Association between Polypharmacy and Adverse Events in Patients with Alzheimer’s Disease: An Analysis of the Japanese Adverse Drug Event Report Database (JADER)
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Source
2.2. Data Processing
2.3. Adverse Events
2.4. Variables
2.5. Statistical Analysis
2.6. Ethical Considerations
3. Results
3.1. Characteristics of the Study Population
3.2. Association between Alzheimer’s Disease Treatment Combinations and Adverse Events
3.3. Association between the Number of Concomitant Medications and Adverse Events
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Alzheimer’s disease |
Frontotemporal lobar degeneration |
Lewy body disease |
Vascular disease |
Traumatic brain injury |
Substance/medication use |
HIV infection |
Prion disease |
Parkinson’s disease |
Huntington’s disease |
Another medical condition |
Multiple etiologies |
Unspecified |
Drug | Mechanism | Pharmacokinetics |
---|---|---|
Donepezil | AChE inhibitor | Absorbed orally, reaching peak plasma concentration in about 3–5 h. Metabolized primarily by CYP2D6 and CYP3A4 in the liver. Excreted mainly in the urine. Half-life is 70–80 h. |
Galantamine | AChE inhibitor APL action on nAchR | Absorbed orally, reaching peak plasma concentration in 1 h. Metabolized by CYP2D6 and CYP3A4 in the liver. Excreted mainly in the urine. Half-life is 5–7 h. |
Rivastigmine | AChE inhibitor BuChE inhibitor | Administered orally or via patch. Metabolized by esterases. The half-life is about 1.5 h for oral administration and 3.4 h for patches. Excreted primarily in urine. |
Memantine | Glutamate NMDA receptor antagonist | Absorbed orally, reaching peak plasma concentration in 1–7 h. Excreted primarily in urine. The half-life is 60–80 h. |
Variables | n | % | |
---|---|---|---|
Sex | Male | 1055 | 39.8% |
Female | 1598 | 60.2% | |
Age | 60–69 | 131 | 4.9% |
70–79 | 786 | 29.6% | |
80–89 | 1420 | 53.5% | |
90+ | 316 | 11.9% | |
Combination with Alzheimer’s disease therapeutics | Memantine | 207 | 7.8% |
Donepezil | 1089 | 41.0% | |
Rivastigmine | 664 | 25.0% | |
Galantamine | 458 | 17.3% | |
Memantine+AChEI | 235 | 8.9% | |
The number of concomitant medications used | 0 drugs | 463 | 17.5% |
1 drug | 271 | 10.2% | |
2 drugs | 227 | 8.6% | |
3 drugs | 264 | 10.0% | |
4 drugs | 162 | 6.1% | |
5 drugs or more | 1266 | 47.7% | |
Comorbidity | Diabetes mellitus | 325 | 12.3% |
Hypertension | 935 | 35.2% | |
Hyperlipidemia | 360 | 13.6% | |
Ischemic heart diseases | 162 | 6.1% | |
Cerebrovascular diseases | 283 | 10.7% | |
Malignant neoplasms | 82 | 3.1% | |
Depression | 124 | 4.7% | |
Parkinson’s disease | 113 | 4.3% | |
