large, population-based cross-sectional analysis of primary care data. Age Ageing 2017, 46, 33–39.
  11. Parsons, C. Polypharmacy and inappropriate medication use in patients with dementia: An underresearched problem. Ther. Adv. Drug Saf. 2017, 8, 31–46.
  12. Growdon, M.E.; Gan, S.; Yaffe, K.; Steinman, M.A. Polypharmacy among older adults with dementia compared with those without dementia in the United States. J. Am. Geriatr. Soc. 2021, 69, 2464–2475.
  13. Charlesworth, C.J.; Smit, E.; Lee, D.S.H.; Alramadhan, F.; Odden, M.C. Polypharmacy among Adults Aged 65 Years and Older in the United States: 1988–2010. J. Gerontol. A Biol. Sci. Med. Sci. 2015, 70, 989–995.
  14. Frazier, S.C. Health outcomes and polypharmacy in elderly individuals: An integrated literature review. J. Gerontol. Nurs. 2005, 31, 4–9.
  15. Safran, D.G.; Neuman, P.; Schoen, C.; Kitchman, M.S.; Wilson, I.B.; Cooper, B.; Li, A.; Chang, H.; Rogers, W.H. Prescription drug coverage and seniors: Findings from a 2003 national survey. Health Aff. 2005, 24, W5–W152.
  16. Mortazavi, S.S.; Shati, M.; Keshtkar, A.; Malakouti, S.K.; Bazargan, M.; Assari, S. Defining polypharmacy in the elderly: A systematic review protocol. BMJ Open 2016, 6.
  17. Gnjidic, D.; Hilmer, S.N.; Blyth, F.M.; Naganathan, V.; Waite, L.; Seibel, M.J.; McLachlan, A.J.; Cumming, R.G.; Handelsman, D.J.; Le Couteur, D.G. Polypharmacy cutoff and outcomes: Five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. J. Clin. Epidemiol. 2012, 65, 989–995.
  18. Veronese, N.; Stubbs, B.; Noale, M.; Solmi, M.; Pilotto, A.; Vaona, A.; Demurtas, J.; Mueller, C.; Huntley, J.; Crepaldi, G.; et al. Polypharmacy Is Associated with Higher Frailty Risk in Older People: An 8-Year Longitudinal Cohort Study. J. Am. Med. Dir. Assoc. 2017, 18, 624–628.
  19. Saum, K.U.; Schöttker, B.; Meid, A.D.; Holleczek, B.; Haefeli, W.E.; Hauer, K.; Brenner, H. Is Polypharmacy Associated with Frailty in Older People? Results from the ESTHER Cohort Study. J. Am. Geriatr. Soc. 2017, 65, e27–e32.
  20. Morin, L.; Larrañaga, A.C.; Welmer, A.K.; Rizzuto, D.; Wastesson, J.W.; Johnell, K. Polypharmacy and injurious falls in older adults: A nationwide nested case-control study. Clin. Epidemiol. 2019, 11, 483–493.
  21. Montero-Odasso, M.; Sarquis-Adamson, Y.; Song, H.Y.; Bray, N.W.; Pieruccini-Faria, F.; Speechley, M. Polypharmacy, Gait Performance, and Falls in Community-Dwelling Older Adults. Results from the Gait and Brain Study. J. Am. Geriatr. Soc. 2019, 67, 1182–1188.
  22. Disalvo, D.; Luckett, T.; Luscombe, G.; Bennett, A.; Davidson, P.; Chenoweth, L.; Mitchell, G.; Pond, D.; Phillips, J.; Beattie, E.; et al. Potentially Inappropriate Prescribing in Australian Nursing Home Residents with Advanced Dementia: A Substudy of the IDEAL Study. J. Palliat. Med. 2018, 21, 1472–1479.
  23. Hukins, D.; Macleod, U.; Boland, J.W. Identifying potentially inappropriate prescribing in older people with dementia: A systematic review. Eur. J. Clin. Pharm. 2019, 75, 467–481.
  24. Barry, H.E.; Cooper, J.A.; Ryan, C.; Passmore, A.P.; Robinson, A.L.; Molloy, G.J.; Darcy, C.M.; Buchanan, H.; Hughes, C.M. Potentially Inappropriate Prescribing among People with Dementia in Primary Care: A Retrospective Cross-Sectional Study Using the Enhanced Prescribing Database. J. Alzheimers Dis. 2016, 52, 1503–1513.
