JAPAN IS NOW enjoying the longest life span in the world (83 years old in 2010). Accordingly, the ratio of the elderly population (65 years old and above) is the highest in the world (23% in 2010), and the ratio of the late elderly population (75 years old and above) is also the highest in the world (10% in 2010). Furthermore, Japan spent just 24 years in transit from an aging society to an aged society, which is the fastest transition in the world. Considering these aspects, Japan is seen as the world top runner in terms of society aging.1
Alzheimer's disease is considered the most ‘malignant’ disease in this century, considering the high prevalence rate, the degree of disability and dysfunction, and long duration of the disease. Alzheimer's disease is a neurodegenerative disorder characterized by progressive deficits in memory and cognitive function, together with impairment in the ability to perform activities of daily life. Behavioral problems and psychiatric symptoms are also frequently associated with Alzheimer's disease.2
Due to the rapid aging of the Japanese society, there are 1.16 million patients with Alzheimer's disease in Japan, which is 4% of the elderly population (28.74 million) in Japan in 2010. The number of Alzheimer's disease patients in Japan is expected to increase to 1.42 million in 2015, 1.67 million in 2020, and 2.2 million in 2025. The prevalence of Alzheimer's disease has increased the need for research aimed at identifying the risk,3,4 pathogenesis,5–8 diagnosis,9 drugs,10,11 non-pharmacological intervention,12–15 care,16–18 and support19,20 for this disease. A diverse range of compounds has been evaluated as potential treatments for Alzheimer's disease, and five compounds have been approved in the world for the treatment of Alzheimer's disease.
This review will focus on the pharmacological properties of cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) and an N-methyl-D-aspartate (NMDA) antagonist (memantine), which are used for the symptomatic treatment of Alzheimer's disease, because rivastigmine, galantamine and memantine have finally been approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan for the symptomatic treatment of Alzheimer's disease this year.
Tacrine, the prototypical cholinesterase inhibitor for the treatment of Alzheimer's disease, was the first centrally acting cholinesterase inhibitor approved by the Food and Drug Administration (FDA), USA, for treatment of mild to moderate Alzheimer's disease, and was marketed by Warner–Lambert under the trade name Cognex in 1993. Studies have found that it may have a small beneficial effect on cognition and other clinical measures, though adequate study data is limited and the clinical relevance of these findings is unclear. The use of tacrine is limited due to poor oral bioavailability, the necessity for four-times daily dose, and considerable adverse drug reactions (including nausea, diarrhea, urinary incontinence and hepatotoxicity) such that few patients could tolerate therapeutic doses. Tacrine is not developed in Japan and it is no longer used worldwide since the introduction of newer cholinesterase inhibitors (Fig. 1).
The phase 1 trial of donepezil was started in Japan in 1989, and in the USA in 1991. The FDA approved donepezil for treatment of mild to moderate Alzheimer's disease in November 1996. Three years later it was approved by the PMDA of Japan (November 1999) and was marketed by Eisai and Pfizer under the registered name of Aricept. Owing to the superior properties of donepezil, such as (i) significantly less hepatotoxicity; (ii) high selectivity to acetylcholinesterase (AChE) inhibition (IC50 = 6.7 nM vs butyrylcholinesterase [BuChE] inhibition [IC50 = 7400 nM]); and (iii) long duration of action (t1/2 = 90 h), donepezil has been widely used to treat Alzheimer's disease patients worldwide. In 2006, donepezil was prescribed in more than 75 countries and regions in the world, and occupied 56% of the entire sales market of drugs for Alzheimer's disease. In 2007, donepezil was approved for its use for severe Alzheimer's disease and the FDA approved a higher-dose 23-mg tablet in 2010.
Alzheimer's disease is associated with loss of cholinergic neurons in parts of the brain. Acetylcholinesterase inhibitors, such as donepezil, delay the breakdown of acetylcholine released into synaptic clefts and so enhance cholinergic neurotransmission. Donepezil is beneficial for patients with mild, moderate and severe dementia of Alzheimer's disease, showing improvements in cognitive function and activities of daily living. Adverse effects were consistent with the cholinergic actions of the drug and were the most likely cause of withdrawal from treatment in the first 12 weeks. Effects on cognition remained measurable and statistically significant at 52 weeks of treatment in one study. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total health-care resource costs. Benefits to patients on the 10-mg/day doses were marginally more significant than to those on the 5-mg/day doses. Taking into consideration the better tolerability of the 5-mg/day donepezil compared with the 10-mg/day doses, together with the lower cost, the lower dose may be the better option. The debate on whether donepezil is effective continues despite the evidence of efficacy from the clinical studies because the treatment effects are small and are not always apparent in practice, and because of the cost of the drug (Fig. 2).21
Rivastigmine was developed at the Hebrew University of Jerusalem and sold to Novartis for commercial development. It has been available in capsule and liquid formulations since 1997. In 2006, it was approved for treatment of mild to moderate dementia associated with Parkinson's disease and the rivastigmine transdermal patch was approved for the first patch treatment for dementia in 2007.
