INTRODUCTION:

Dementia is an acquired cognitive impairment at the core; the syndrome significantly decreases the patient's daily living ability, learning ability, workability, and social interaction ability. As age increases, the prevalence of Alzheimer's disease also increases. According to data released by Alzheimer's Disease International in 2018, it is estimated that more than 50 million people worldwide have dementia, and the number of people affected will increase to 152 million by 2050^1,2. A meta-analysis showed that in China, the prevalence of Alzheimer's disease is 5.3%, and the prevalence is gradually increasing over time^3,4. At present, the drug treatment of dementia is mainly symptomatic. This article retrieves domestic and foreign guidelines, literature, and related materials on the treatment of dementia in the past five years.

After induction, analysis, and evidence-based evaluation of the policies, the drug treatment options and progress of dementia are summarized as dementia drug treatment decisions^5,6.

1. Classification of dementia:

There are various clinical methods for classifying dementia, which are classified according to whether it is a degenerative disease; according to the cause, it can be divided into degenerative dementia of the nervous system and non-degenerative dementia. The former include Alzheimer's disease (AD), dementia with Lewy body (DLB), Parkinson's disease Parkinson disease with dementia (PDD), etc., the latter including vascular dementia (vascular dementia), normal pressure hydrocephalus, and dementia caused by other diseases^7-9.

2. Drug treatments for dementia:

At present, there is no definite and effective treatment for dementia. According to the guidelines of many countries, South, the anti-dementia drugs on the market are mainly divided into cholinesterase inhibitors (ChEI), such as donepezil, rivastigmine, galantamine, huperzine A; N-methyl -D-aspartate receptor antagonists, such as memantine hydrochloride; antioxidants, such as ginkgo leaf extract; nootropics, such as oxiracetam, piracetam, and aniracetam; ergot alkaloids, such as dihydroergoline mesylate, nicergoline; the intestinal axis-targeting drug mannate sodium (GV-971), a new drug independently developed in China and a monoclonal antibody targeting amyloid-β (AB) Aducanumab. Search the National Medical Products Administration, the U.S. Food and Drug Administration (FDA), and the National Medical Insurance^10-12.

2. 1 N-methyl-D-aspartate receptor antagonist:

Memantine hydrochloride is an excitatory amino acid receptor antagonist. It has the characteristics of low affinity and non-competitiveness, which can reduce the excitatory neurotoxic effects of glutamatergic and protect neurons to improve learning and memory disorders^12-13. Research results show that memantine hydrochloride has a negligible impact on patients with moderate and severe AD but has no effect on patients with mild AD. It has little clinical impact on the behavior and emotions of patients with vascular dementia (VaD), PDD, and DLB. It has little effect on the behavior and emotions of patients with VaD, PDD, and DLB. More experimental data are needed for further research^14,15.

2. 2 Cholinesterase inhibitors:

Increase acetylcholine levels in patients by inhibiting cholinesterase, thereby improving cognitive and behavioral disorders and delaying disease progression. ChEI has been recommended by many domestic and foreign guidelines and expert consensus to improve cognitive impairment in patients with AD, PDD, DLB, or VaD. 2. 2. 1 Donepezil is a reversible, non-competitive ChEI widely used clinically. The results of 2 systematic reviews showed that the efficacy of donepezil ten mg/d in treating mild, moderate, or severe AD is slightly higher than five mg/d. High-dose (23 mg/d) donepezil can also be used to treat severe AD, but the incidence of adverse reactions increases. Increase. In addition to AD, donepezil has been widely used clinically for the treatment of cognitive dysfunction in patients with PDD, DLB, and VaD. Katsayal et al.^16,17The results of the systematic review and meta-analysis show that treatment with donepezil positively impacts cognitive function, behavioral disorders, and other aspects of patients with PDD, DLB, and VaD.

2. 2. 2 Rivastigmine A highly selective ChEI with double:

Heavy inhibitory effect. Rivastigmine is currently available in two dosage forms: capsules and patches. Sridhar et al.¹⁸ have shown that oral formulations of rivastigmine are beneficial in cognitive impairment and executive function in patients with subcortical VaD and PDD. Rivastigmine transdermal patch was approved for marketing in China in 2017. Compared with oral preparations, rivastigmine transdermal patches delay the peak time, reduce fluctuations in blood concentration, and provide a continuous and stable route of administration, thereby reducing the occurrence of gastrointestinal and other adverse reactions. Patients with poor oral ChEI effects Can benefit from rivastigmine transdermal patch treatment and improve compliance^20-21.

2. 2. 3 Galantamine is an alkaloid derived from Lycoris plants.

