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Senile Dementia

Recent advances in the research of the Alzheimer’s disease have broughtnew drugs for treating the cognitive decline of elderly demented patients. The acetylcholinesterase inhibitors have found a place for the symptomatic treatments of these patients. Other drug classes such as the muscarinicagents seem to be less promising due to severe side-effects. Older nootropicdrugs such as derivatives of the ergot alkaloids seem to have only marginaleffects.
 

1. Introduction
The objectives of drug treatment of the cognitive decline seen in theAlzheimer’s disease aimed at improving several areas (1.Pryse-Phillips,1999):

1. to improve the patient’s ability to pursue his daily activitiesand obligations
2. to improve the patient and the family members, taking care of him,to feel better and happier, and fulfill a more harmonious life
3. To improve the patient’s memory and other mental capacities such as recognizing his familiar environment.

2. 1 The acetylcholinesterase inhibitors

The brain of a patient suffering from Alzheimer’s disease has too littleacetylcholine, which has an important modulating function in the brainof a normal person. The acetylcholinesterase inhibitors slow down the inactivationof acetylcholine. Hence, the level of this neurotransmitter is raised inthe brain of a patient suffering from the Alzheimer’s disease. This patientwill get an improved cognition and better functioning in his daily activitiesand maintain longer his ability to care for his basic activities such astoiletting.

Four drugs of the acetyl cholinesterase inhibitor group are alreadyintroduced in many countries. They are donepezil, finasteride, tacrine,and huperzine, the latter not developed according to Western standard (exceptmay be in China). A fifth one, galantamine will soon be available in Europe.

2.1.1Donepezil (ARICEPT)
Donepezil has been introduced in Thailand by the drug-company Esaiin 1998. The efficacy of this drug has been demonstrated in two importantpivotal studies, one lasting 14 weeks and the other 30 weeks. (2. RogersSL, 1996) (3.Rogers SL, 1998). An open extension study from that one lasting14 weeks has demonstrated that the effect is maintained during 58 weeks.5 – 10 mg donepezil taken once daily had no hepatotoxic effect and a lowprevalence of adverse effects associated to the autonomic nervous system.This very good tolerability has positioned donezepil as the leading drugin its group. (4.Gauthier, 1999). The improvement of three points on theADAS-Cog, compared to placebo is appraised to be statistically highly significant(P less than 0.0001). After 6 months of treatment, about half the patientsshowed an improvement and 35% had a stabilization of their condition. Ifone considers an other aspect of efficacy of that drug, 20 % of patientswith active drug and 42  % of patients with placebo showed worseningduring the course of the study. However, if one considers more stringentcriteria such as an improvement of 7 points on the ADAS-Cog scale, 8% underplacebo and 15% under donepezil reached that requirement. (1.Pryse-PhillipsW, 1999) The long-term improvement shown in patients under this drug canbe documented up to 4years and half.  (5.Aertzte-Zeitung  1998)
Side-effects:
The side effects with donepezil are generally transitory and of mildto moderate severity. The most frequent ones are nausea, vomiting, fatigue,muscle cramps, and dizziness. About 10% of patients on the average areaffected, the rate being higher among patients receiving the higher doseof 10-mg donepezil.
Dosage:
The recommended dose of donepezil (ARICEPT) is 5 mg per day and uptitrate to 10 mg after 1 month as a minimum.
Indication:
Donepezil or Aricept is indicated for Alzheimer's disease. Its useis associated with modest improvements in memory and learning, but it doesnot slow the disease's progression. (6.Virtual drugstore)
2.1.2 Rivastigmine (EXELON)
Rivastigmine from Norvatis has been introduced in Europe in 1998, inThailand 99, and it is currently in its introduction phase in the USA.
The efficacy of rivastigmine was particularly demonstrated in a programof clinical studies, the ADENA program run by R. Anand (7. 1996) this program included 4 pivotal studies aimed at overcoming the weaknesses of the standard clinical trials run before:
 Small number of patients
 Short-duration of treatment
 Restrictive entry criteria
 The ADEMA program included more than 2000 patients receiving6-12mg rivastigmine twice a day during 6 months. (8. Schneider, 1998) (9.Winblad B, 1999)
Hence, the patient base was here larger than that of donepezil to document clinical efficacy. (10.Burns, 1999) The efficacy was measured with thefollowing rating scales: ADAS-cog, CIBC-plus and the PDS (Progressive Deterioration Scale) specifically measuring the activities of daily life. The resultsof these studies showed that 21% of patients under active drug improvedcompared to 12 % under placebo. The respective figures on the other scaleswere 29% versus 18% on the CIBC-plus, and 26% versus 17% on the PDS. Theimprovement was maintained up to 40 weeks of treatment, particularly inpatients with higher doses of active drug. (11. Corey-Bloom, 1999)
Side-effects:
The most common side-effects found in more than 5% of patients andtwice as frequent as in placebo were: asthenia, anorexia, dizziness, nausea,somnolence, and vomiting. The contra-indications are known hypersensitivityto rivastigmine or to any substance contained in the tablet.
Special warnings:
The drug should be used with special caution in patients with cardiacproblems, those who are predisposed to ulcerative conditions, those havinga history of asthma or obstructive pulmonary disease. Also, patients whotend to have urinary obstruction and seizure must be monitored carefully.(12Corey-Bloom, 1998)
Dosage:
The recommended maintenance daily doses are 3-12mg. Uptitration shouldstart with 1.5mg twice a day and increased by 1.5mg per dose after a minimumof 2 weeks up to a maximum of 6 mg per dose or up to highest well-tolerateddose. During the uptitration phase nausea and vomiting can occur. One shouldbe watchful to weight loss. (35. Novartis Information on EXELON)

2.1.3 Tacrine (COGNEX)

Tacrine (COGNEX) from Warner-Lambert was the first central acting reversible acetylcholinesterase inhibitor having been marketed in the USA since 1993. Titration of the drug and monitoring the liver function is complicated.Furthermore, due to its hepatoxicity and the high dropout rate, becauseof severe side effects, this drug is not recommended for routine use. (1.Physe-Phillips, 1999) (10.Burns, 1999)
However, the main benefit of that drug to patients was to pave theway for other acetylcholinesterase inhibitors in the USA and the world,which are much better tolerated.