Sleep disorders | 197 | 7.4% |
Number of Cases | Percentage | Cumulative Percentage | |
---|---|---|---|
Bradycardia | 171 | 6.4% | 6.4% |
Pneumonia | 122 | 4.6% | 11.0% |
Altered state of consciousness | 96 | 3.6% | 14.7% |
Seizures | 93 | 3.5% | 18.2% |
Decreased appetite | 93 | 3.5% | 21.7% |
Vomiting | 92 | 3.5% | 25.1% |
Loss of consciousness | 91 | 3.4% | 28.6% |
Fractures | 91 | 3.4% | 32.0% |
Cardiac failure | 84 | 3.2% | 35.2% |
Falls | 80 | 3.0% | 38.2% |
Bradycardia | Pneumonia | ||||||||||
Bivariate | Multivariate | Bivariate | Multivariate | ||||||||
Total | n | OR | p | AOR | p | n | OR | p | AOR | p | |
Sex | |||||||||||
Male | 1055 | 66 | ref | 0.746 | ref | 0.920 | 72 | ref | <0.0001 | ref | <0.0001 |
Female | 1598 | 105 | 1.05 | 1.02 | 50 | 0.44 | 0.40 | ||||
Age | |||||||||||
60–69 | 131 | 7 | ref | 0.032 | ref | 0.063 | 3 | ref | 0.071 | ref | 0.067 |
70–79 | 786 | 39 | 0.92 | 0.89 | 28 | 1.58 | 1.48 | ||||
80–89 | 1420 | 110 | 1.49 | 1.38 | 70 | 2.21 | 2.22 | ||||
90 and older | 316 | 15 | 0.88 | 0.84 | 21 | 3.04 | 3.00 | ||||
Combination with Alzheimer’s disease therapeutics | |||||||||||
Memantine | 201 | 6 | ref | 0.018 | ref | 0.016 | 13 | ref | <0.0001 | ref | <0.0001 |
Donepezil | 1006 | 83 | 2.76 | 3.07 | 25 | 0.35 | 0.37 | ||||
Rivastigmine | 632 | 32 | 1.70 | 2.00 | 60 | 1.48 | 1.43 | ||||
Galantamine | 423 | 35 | 2.77 | 3.12 | 21 | 0.72 | 0.73 | ||||
Memantine + AChEI | 220 | 15 | 2.28 | 2.49 | 3 | 0.19 | 0.19 | ||||
The number of concomitant medications used | |||||||||||
0 drugs | 163 | 20 | ref | 0.201 | ref | 0.207 | 31 | ref | 0.201 | ref | 0.845 |
1 drug | 271 | 20 | 1.76 | 1.65 | 13 | 0.70 | 0.79 | ||||
2 drugs | 227 | 15 | 1.57 | 1.36 | 8 | 0.51 | 0.82 | ||||
3 drugs | 264 | 24 | 2.22 | 2.16 | 10 | 0.55 | 0.75 | ||||
4 drugs | 162 | 9 | 1.30 | 1.03 | 4 | 0.35 | 0.64 | ||||
5 drugs or more | 1266 | 83 | 1.55 | 1.38 | 56 | 0.64 | 1.02 | ||||
Comorbidities | |||||||||||
Diabetes mellitus | 325 | 23 | 1.12 | 0.625 | 0.93 | 0.828 | 11 | 0.70 | 0.246 | 0.72 | 0.319 |
Hypertension | 935 | 86 | 1.95 | <0.0001 | 2.00 | <0.0001 | 27 | 0.51 | 0.001 | 0.55 | 0.013 |
Hyperlipidemia | 360 | 21 | 0.89 | 0.611 | 0.66 | 0.083 | 14 | 0.82 | 0.480 | 1.45 | 0.257 |
Ischemic heart diseases | 162 | 16 | 1.65 | 0.069 | 1.48 | 0.196 | 6 | 0.79 | 0.563 | 0.90 | 0.803 |
Cerebrovascular diseases | 283 | 15 | 0.79 | 0.408 | 0.67 | 0.141 | 11 | 0.82 | 0.536 | 0.97 | 0.937 |
Malignant neoplasms | 82 | 2 | 0.36 | 0.170 | 0.31 | 0.056 | 9 | 2.68 | 0.016 | 2.16 | 0.066 |
Depression | 124 | 4 | 0.47 | 0.186 | 0.48 | 0.125 | 6 | 1.06 | 0.897 | 1.55 | 0.356 |