  25. Spinewine, A.; Schmader, K.E.; Barber, N.; Hughes, C.; Lapane, K.L.; Swine, C.; Hanlon, J.T. Appropriate prescribing in elderly people: How well can it be measured and optimised? Lancet 2007, 370, 173–184.
  26. O’mahony, D.; O’sullivan, D.; Byrne, S.; O’connor, M.N.; Ryan, C.; Gallagher, P. STOPP/START criteria for potentially inappropriate prescribing in older people: Version 2. Age Ageing 2015, 44, 213–218.
  27. Xing, X.X.; Zhu, C.; Liang, H.Y.; Wang, K.; Chu, Y.Q.; Zhao, L.B.; Jiang, D.C.; Wang, Y.Q.; Yan, S.Y. Associations between Potentially Inappropriate Medications and Adverse Health Outcomes in the Elderly: A Systematic Review and Meta-analysis. Ann. Pharmacother. 2019, 53, 1005–1019.
  28. Porter, B.; Arthur, A.; Savva, G.M. How do potentially inappropriate medications and polypharmacy affect mortality in frail and non-frail cognitively impaired older adults? A cohort study. BMJ Open 2019, 9, e026171.
  29. Harrison, S.L.; Kouladjian O’Donnell, L.; Bradley, C.E.; Milte, R.; Dyer, S.M.; Gnanamanickam, E.S.; Liu, E.; Hilmer, S.N.; Crotty, M. Associations between the Drug Burden Index, Potentially Inappropriate Medications and Quality of Life in Residential Aged Care. Drugs Aging 2018, 35, 83–91.
  30. Renom-Guiteras, A.; Thürmann, P.A.; Miralles, R.; Klaaßen-Mielke, R.; Thiem, U.; Stephan, A.; Bleijlevens, M.H.C.; Jolley, D.; Leino-Kilpi, H.; Hallberg, I.R.; et al. Potentially inappropriate medication among people with dementia in eight European countries. Age Ageing 2018, 47, 68–74.
  31. Murphy, C.; Dyer, A.H.; Lawlor, B.; Kennelly, S. Potentially inappropriate medication use in older adults with mild-moderate Alzheimer’s disease: Prevalence and associations with adverse events. Age Ageing 2020, 49, 580–587.
  32. Prescribing cascade: Calcium-channel blockers and diuretics. Drug Ther. Bull 2021, 59, 19.
  33. Kverno, K. First Do No Harm: Psychotropic Prescribing Principles and Guidelines for Older Adults. J. Psychosoc. Nurs. Ment. Health Serv. 2020, 58, 12–16.
  34. Singh, S.; Cocoros, N.M.; Haynes, K.; Nair, V.P.; Harkins, T.P.; Rochon, P.A.; Platt, R.; Dashevsky, I.; Reynolds, J.; Mazor, K.M.; et al. Antidopaminergic-Antiparkinsonian Medication Prescribing Cascade in Persons with Alzheimer’s Disease. J. Am. Geriatr. Soc. 2021, 69, 1328–1333.
  35. Storms, H.; Marquet, K.; Aertgeerts, B.; Claes, N. Prevalence of inappropriate medication use in residential long-term care facilities for the elderly: A systematic review. Eur. J. Gen. Pract. 2017, 23, 69–77.
  36. Sköldunger, A.; Fastbom, J.; Wimo, A.; Fratiglioni, L.; Johnell, K. Impact of Inappropriate Drug Use on Hospitalizations, Mortality, and Costs in Older Persons and Persons with Dementia: Findings from the SNAC Study. Drugs Aging 2015, 32, 671–678.
  37. Lyketsos, C.G.; Lopez, O.; Jones, B.; Fitzpatrick, A.L.; Breitner, J.; Dekosky, S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: Results from the cardiovascular health study. JAMA 2002, 288, 1475–1483.
  38. Kaufer, D.I.; Cummings, J.L.; Christine, D.; Bray, T.; Castellon, S.; Masterman, D.; MacMillan, A.; Ketchel, P.; DeKosky, S.T. Assessing the impact of neuropsychiatric symptoms in Alzheimer’s disease: The Neuropsychiatric Inventory Caregiver Distress Scale. J. Am. Geriatr. Soc. 1998, 46, 210–215.
  39. Gauthier, S.; Molinuevo, J.L. Benefits of combined cholinesterase inhibitor and memantine treatment in moderate-severe Alzheimer’s disease. Alzheimers Dement 2013, 9, 326–331.
