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On February 9, 2021, the latest research result of Professor Qu Qiumin's team from the First Affiliated Hospital of Xi'an Jiaotong University "Donepezil Combined with DL-3-n-Butylphthalide Delays Cognitive Decline in Patients with Mild to Moderate Alzheimer's Disease: A Multicenter, Prospective Cohort Study" Published in the journal "Journal of Alzheimer's Disease" (IF=3.
909).
This study aimed to explore the efficacy of donepezil combined with NBP in the treatment of patients with mild to moderate AD.
The results found that donepezil combined with NBP for 48 weeks can significantly improve patients' cognitive decline and activities of daily living.
It shows that the multi-target therapeutic effect of NBP may be a new option for AD treatment.
Research background Alzheimer's disease (AD) is the most common cause of dementia.
There is no curable drug, and current drugs can only temporarily improve the symptoms of AD patients.
Cerebral microcirculation disorders and mitochondrial dysfunction may play an important role in the pathogenesis of AD, and are currently the hotspots of research on the pathogenesis of AD.
Butylphthalide (NBP) has a unique role in protecting mitochondria and improving microcirculation.
It is widely used in patients with acute ischemic stroke and can significantly improve patients' nervous system damage.
A multi-center clinical trial published in "Alzheimer's Dementia" showed that NBP continuous treatment for 6 months can effectively improve the cognition and overall function of patients with non-dementia subcortical vascular cognitive dysfunction.
Many other studies have explored the effect of NBP on AD, indicating that NBP can improve the cognitive function of patients with mild to moderate AD, but the follow-up time is shorter.
This study used the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), the Clinical Impression Change Scale (CIBIC-plus), the Alzheimer’s Disease Collaborative Research Daily Ability Scale (ADCS-ADL) and The neuropsychiatric questionnaire (NPI) assessed the overall efficacy of NBP, followed up for 48 weeks.
The results further proved the effect of the combination of donepezil and NBP in the treatment of AD.
Research methods 1.
Inclusion criteria 1) age 50-85 years; 2) meet the diagnostic criteria for suspicious AD; 3) patients with mild to moderate AD, that is, 11 points ≤ MMSE total score ≤ 26 points (or elementary school education: 11 Score ≤ MMSE total score ≤ 22 points); 4) Hachinski Ischemia Index Scale (HIS) score ≤ 4 points; 5) Memory loss for at least 12 months, with a trend of gradual deterioration; 6) Brain MRI scans suggest the presence of AD It is more likely to have a visual acuity rating of 2 or higher on the Medial Temporal Lobe Atrophy Assessment Scale (MTA), Fazekas rating ≤ 2); 7) No obvious signs in neurological examination; 8) Stable and reliable caregivers; ) Primary school or higher education level, have the ability to complete the required cognitive ability test and other tests; 10) Sign informed consent.
2.
Intervention measures According to the patient's condition, family income, compliance, etc.
, patients with mild to moderate AD were divided into donepezil group and donepezil combined with NBP group.
The donepezil group was treated with 5 mg donepezil once a day; the donepezil combined with NBP group received donepezil 5 mg and NBP 200 mg 3 times a day for 48 weeks.
3.
The primary end point of the evaluation index is the ADAS-Cog score, and the secondary end point is the CIBIC-Plus, ADCS-ADL and NPI scale scores.
The safety assessment includes physical examination, vital signs and adverse event (AE) reports.
Each patient underwent a total of 5 visits, including baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.
The scale was evaluated at each follow-up and adverse events were recorded.
Each center has at least two neuropsychological evaluators, one is responsible for MMSE and ADAS-cog evaluations, and the other is responsible for ADL, NPI and CIBIC-plus evaluations, and the neuropsychological evaluators do not know what treatment each patient receives .
All subjects passed the scale conformance test before participating in the trial.
Research results 1.
General patient information From January 2016 to June 2018, 126 patients with dementia were selected from the neurology departments of 5 hospitals in Xi'an, of which 92 patients with mild to moderate AD met the inclusion criteria.
At baseline, the age of the donepezil combined with NBP group was younger than that of the donepezil group alone (p=0.
005), and there were no significant differences in other demographic information and clinical characteristics between the two groups.
2.
Neuropsychological score changes compared with baseline ADAS-cog score changes at the 48th week, the donepezil group was significantly higher than the donepezil combined with NBP group, the PP population was (1.
82±5.
20 vs -0.
38±4.
46, p=0.
048), ITT The population was (1.
56±4.
86 vs -0.
40±4.
08, p=0.
039).