Parkinson’s disease | 113 | 4 | 0.52 | 0.206 | 0.57 | 0.235 | 11 | 2.36 | 0.019 | 2.29 | 0.031 |
Sleep disorders | 197 | 9 | 0.68 | 0.268 | 0.67 | 0.235 | 4 | 0.41 | 0.047 | 0.43 | 0.077 |
Altered State of Consciousness | Seizures | ||||||||||
Bivariate | Multivariate | Bivariate | Multivariate | ||||||||
Total | n | OR | p | AOR | p | n | OR | p | AOR | p | |
Sex | |||||||||||
Male | 1055 | 36 | ref | 0.643 | ref | 0.612 | 42 | ref | 0.282 | ref | 0.234 |
Female | 1598 | 60 | 1.10 | 1.12 | 51 | 0.80 | 0.77 | ||||
Age | |||||||||||
60–69 | 131 | 7 | ref | 0.386 | ref | 0.419 | 6 | ref | 0.881 | ref | 0.793 |
70–79 | 786 | 25 | 0.58 | 0.58 | 29 | 0.80 | 0.78 | ||||
80–89 | 1420 | 56 | 0.73 | 0.71 | 48 | 0.73 | 0.68 | ||||
90 and older | 316 | 8 | 0.46 | 0.45 | 10 | 0.68 | 0.62 | ||||
Combination with Alzheimer’s disease therapeutics | |||||||||||
Memantine | 201 | 13 | ref | 0.096 | ref | 0.502 | 11 | ref | 0.058 | ref | 0.103 |
Donepezil | 1006 | 43 | 0.61 | 0.74 | 45 | 0.77 | 0.84 | ||||
Rivastigmine | 632 | 15 | 0.34 | 0.51 | 15 | 0.41 | 0.46 | ||||
Galantamine | 423 | 17 | 0.58 | 0.75 | 11 | 0.44 | 0.47 | ||||
Memantine + AChEI | 220 | 8 | 0.53 | 0.57 | 11 | 0.88 | 0.96 | ||||
The number of concomitant medications used | |||||||||||
0 drugs | 163 | 2 | ref | <0.0001 | ref | <0.0001 | 14 | ref | 0.856 | ref | 0.839 |
1 drug | 271 | 8 | 7.01 | 6.93 | 10 | 1.23 | 1.20 | ||||
2 drugs | 227 | 6 | 6.26 | 5.90 | 7 | 1.02 | 0.85 | ||||
3 drugs | 264 | 19 | 17.88 | 17.53 | 8 | 1.00 | 0.90 | ||||
4 drugs | 162 | 5 | 7.34 | 6.80 | 4 | 0.81 | 0.63 | ||||
5 drugs or more | 1266 | 56 | 10.67 | 10.45 | 50 | 1.32 | 1.13 | ||||
Comorbidities | |||||||||||
Diabetes mellitus | 325 | 9 | 0.73 | 0.364 | 0.61 | 0.153 | 5 | 0.40 | 0.023 | 0.34 | 0.008 |
Hypertension | 935 | 37 | 1.16 | 0.494 | 0.96 | 0.874 | 35 | 1.11 | 0.625 | 1.13 | 0.621 |
Hyperlipidemia | 360 | 15 | 1.19 | 0.557 | 1.02 | 0.944 | 11 | 0.85 | 0.611 | 0.79 | 0.482 |
Ischemic heart diseases | 162 | 7 | 1.22 | 0.631 | 1.09 | 0.829 | 7 | 1.26 | 0.573 | 1.26 | 0.589 |
Cerebrovascular diseases | 283 | 11 | 1.09 | 0.800 | 0.94 | 0.861 | 12 | 1.25 | 0.489 | 1.23 | 0.533 |
Malignant neoplasms | 82 | 3 | 1.13 | 1.000 | 0.88 | 0.835 | 1 | 0.33 | 0.367 | 0.32 | 0.175 |
Depression | 124 | 5 | 1.53 | 0.803 | 0.93 | 0.881 | 2 | 0.44 | 0.321 | 0.38 | 0.123 |
Parkinson’s disease | 113 | 6 | 1.53 | 0.300 | 1.43 | 0.437 | 2 | 0.48 | 0.435 | 0.44 | 0.208 |
Sleep disorders | 197 | 7 | 0.98 | 0.959 | 0.78 | 0.537 | 11 | 1.71 | 0.126 | 1.68 | 0.149 |
Decreased Appetite | Vomiting | ||||||||||
Bivariate | Multivariate | Bivariate | Multivariate | ||||||||
Total | n | OR | p | AOR | p | n | OR | p | AOR | p | |