Reverse ChEI is highly selective for the brain, well tolerated, and adverse reactions few. It is mainly used clinically to treat patients with mild and moderate AD. Several studies show that galantamine has a vital role in the recognition of AD patients. Changes in knowledge, living ability, and behavioral abilities have specific therapeutic effects, but sufficient evidence is still needed ^22-23.

2. 2. 4 Huperzine:

Under the name "Qian Ceng Ta," Huperzia serrata has been used in traditional Chinese medicine to treat schizophrenia, inflammation, swelling, poisoning, pain, and memory loss²⁴. China has conducted extensive research on every aspect of H. serrata's characteristics, and most of its biological action seems to be attributed to the chemical Huperzine A (HupA). HupA is an alkaloid compound that is unsaturated sesquiterpene and can cross the blood-brain barrier (BBB). It functions as an AChE inhibitor that is selective, reversible, and mixed-competitive. Its half-life in the bloodstream is 5 hours, reaching its peak concentration in humans at around 60 minutes. Its calculated t½ is approximately 4-5hours. A is a natural sesquiterpene alkaloid extracted from the Chinese herbal medicine Huperzia serrata. It has the advantages of low toxicity and high efficiency. Compared with other ChEIs (donepezil, rivastigmine), Huperzine A has. It has more substantial penetration in the blood-brain barrier and a more prolonged inhibitory effect, which can significantly improve AD patients' memory and cognitive impairment. It has a low incidence of adverse reactions, has good clinical safety, and can be used as a clinical reference.^24-25

In addition to treating AD, huperzine A is currently widely used clinically to treat VaD, which can significantly improve the memory and cognitive functions of VaD patients^26,27.

2.3 Memantine hydrochloride combined with cholinesterase inhibitors:

is suitable for patients with moderate and severe AD, especially those with obvious mental behaviors. For symptomatic patients with severe AD, combination therapy is more effective than ChEI monotherapy in improving patients' cognition and overall clinical condition. It has been recommended by many domestic and foreign guidelines^7,10. The combination therapy of ChEI and memantine hydrochloride is currently one of the standard treatments for moderate and severe AD²⁷. Research results show that for patients with moderate to severe AD, memantine hydrochloride combined with ChEI treatment has better clinical efficacy and higher safety compared with ChEI alone^28-29

2.4 In addition to ChEI, memantine hydrochloride and their combination for the treatment of dementia:

other drugs in China are Other drugs such as ginkgo leaf extract, nootropic drugs, ergot alkaloids, etc., are also recommended in internal and external guidelines³⁰ for anti-dementia treatment.

2. 4. 1 Ginkgo leaf extract is essential to improve brain metabolism:

It contains ginkgo flavonoid glycosides, terpenoid lactones, etc. Muller et al.³⁰ found that Ginkgo biloba extract can effectively improve cognitive symptoms and memory impairment in AD patients and can also be used to treat VaD. Some experts³¹ believe that based on the existing data, Ginkgo leaf extract has the role of an intervention strategy in multiple fields of mild cognitive impairment management, but whether the timing, dosage, course of treatment, and long-term treatment of Ginkgo leaf extract are There is a lack of a large amount of research and data on the potential for continued improvement or stable benefits, and further targeted research in these areas will be a hot topic in the future.

2. 4. 2 Nootropics: A class of drugs that selectively act on the hippocampus and brain:

Cortex, drugs that speed up the recovery of neurological function. Oxiracetam can improve cerebral metabolic disorders caused by cerebrovascular damage, has a specific neuroprotective effect, and is often used clinically in VaD patients³². Piracetam is clinically used to treat brain dysfunction and cognitive dysfunction caused by cerebrovascular accidents and other reasons and has the effect of enhancing memory³³. At present, there are few studies on the use of piracetam in patients with VaD. The routine use of piracetam in the treatment of VaD is not recommended. In the future, more researchers are needed to research the effectiveness and safety of nootropic drugs in the treatment of dementia.^34,35.

2. 4. 3 Ergot alkaloids Nicergoline is a semi-synthetic ergot alkaloid:

Alkaloids, studies have shown that nicergoline alone, compared with huperzine A, showed No significant difference in clinical efficacy found in VaD treatment. In terms of direct medical costs, the difference varied with dose^35-36. The effectiveness and cost of nicergoline are similar to those of huperzine A, so it is a valuable supplement. Dihydroergotine mesylate is the earliest dihydroergotine drug on the market in my country. It can be used clinically for VaD to improve the cognitive function of patients with cerebrovascular disease³⁷. There are few studies on the use of ergot alkaloids in anti-dementia treatment at home and abroad. In the future, more data will be needed to confirm their effectiveness and safety in treating dementia.