At other follow-up time points, there was no significant difference in the change of ADAS-cog score from baseline between the two groups.
Regarding the MMSE score, there was a significant difference between the two groups compared with the baseline changes at week 12, in the ITT population (-0.
48±1.
97 vs -0.
40±1.
93, p=0.
037), there was no difference between the two groups at other follow-up time points.
The changes in ADCS-ADL, NPI and CIBIC-plus scores from baseline were not different between the two groups at all follow-up time points.
The results are shown in Table 2 and Fig 2.
Click on the picture to see a clear big picture: 3.
Multiple logistic regression analysis is in the multiple logistic regression analysis.
In Model 1, the improvement in scale score (yes or no) is the dependent variable, and age, gender, and education are covariates.
In Model 2, the improvement in scale score (yes or no) is the dependent variable, and age, gender, education level, uncontrollable hypertension and diabetes are covariates.
Multiple logistic regression analysis showed that in the ITT population, the ADAS-cog (OR= 2.
778, 95% CI: [1.
087, 7.
100], p=0.
033), ADCS-ADL (OR=2.
733, 95%CI: [1.
002,7.
459], p=0.
049), the difference is significant; MMSE (OR=1.
563, 95%CI: [0.
615,3.
971], p=0.
348), NPI (OR=1.
145, 95%CI) : [0.
463, 2.
829], p=0.
769) and CIBIC-plus (OR=2.
593, 95% CI: [0.
696, 9.
685], p=0.
156), there was no significant difference between the two groups.
See Table 3 for the results.
Click on the picture to see a clearer picture: 4.
Safety The incidence of adverse events in the two groups is similar (see Table 2).
The main adverse reactions are gastrointestinal reactions, such as nausea, vomiting and anorexia.
Patients with good tolerance usually do not Affect the continued use of drugs.
The conclusion of the study is that during the 48-week treatment period, patients in the donepezil combined with NBP group had slower cognitive decline and improved activities of daily living, indicating that the multi-targeted therapeutic effect of NBP may be a new option for AD treatment, which is currently ongoing The development of butylphthalide in the treatment of vascular dementia has provided strong evidence support.
References: Wang J, Guo X, Lu W, et al.
Donepezil Combined withDL-3-n-Butylphthalide Delays Cognitive Decline in Patients with Mild toModerate Alzheimer's Disease: A Multicenter, Prospective Cohort Study[J].
Journal of Alzheimer's disease: JAD, 2021(Suppl 2): 1-9.
909).
This study aimed to explore the efficacy of donepezil combined with NBP in the treatment of patients with mild to moderate AD.
The results found that donepezil combined with NBP for 48 weeks can significantly improve patients' cognitive decline and activities of daily living.
It shows that the multi-target therapeutic effect of NBP may be a new option for AD treatment.
Research background Alzheimer's disease (AD) is the most common cause of dementia.
There is no curable drug, and current drugs can only temporarily improve the symptoms of AD patients.
Cerebral microcirculation disorders and mitochondrial dysfunction may play an important role in the pathogenesis of AD, and are currently the hotspots of research on the pathogenesis of AD.
Butylphthalide (NBP) has a unique role in protecting mitochondria and improving microcirculation.
It is widely used in patients with acute ischemic stroke and can significantly improve patients' nervous system damage.
A multi-center clinical trial published in "Alzheimer's Dementia" showed that NBP continuous treatment for 6 months can effectively improve the cognition and overall function of patients with non-dementia subcortical vascular cognitive dysfunction.
Many other studies have explored the effect of NBP on AD, indicating that NBP can improve the cognitive function of patients with mild to moderate AD, but the follow-up time is shorter.
This study used the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), the Clinical Impression Change Scale (CIBIC-plus), the Alzheimer’s Disease Collaborative Research Daily Ability Scale (ADCS-ADL) and The neuropsychiatric questionnaire (NPI) assessed the overall efficacy of NBP, followed up for 48 weeks.
The results further proved the effect of the combination of donepezil and NBP in the treatment of AD.
Research methods 1.
Inclusion criteria 1) age 50-85 years; 2) meet the diagnostic criteria for suspicious AD; 3) patients with mild to moderate AD, that is, 11 points ≤ MMSE total score ≤ 26 points (or elementary school education: 11 Score ≤ MMSE total score ≤ 22 points); 4) Hachinski Ischemia Index Scale (HIS) score ≤ 4 points; 5) Memory loss for at least 12 months, with a trend of gradual deterioration; 6) Brain MRI scans suggest the presence of AD It is more likely to have a visual acuity rating of 2 or higher on the Medial Temporal Lobe Atrophy Assessment Scale (MTA), Fazekas rating ≤ 2); 7) No obvious signs in neurological examination; 8) Stable and reliable caregivers; ) Primary school or higher education level, have the ability to complete the required cognitive ability test and other tests; 10) Sign informed consent.