Rivastigmine is a cholinesterase inhibitor that inhibits both AChE and BuChE. In Alzheimer's disease, brain BuChE levels are reported to increase, whereas AChE levels decrease. BuChE is widely distributed in the brain regions affected in Alzheimer's disease, such as the temporal cortex, hippocampus and amygdala. This has led to the theory that acetylcholine metabolism may become more dependent on BuChE activity than on AChE activity as Alzheimer's disease progresses. The increase in BuChE activity may result from a combination of reactive gliosis and an accumulation of BuChE in neuritic plaques. It has been reported that the area of plaques displaying BuChE reactivity is five- to sixfold higher in dementia versus age-matched controls. It is thought that rivastigmine may function by inhibiting AChE and BuChE, leading to better improvement of cognitive function of Alzheimer's disease patients (Fig. 3).
Galantamine was originally extracted as a natural alkaloid from Galanthus elwesii, for AChE inhibitor activity in the Soviet Union in the 1950s. Galantamine was used for decades in Eastern Europe for various indications, such as treatment of myasthenia, myopathy, and sensory and motor dysfunction associated with disorders of the central nervous system, and it has been sold as a supplement for memory and dream support in the USA. The synthesized galanthamine hydrobromide was deployed by Janssen Pharmaceutica as the drug for Alzheimer's disease, and the galantamine tablet was approved by the FDA for Alzheimer's disease in February 2001. Galantamine solution was approved in July 2001 and the galantamine extended-release capsule was approved in 2003 aiming for once a day administration. Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimer's disease.
Galantamine shows specific inhibition of AChE and it also acts as the allosteric potentiation ligand (APL) of nicotinic receptor. Due to this APL effect, galantamine is believed to potentiate nicotinic receptor signals, which results in the increased release of transmitters, such as dopamine, norepinephrine, serotonin, gamma-aminobutyric acid and glutamate. Galantamine is shown to have the suppression of neurotoxicity by amyloid beta peptide (Fig. 4).
Memantine was first synthesized by Eli Lilly in 1968, and then developed by Merz in Germany, which is licensed to Forest for the USA and Lundbeck for selected European and international markets. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm. Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system. It is a voltage-dependent, moderate-affinity, uncompetitive NMDA receptor antagonist that blocks the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction. Glutamate aids in memory and learning at normal levels, but if levels are too high, glutamate may overstimulate nerve cells, leading to neuronal death by its toxicity.
Memantine is approved for treatment of moderate to severe Alzheimer's disease, and has now received a limited recommendation by the UK's National Institute for Clinical Excellence for patients who fail other treatment options. Within the new guidance, memantine is recommended as an option for managing Alzheimer's disease for people with moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE inhibitors or those with severe Alzheimer's disease. Despite years of research, whether memantine has any effect in mild to moderate Alzheimer's disease is unknown (Fig. 5).
BRIEF HISTORY OF ALZHEIMER'S DRUG DEVELOPMENT IN JAPAN
Historically, many drugs for improving cerebral metabolism and/or cerebral circulation were developed and widely used in Japan to treat dementia patients, including Alzheimer's disease and vascular dementia.22 Examples of cerebral metabolic enhancers include adenosine triphosphate, calcium hopantenate, cytidine5′-diphosphocholine, dihydroergotamine mesylate, gamma-aminobutyric acid, meclofenoxate, pyrithioxine and idebenone. Drugs for cerebral circulation are bencyclane, brovincamine, cinnarizine, cinepazide, cyclandelate, dilazep, flunarizine, moxisylyte, ifenprodil, tocopherol, kallidinogenase, pentoxifylline, trapidil and vinpocetine. Many of these drugs were evaluated for their efficacy in comparison with calcium hopantenate as the standard drug. When calcium hopantenate failed to demonstrate its efficacy to dementia patients in its re-evaluation, the Japanese Ministry of Health and Welfare denied approval of most cerebral metabolic enhancers and cerebral circulation enhancers in 1999. Most of those cerebral metabolic enhancers and cerebral circulation enhancers cited above were abandoned from clinical use, and only five compounds, nicergoline, nilvadipine, ibudilast, vinpocetine, ifenprodil, and aniracetam, remained on the market based on indications other than dementia or cerebral circulation insufficiency.
The new stage of pharmacotherapy for Alzheimer's disease was initiated by the introduction of donepezil in 1999. Donepezil was approved by the PMDA in November 1999, and was used to treat mild to moderate Alzheimer's disease patients. It was approved for severe Alzheimer's disease in 2007. Partly due to the actual increase in the number of Alzheimer's disease patients and also due to the better recognition of Alzheimer's disease in public, prescription of donepezil increased significantly during these 10 years. The sales of donepezil were estimated to be ¥100bn in 2010. As donepezil was the only drug available for Alzheimer's disease in Japan for 12 years, new drug options have been long awaited.