2.4.4 Monoclonal antibodies targeting amyloid-β (Aβ) Aβ:

This hypothesis is one of the currently recognized pathogenesis mechanisms of AD. Aducanumab is a human IgG1 monoclonal antibody that selectively targets soluble Aβ oligomers and can significantly reduce amyloid plaques³⁹. The US companies Biogen and Eisai announced that the trial failed on March 21, 2019, but applied for FDA approval for marketing on October 22, 2019, after reanalyzing the trial data⁴⁰

On June 7, 2021, the FDA approved the biologics license application for Aducanumab to treat patients with early-stage AD through the accelerated approval pathway. The trade name is Aduhelm. This is the first new drug to treat AD approved by the FDA since 2003 ⁴¹.

Whether the current academic evidence for Aducanumab proves its effectiveness and safety is still controversial^42-43, and the FDA requires Bogen to conduct a clinical trial after approval to verify the drug’s clinical benefits. If trials fail to demonstrate clinical benefit from aducanumab, the FDA may initiate proceedings to withdraw approval of the drug. Although there is a lack of solid evidence for Aducanumab’s ability to delay patients’ cognitive decline, and its safety has been questioned, the approval of Aducanumab brings a glimmer of hope to AD patients and their families. Also, it brings excellent impetus to the development and innovation of new drugs in this field. Motivation is a revolutionary breakthrough in the fight to prevent the occurrence and development of dementia.

3 Dementia drug treatment options and progress:

3.1 Mild dementia:

3. 1. 1 Selection of therapeutic drugs:

At present, my country’s national drug supervision and administration drugs approved by the bureau and FDA for mild dementia include ChEIs, nootropics, ergot alkaloids, and the newly approved GV-971 and Aducanumab. Among them, the most widely used drugs in clinical practice are ChEIs. A large amount of data has confirmed that they are effective in patients with mild dementia and have many tolerable adverse reactions. Domestic and foreign guidelines recommend them. Nootropic drugs and ergot alkaloids have been approved for mild to moderate VaD indications in China, as well as Ginkgo biloba extract, nimodipine, aniracetam, and other drugs whose instructions do not mention indications for specific stages of dementia, as well as the two newly approved conditionally approved new drugs GV-971 and Aducanumab. Research data on the effectiveness of these drugs is still lacking, and more research is needed to confirm their ability to delay cognitive decline in patients⁴⁴.

3. 1. 2 Pharmaceutical Monitoring The current instructions for ChEI drugs and existing:

Adverse reactions reported in the literature include nausea, vomiting, diarrhea, headache, dizziness, etc. ⁴⁴. Research by Zhang Lifeng ⁴⁵ shows that the adverse reactions of rivastigmine are mainly gastrointestinal, more than donepezil, and can disappear independently after reducing the dose. It is recommended that the dosage of rivastigmine for Chinese AD patients is six mg/d. Donepezil can increase gastric acid secretion, and symptoms of gastrointestinal bleeding should be closely monitored during treatment, especially in patients with an increased risk of ulcers. Because these drugs can cause dizziness, you should avoid driving or operating machinery while taking them. Domestic and foreign guidelines recommend that when a specific ChEI drug is ineffective or cannot be tolerated due to adverse reactions, other ChEIs, other administration routes, or other types of drugs can be used based on the patient’s condition and the degree of adverse reactions. Carry out treatment and closely observe the patient’s possible adverse reactions during the treatment process.

In the drug metabolism of ChEI drugs, there are relatively few mechanical interactions, mainly with CYP2D6 and CYP3A4 inhibitors or inducers. Rivastigmine is the only drug that does not interact with others. Adverse reactions are high, and the safety of donepezil combined with memantine hydrochloride treatment is good ^46-48. If the patient is severely intolerant, the safer memantine hydrochloride monotherapy can be used. Nootropic drugs, ergot alkaloids, etc., can be used as auxiliary treatment drugs and are recommended by guidelines, but there is a lack of evidence. More relevant research is needed to prove theffecttiveness and safety of these drugs in combination with other drugs. When single-drug treatment is ineffective for moderately severe patients, especially severe patients with obvious mental and behavioral symptoms, combined treatment options can be considered, and patients should be informed of the benefits and possible adverse reactions of combined treatment. Clinical pharmacists should pay close attention to patients who take combination therapy, and the combination of ChEI drugs and memantine hydrochloride with evidence-based evidence is the first choice. For patients who cannot tolerate it, they should promptly adjust the dosage regimen and use other anti-dementia drugs with caution ⁴⁹.

CONFLICT OF INTEREST:

None.

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Received on 21.08.2022 Modified on 16.09.2023

Research J. Pharm. and Tech 2024; 17(4):1674-1678.

DOI: 10.52711/0974-360X.2024.00265