2.
Intervention measures According to the patient's condition, family income, compliance, etc.
, patients with mild to moderate AD were divided into donepezil group and donepezil combined with NBP group.
The donepezil group was treated with 5 mg donepezil once a day; the donepezil combined with NBP group received donepezil 5 mg and NBP 200 mg 3 times a day for 48 weeks.
3.
The primary end point of the evaluation index is the ADAS-Cog score, and the secondary end point is the CIBIC-Plus, ADCS-ADL and NPI scale scores.
The safety assessment includes physical examination, vital signs and adverse event (AE) reports.
Each patient underwent a total of 5 visits, including baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks.
The scale was evaluated at each follow-up and adverse events were recorded.
Each center has at least two neuropsychological evaluators, one is responsible for MMSE and ADAS-cog evaluations, and the other is responsible for ADL, NPI and CIBIC-plus evaluations, and the neuropsychological evaluators do not know what treatment each patient receives .
All subjects passed the scale conformance test before participating in the trial.
Research results 1.
General patient information From January 2016 to June 2018, 126 patients with dementia were selected from the neurology departments of 5 hospitals in Xi'an, of which 92 patients with mild to moderate AD met the inclusion criteria.
At baseline, the age of the donepezil combined with NBP group was younger than that of the donepezil group alone (p=0.
005), and there were no significant differences in other demographic information and clinical characteristics between the two groups.
2.
Neuropsychological score changes compared with baseline ADAS-cog score changes at the 48th week, the donepezil group was significantly higher than the donepezil combined with NBP group, the PP population was (1.
82±5.
20 vs -0.
38±4.
46, p=0.
048), ITT The population was (1.
56±4.
86 vs -0.
40±4.
08, p=0.
039).
At other follow-up time points, there was no significant difference in the change of ADAS-cog score from baseline between the two groups.
Regarding the MMSE score, there was a significant difference between the two groups compared with the baseline changes at week 12, in the ITT population (-0.
48±1.
97 vs -0.
40±1.
93, p=0.
037), there was no difference between the two groups at other follow-up time points.
The changes in ADCS-ADL, NPI and CIBIC-plus scores from baseline were not different between the two groups at all follow-up time points.
The results are shown in Table 2 and Fig 2.
Click on the picture to see a clear big picture: 3.
Multiple logistic regression analysis is in the multiple logistic regression analysis.
In Model 1, the improvement in scale score (yes or no) is the dependent variable, and age, gender, and education are covariates.
In Model 2, the improvement in scale score (yes or no) is the dependent variable, and age, gender, education level, uncontrollable hypertension and diabetes are covariates.
Multiple logistic regression analysis showed that in the ITT population, the ADAS-cog (OR= 2.
778, 95% CI: [1.
087, 7.
100], p=0.
033), ADCS-ADL (OR=2.
733, 95%CI: [1.
002,7.
459], p=0.
049), the difference is significant; MMSE (OR=1.
563, 95%CI: [0.
615,3.
971], p=0.
348), NPI (OR=1.
145, 95%CI) : [0.
463, 2.
829], p=0.
769) and CIBIC-plus (OR=2.
593, 95% CI: [0.
696, 9.
685], p=0.
156), there was no significant difference between the two groups.
See Table 3 for the results.
Click on the picture to see a clearer picture: 4.
Safety The incidence of adverse events in the two groups is similar (see Table 2).
The main adverse reactions are gastrointestinal reactions, such as nausea, vomiting and anorexia.
Patients with good tolerance usually do not Affect the continued use of drugs.
The conclusion of the study is that during the 48-week treatment period, patients in the donepezil combined with NBP group had slower cognitive decline and improved activities of daily living, indicating that the multi-targeted therapeutic effect of NBP may be a new option for AD treatment, which is currently ongoing The development of butylphthalide in the treatment of vascular dementia has provided strong evidence support.
References: Wang J, Guo X, Lu W, et al.
Donepezil Combined withDL-3-n-Butylphthalide Delays Cognitive Decline in Patients with Mild toModerate Alzheimer's Disease: A Multicenter, Prospective Cohort Study[J].
Journal of Alzheimer's disease: JAD, 2021(Suppl 2): 1-9.