  40. Krolak-Salmon, P.; Dubois, B.; Sellal, F.; Delabrousse-Mayoux, J.P.; Vandel, P.; Amieva, H.; Jeandel, C.; Andrieu, S.; Perret-Liaudet, A. France Will No More Reimburse Available Symptomatic Drugs against Alzheimer’s Disease. J. Alzheimers Dis. 2018, 66, 425–427.
  41. Moore, T.J.; Mattison, D.R. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern. Med. 2017, 177, 274–275.
  42. Maust, D.T.; Strominger, J.; Bynum, J.P.W.; Langa, K.M.; Gerlach, L.B.; Zivin, K.; Marcus, S.C. Prevalence of Psychotropic and Opioid Prescription Fills among Community-Dwelling Older Adults with Dementia in the US. JAMA 2020, 324, 706–709.
  43. Maust, D.T.; Gerlach, L.B.; Gibson, A.; Kales, H.C.; Blow, F.C.; Olfson, M. Trends in Central Nervous System-Active Polypharmacy among Older Adults Seen in Outpatient Care in the United States. JAMA Intern. Med. 2017, 177, 583–585.
  44. Fick, D.M.; Semla, T.P.; Steinman, M.; Beizer, J.; Brandt, N.; Dombrowski, R.; DuBeau, C.E.; Pezzullo, L.; Epplin, J.J.; Flanagan, N.; et al. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J. Am. Geriatr. Soc. 2019, 67, 674–694.
  45. Girotra, P.; Behl, T.; Sehgal, A.; Singh, S.; Bungau, S. Investigation of the Molecular Role of Brain-Derived Neurotrophic Factor in Alzheimer’s Disease. J. Mol. Neurosci. 2022, 72, 173–186.
  46. Gnjidic, D.; Hilmer, S.N.; Hartikainen, S.; Tolppanen, A.M.; Taipale, H.; Koponen, M.; Bell, J.S. Impact of high risk drug use on hospitalization and mortality in older people with and without Alzheimer’s disease: A national population cohort study. PLoS ONE 2014, 9, 1–8.
  47. Thorpe, J.M.; Thorpe, C.T.; Gellad, W.F.; Good, C.B.; Hanlon, J.T.; Mor, M.K.; Pleis, J.R.; Schleiden, L.J.; Van Houtven, C.H. Dual Health Care System Use and High-Risk Prescribing in Patients with Dementia: A National Cohort Study. Ann. Intern. Med. 2017, 166, 157–163.
  48. Bayliss, E.A.; Shetterly, S.M.; Drace, M.L.; Norton, J.; Green, A.R.; Reeve, E.; Weffald, L.A.; Wright, L.; Maciejewski, M.L.; Sheehan, O.C.; et al. The OPTIMIZE patient- and family-centered, primary care-based deprescribing intervention for older adults with dementia or mild cognitive impairment and multiple chronic conditions: Study protocol for a pragmatic cluster randomized controlled trial. Trials 2020, 21, 542.
  49. Rasu, R.S.; Shrestha, N.; Karpes Matusevich, A.R.; Zalmai, R.; Large, S.; Johnson, L.; O’Bryant, S.E. Polypharmacy and Cognition Function among Rural Adults. J. Alzheimers Dis. 2021, 82, 607–619.
  50. Stoehr, G.P.; Lu, S.Y.; Lavery, L.; Bilt J vander Saxton, J.A.; Chang, C.C.H.; Ganguli, M. Factors associated with adherence to medication regimens in older primary care patients: The Steel Valley Seniors Survey. Am. J. Geriatr. Pharm. 2008, 6, 255–263.
  51. Turner, B.J.; Hollenbeak, C.; Weiner, M.G.; ten Have, T.; Roberts, C. Barriers to adherence and hypertension control in a racially diverse representative sample of elderly primary care patients. Pharm. Drug Saf. 2009, 18, 672–681.
  52. Gray, S.L.; Mahoney, J.E.; Blough, D.K. Medication adherence in elderly patients receiving home health services following hospital discharge. Ann. Pharm. 2001, 35, 539–545.
  53. Chapman, R.H.; Petrilla, A.A.; Benner, J.S.; Schwartz, J.S.; Tang, S.S.K. Predictors of adherence to concomitant antihypertensive and lipid-lowering medications in older adults: A retrospective, cohort study. Drugs Aging 2008, 25, 885–892.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , ,
View Times: 229
Revisions: 2 times (View History)
Update Date: 27 Oct 2022
1000/1000
Video Production Service