Sex | |||||||||||
Male | 1055 | 35 | ref | 0.668 | ref | 0.647 | 18 | ref | <0.0001 | ref | <0.0001 |
Female | 1598 | 58 | 1.10 | 1.11 | 74 | 2.80 | 2.71 | ||||
Age | |||||||||||
60–69 | 131 | 1 | ref | 0.351 | ref | 0.244 | 3 | ref | 0.680 | ref | 0.216 |
70–79 | 786 | 30 | 5.16 | 5.00 | 31 | 1.75 | 1.71 | ||||
80–89 | 1420 | 51 | 4.84 | 4.25 | 49 | 1.52 | 1.22 | ||||
90 and older | 316 | 11 | 4.69 | 4.32 | 9 | 1.25 | 0.80 | ||||
Combination with Alzheimer’s disease therapeutics | |||||||||||
Memantine | 201 | 5 | ref | 0.270 | ref | 0.126 | 5 | ref | 0.001 | ref | <0.0001 |
Donepezil | 1006 | 48 | 1.86 | 2.22 | 25 | 0.95 | 1.01 | ||||
Rivastigmine | 632 | 22 | 1.38 | 2.06 | 39 | 2.52 | 3.56 | ||||
Galantamine | 423 | 12 | 1.09 | 1.41 | 19 | 1.75 | 2.10 | ||||
Memantine + AChEI | 220 | 6 | 1.06 | 0.99 | 4 | 0.70 | 0.63 | ||||
The number of concomitant medications used | |||||||||||
0 drugs | 163 | 3 | ref | 0.000 | ref | 0.000 | 6 | ref | 0.011 | ref | 0.000 |
1 drug | 271 | 9 | 5.27 | 5.06 | 9 | 2.62 | 3.11 | ||||
2 drugs | 227 | 6 | 4.16 | 4.31 | 15 | 5.39 | 7.87 | ||||
3 drugs | 264 | 6 | 3.57 | 3.66 | 9 | 2.69 | 3.78 | ||||
4 drugs | 162 | 9 | 9.02 | 9.72 | 8 | 3.96 | 6.85 | ||||
5 drugs or more | 1266 | 60 | 7.63 | 7.92 | 45 | 2.81 | 4.74 | ||||
Comorbidities | |||||||||||
Diabetes mellitus | 325 | 14 | 1.28 | 0.415 | 0.99 | 0.970 | 10 | 0.87 | 0.676 | 0.89 | 0.725 |
Hypertension | 935 | 44 | 1.68 | 0.015 | 1.18 | 0.468 | 36 | 1.19 | 0.430 | 1.09 | 0.714 |
Hyperlipidemia | 360 | 17 | 1.45 | 0.195 | 1.06 | 0.831 | 13 | 1.05 | 0.874 | 0.89 | 0.724 |
Ischemic heart diseases | 162 | 11 | 2.14 | 0.035 | 1.59 | 0.198 | 6 | 1.08 | 0.867 | 1.16 | 0.741 |
Cerebrovascular diseases | 283 | 12 | 1.25 | 0.489 | 0.90 | 0.752 | 7 | 0.68 | 0.311 | 0.59 | 0.173 |
Malignant neoplasms | 82 | 4 | 1.43 | 0.532 | 1.32 | 0.616 | 1 | 0.34 | 0.367 | 0.37 | 0.255 |
Depression | 124 | 3 | 0.67 | 0.800 | 0.48 | 0.183 | 0 | - | - | - | - |
Parkinson’s disease | 113 | 4 | 1.01 | 1.000 | 0.84 | 0.729 | 2 | 0.49 | 0.434 | 0.38 | 0.126 |
Sleep disorders | 197 | 9 | 1.35 | 0.418 | 1.05 | 0.890 | 7 | 1.03 | 0.946 | 0.93 | 0.865 |
Loss of Consciousness | Fractures | ||||||||||
Bivariate | Multivariate | Bivariate | Multivariate | ||||||||
Total | n | OR | p | AOR | p | n | OR | p | AOR | p | |
Sex | |||||||||||
Male | 1055 | 34 | ref | 0.632 | ref | 0.613 | 18 | ref | <0.0001 | ref | 0.000 |
Female | 1598 | 57 | 1.11 | 1.11 | 73 | 2.76 | 2.60 | ||||
Age | |||||||||||
60–69 | 131 | 7 | ref | 0.230 | ref | 0.171 | 1 | ref | 0.057 | ref | 0.523 |
70–79 | 786 | 24 | 0.56 | 0.55 | 22 | 3.74 | 3.24 | ||||