ALZHEIMER'S DRUGS RELEASED THIS YEAR IN JAPAN
Galantamine and memantine were filed for approval by the PMDA in February 2010 and rivastigmine was also filed 1 month later, in March 2010. As donepezil was the only drug to be used for Alzheimer's disease for more than 10 years in Japan, new drugs have been eagerly awaited by medical doctors, patients and families of patients. Pushed by public needs and also by public opinions issued by academic organizations and Alzheimer associations, the process of evaluation of these filed drugs for Alzheimer's disease was significantly accelerated. Eleven months after the filing, galantamine was approved by the PMDA on 21 January 2011, and galantamine was released on 22 March 2011, as the second drug for Alzheimer's disease. Considering the handling capacity of PMDA, it is unusual the approval was made after such a short period because 1.5–2 years is usually required for the PMDA to complete the evaluation process of a new drug. New drugs for Alzheimer's disease were approved after 11–13 months, which is probably due to the public need and the endeavors by the PMDA to hasten the evaluation process of new compounds for Alzheimer's disease.
The product (Remynil) is supplied in twice-a-day tablets (4 mg, 8 mg, and 12 mg), once-a-day extended release capsules (8 mg, 16 mg, and 24 mg), and in an oral solution (4 mg/mL). Janssen Japan together with Takeda Pharmaceuticals is co-promoting the product, under the brand name Remynil.
Memantine (Memary) was approved on 21 January 2011 and it was scheduled to be released on 18 March 2011. Due to the plant damage of Daiichi Sankyo Co. by the Great Eastern Japan Earthquake on 11 March 2011, however, the release of memantine (Memary) was postponed and it was released on 8 June 2011 in the form of Mamary tablets of 5 mg, 10 mg, and 20 mg.
Since the failure of clinical trials of rivastigmine tablets, Novartis Japan has switched from the oral tablet to the transdermal patch of rivastigmine. The data of rivastigmine patch clinical trials were filed for approval in March 2010 and it was approved by the PMDA on 22 April 2011. Novartis Japan will start selling rivastigmine under the brand name of Exelon Patch and Ono Pharmaceuticals Co. will do so under the name Rivastach Patch in July 2011.
WHAT CLINICIANS SHOULD KNOW TO SERVE ALZHEIMER'S PATIENTS BETTER
Aricept is distributed in tablets (3 mg, 5 mg, and 10 mg), oral disintegrant tablets (3 mg, 5 mg, 10 mg), fine granule (0.5%), and jelly form (3 mg, 5 mg, and 10 mg). Aricept is started with 3 mg once a day for mild to moderate patients. After 1–2 weeks, it is raised to 5 mg/day, which is the maintenance dose of Aricept for mild to moderate Alzheimer's disease patients. In cases of severe Alzheimer's disease, after maintaining a dose of 5 mg for at least 4 weeks, it is raised to 10 mg/day. Since donepezil has been used for 12 years in Japan, there have been enough data accumulated for its efficacy and adverse side-effects in Japan.23
Reminyl is used for mild to moderate Alzheimer's disease patients. It is started at 8 mg/day (a 4-mg tablet twice), and it is increased to 16 mg/day (an 8-mg tablet twice) and maintained for clinical effects. In case the 16-mg/day dose is not sufficient, it will be increased to 24 mg/day (a 12-mg tablet twice) after the 16-mg dose has been taken for at least 4 weeks.
Exelon Patch (Rivastach Patch) is available as a transdermal patch in a 4.5-mg, 9-mg, 13.5-mg, and 18-mg dose, which is indicated for mild to moderate Alzheimer's disease. It is started with 4.5 mg once a day and increased by 4.5 mg every 4 weeks and maintained at 18 mg/day.
Donepezil, galantamine, and rivastigmine are all AChE inhibitors, and some additional difference in mechanism of action is theoretically speculated. However, clinical data have not been reported indicating different target signs and symptoms of Alzheimer's disease patients among these three drugs. Even though there is a possibility that some patients are responsive to some AChE inhibitors and others are not,24 the choice of these drugs may be determined mainly by the tolerability of the patients. Especially for the patients who have difficulty in per-os medication, the transdermal patch of rivastigmine is used.
Memary is indicated for moderate to severe Alzheimer's disease, which is started at 5 mg once a day. It is increased by 5 mg per week and the maintenance dose is 20 mg/day. As memantine is an NMDA antagonist acting on glutamatergic receptors, it could be used with AChE inhibitors.
It should be noted that all of these drugs (donepezil, galantamine, rivastigmine, and memantine) do not suppress the pathological process of Alzheimer's disease, which implies that patients treated by any of these drugs still show deterioration due to the disease process.
Considering the limitations of the drugs available, clinicians should be prepared for the progression of the disease of the patients in the long run. Controlling of behavioral and psychological symptoms of the patients is important for the family and caregivers of the patients.11,18,25–29 Non-pharmacological intervention,12–14,30 a care program,31 and support of the patients and family19,32 will be even more important for the treatment of Alzheimer's disease patients.