80–89 | 1420 | 44 | 0.57 | 0.44 | 52 | 4.94 | 3.47 | ||||
90 and older | 316 | 16 | 0.94 | 0.75 | 16 | 6.93 | 3.47 | ||||
Combination with Alzheimer’s disease therapeutics | |||||||||||
Memantine | 201 | 16 | ref | <0.0001 | ref | <0.0001 | 12 | ref | <0.0001 | ref | 0.000 |
Donepezil | 1006 | 13 | 0.14 | 0.15 | 16 | 0.24 | 0.28 | ||||
Rivastigmine | 632 | 16 | 0.29 | 0.34 | 36 | 0.93 | 0.99 | ||||
Galantamine | 423 | 31 | 0.87 | 0.96 | 19 | 0.70 | 0.80 | ||||
Memantine + AChEI | 220 | 15 | 0.81 | 0.83 | 8 | 0.57 | 0.62 | ||||
The number of concomitant medications used | |||||||||||
0 drugs | 163 | 7 | ref | 0.126 | ref | 0.318 | 18 | ref | 0.143 | ref | 0.184 |
1 drug | 271 | 8 | 1.98 | 2.27 | 11 | 1.05 | 1.21 | ||||
2 drugs | 227 | 10 | 3.00 | 3.18 | 3 | 0.33 | 0.42 | ||||
3 drugs | 264 | 9 | 2.30 | 2.18 | 5 | 0.48 | 0.59 | ||||
4 drugs | 162 | 6 | 2.51 | 2.28 | 4 | 0.63 | 0.87 | ||||
5 drugs or more | 1266 | 51 | 2.73 | 2.25 | 50 | 1.02 | 1.31 | ||||
Comorbidities | |||||||||||
Diabetes mellitus | 325 | 8 | 0.68 | 0.285 | 0.65 | 0.244 | 5 | 0.41 | 0.027 | 0.50 | 0.108 |
Hypertension | 935 | 36 | 1.21 | 0.384 | 1.00 | 0.998 | 35 | 1.15 | 0.516 | 1.25 | 0.363 |
Hyperlipidemia | 360 | 14 | 1.16 | 0.613 | 0.97 | 0.928 | 7 | 0.52 | 0.074 | 0.45 | 0.033 |
Ischemic heart diseases | 162 | 13 | 2.70 | 0.004 | 3.01 | 0.003 | 5 | 0.89 | 0.801 | 1.02 | 0.975 |
Cerebrovascular diseases | 283 | 16 | 1.83 | 0.044 | 1.87 | 0.050 | 7 | 0.69 | 0.328 | 0.71 | 0.386 |
Malignant neoplasms | 82 | 2 | 0.70 | 1.000 | 0.74 | 0.678 | 1 | 0.34 | 0.528 | 0.37 | 0.258 |
Depression | 124 | 2 | 0.45 | 0.442 | 0.51 | 0.308 | 1 | 0.22 | 0.127 | 0.22 | 0.059 |
Parkinson’s disease | 113 | 3 | 0.76 | 1.000 | 0.82 | 0.733 | 4 | 1.03 | 0.794 | 1.05 | 0.931 |
Sleep disorders | 197 | 4 | 0.56 | 0.228 | 0.47 | 0.118 | 10 | 1.57 | 0.191 | 1.57 | 0.240 |
Cardiac Failure | Falls | ||||||||||
Bivariate | Multivariate | Bivariate | Multivariate | ||||||||
Total | n | OR | p | AOR | p | n | OR | p | AOR | p | |
Sex | |||||||||||
Male | 1055 | 32 | ref | 0.751 | ref | 0.850 | 24 | ref | 0.065 | ref | 0.129 |
Female | 1598 | 52 | 1.08 | 1.05 | 56 | 1.56 | 1.47 | ||||
Age | |||||||||||
60–69 | 131 | 2 | ref | 0.007 | ref | 0.006 | 3 | ref | 0.587 | ref | 0.749 |
70–79 | 786 | 23 | 1.94 | 2.00 | 19 | 1.06 | 0.88 | ||||
80–89 | 1420 | 38 | 1.77 | 1.78 | 48 | 1.49 | 1.02 | ||||
90 and older | 316 | 21 | 4.59 | 4.80 | 10 | 1.39 | 0.70 | ||||
Combination with Alzheimer’s disease therapeutics | |||||||||||
Memantine | 201 | 4 | ref | 0.708 | ref | 0.607 | 12 | ref | <0.0001 | ref | 0.000 |
Donepezil | 1006 | 36 | 1.74 | 2.04 | 14 | 0.21 | 0.28 | ||||
Rivastigmine | 632 | 20 | 1.58 | 1.64 | 25 | 0.64 | 0.98 | ||||
Galantamine | 423 | 14 | 1.60 | 1.80 | 15 | 0.55 | 0.76 | ||||
Memantine + AChEI | 220 | 10 | 2.26 | 2.27 | 14 | 1.03 | 1.16 | ||||
The number of concomitant medications used | |||||||||||
0 drug | 163 | 14 | ref | 0.670 | ref | 0.594 | 4 | ref | 0.004 | ref | 0.002 |
1 drug | 271 | 7 | 0.85 | 0.82 | 10 | 4.40 | 5.33 | ||||
2 drugs | 227 | 6 | 0.87 | 0.92 | 5 | 2.58 | 3.04 | ||||
3 drugs | 264 | 5 | 0.62 | 0.61 | 8 | 3.59 | 4.49 | ||||
4 drugs | 162 | 6 | 1.23 | 1.37 | 2 | 1.43 | 1.72 | ||||
5 drugs or more | 1266 | 46 | 1.21 | 1.28 | 51 | 4.82 | 5.95 | ||||
Comorbidities | |||||||||||
Diabetes mellitus | 325 | 13 | 1.32 | 0.375 | 1.41 | 0.301 | 4 | 0.37 | 0.025 | 0.35 | 0.022 |
Hypertension | 935 | 29 | 0.97 | 0.888 | 0.84 | 0.486 | 30 | 1.11 | 0.669 | 1.00 | 0.986 |
Hyperlipidemia | 360 | 10 | 0.86 | 0.645 | 0.79 | 0.511 | 9 | 0.80 | 0.528 | 0.70 | 0.322 |
Ischemic heart diseases | 162 | 6 | 1.19 | 0.694 | 1.06 | 0.893 | 2 | 0.39 | 0.234 | 0.39 | 0.142 |
Cerebrovascular diseases | 283 | 10 | 1.14 | 0.713 | 1.15 | 0.698 | 7 | 0.80 | 0.562 | 0.76 | 0.502 |
Malignant neoplasms | 82 | 4 | 1.60 | 0.329 | 1.62 | 0.396 | 1 | 0.39 | 0.516 | 0.37 | 0.259 |
Depression | 124 | 3 | 0.75 | 0.797 | 0.70 | 0.540 | 1 | 0.25 | 0.181 | 0.22 | 0.056 |
Parkinson’s disease | 113 | 1 | 0.26 | 0.264 | 0.28 | 0.117 | 1 | 0.28 | 0.259 | 0.24 | 0.077 |
Sleep disorders | 197 | 7 | 1.14 | 0.751 | 0.97 | 0.939 | 12 | 2.28 | 0.002 | 2.15 | 0.035 |
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© 2024 by the authors. Published by MDPI on behalf of the Lithuanian University of Health Sciences. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Otani, N.; Kanda, K.; Ngatu, N.R.; Murakami, A.; Yamadori, Y.; Hirao, T. Association between Polypharmacy and Adverse Events in Patients with Alzheimer’s Disease: An Analysis of the Japanese Adverse Drug Event Report Database (JADER). Medicina 2024, 60, 1633. https://doi.org/10.3390/medicina60101633
Otani N, Kanda K, Ngatu NR, Murakami A, Yamadori Y, Hirao T. Association between Polypharmacy and Adverse Events in Patients with Alzheimer’s Disease: An Analysis of the Japanese Adverse Drug Event Report Database (JADER). Medicina. 2024; 60(10):1633. https://doi.org/10.3390/medicina60101633
Chicago/Turabian StyleOtani, Nobuhiro, Kanae Kanda, Nlandu Roger Ngatu, Akitsu Murakami, Yusuke Yamadori, and Tomohiro Hirao. 2024. "Association between Polypharmacy and Adverse Events in Patients with Alzheimer’s Disease: An Analysis of the Japanese Adverse Drug Event Report Database (JADER)" Medicina 60, no. 10: 1633. https://doi.org/10.3390/medicina60101633