2.1.4 Huperzine A (HupA)
Huperzine A (HupA) is an alkaloid, inhibitor of acetylcholinesterase,extracted from the club moss (Huperzia serrata). It has been used for itsmental improving performances in China since centuries. It produces memorystimulation in animals and humans. Furthermore, it may also have neuroprotectantactivity. (13.Bai DL, 2000) (14.Skolnick AA, 1997)  There are clinicaldata from China showing that 60% of patients with Alzheimer’s disease underthe active drug showed improved performance in memory and behavior comparedto 36% under placebo after 8 weeks of treatment. (15.www, Homestead) Little is known in the West, concerning details on those clinical trials,which are written in Chinese. However, extract is already available inmany countries from many sources. For instance, an extract of 50mcg ofhuperzine to be taken twice daily is available in the US as an herbal nutritionalsupplement. This category of drugs is not submitted to the stringent requirementsof the US FDA controlling efficacy and safety of medical drugs. However,huperzine raises considerable interest in the West and many research projectsare on going. (16.www, alzforum, 2000)
 

2.1.5Acetylcholinesterase inhibitors in advanced stage of development
2.1.5.1Galantamine (REMINYL)
Galanthamine from Shire and Janssen(the latter company a subsidiaryof Johnson&Johnson) is an alkaloid extracted from a flower called snowdrop (Galanthus woronowii) . However, now the substance is produced synthetically.It is an acetylcholinesterase inhibitor, which also modulates neural nicotinicreceptors. The clinical relevance of that latter property is not yet established.May be it could slow down the disease progression. To-date, little is knownabout the results of clinical research. According to highlights from the6th International Conference on Alzheimer’s disease, about half of patientssuffering from mild to moderate forms of the diseases have either slightlyimproved cognitive performances or the worsening was less than the controlpatients with placebo after 1 year of treatment.
 Little is known about its clinical properties. According to theinitial data (unpublished) reported at the 6th International Conferenceon Alzheimer's Disease and Related Disorders, half of patients with mildto moderate forms of this disease have cognitive scores maintained at orabove baseline during one year of treatment. Without treatment, these patientsusually worsen.
 Dosage:
The daily dose is from 22.5mg – 45mg per day
Side effects: The most common side effects are nausea, vomiting, andother cholinergic effects (~10% in patients with active drugs vs. 5% ofcontrols with placebo). Most side effects occur during the early weeksof treatment. (17, www, alzforum) (18.Fulton B, 1996) (19. Bores GM, 1996)(20.psychiatry-medscape, 2000)

2.1.5.2Metrifonate from Bayer is an irreversible acetylcholinesterase inhibitor, different from the others described in this report which arereversible inhibitors. It produces higher level of acetylcholinesteraseinhibition than the reversible ones. (21. Becker, 1996)
1757 patients suffering from mild to moderate Alzheimer’s disease have been included in four double-blind placebo controlled clinical studies.The inclusion criteria were the NINCDS-ADRDA criteria for probable Alzheimer’s disease.
550 patients received placebo and 1207 patients got active drug withloading doses ranging from 25mg up to 180mg once-daily during 2 weeks,followed by maintenance doses ranging from 10mg up to 60 mg during 12 or24 weeks. The primary efficacy measurements were in all 4 studies: ADAS-Cogmeasuring the cognitive performance of the patients and the CIBC Plus,measuring global performances, based on care-givers reports of behavioraldisturbances. Secondary efficacy variables were Neuro-Psychiatric Inventory(NIP), the Disability Assessment in Dementia (DAD), and the Global DeteriorationScale (GDS).
Significant improvement was shown on the ADAS-Cog scale. After 12 weeksof treatment in patients on higher doses, the difference between the activedrug treated patients were 2.98 points on the ADAS-Cog scale compared tothose treated with placebo which correspond to a delay of the progressionof the disease progression of 5 months. The side effects were generallyacceptable, involving the gastrointestinal tract. However, concerns onthe drug safety lead the American FDA to put the registration of that drugon hold, awaiting clarification on 5 patients with respiratory paralysiswhile treated with that drug. (22. www,alsforum, 2000)

2.1.6Other Cholinesterase Inhibitors

Other cholinesterase inhibitors formerly in clinical trial are either discontinued or seem to be in no further active development (22. Alzheimer’s Research Forum, 2000) Dropped projects are physostigmine from Forest, velnacrine and possibly eptastigmine from Mediolanum due to potential adverse hematological effects.
Icopezil from Pfizer seems to be in no further development activities.

2.2 The Muscarinic Agonists

The muscarinic agonists increase the availability of acetyl-cholineat neuronal synapses, as do the acetylcholinesterase inhibitors. In addition to that it was hoped that some drugs of this drug family could slow downthe disease progression in altering the amyloid precursor protein (APP)processing. But the development of many muscarinic agonists was discontinued,including those of which clinical progress was most advanced: let us mentionmilameline developed by Hoechst-Marrion-Roussel and Warner Lambert. Milameline induced severe cholinergic symptoms, particularly at higher doses of 2 – 3 mg doses.Due to poor tolerability the development has been discontinued. (23. SramekJJ, 1995)  (24.Alzheimer Forum2000) (25. www, aafp Arzeneimittelforschung)
 SB-202026 developed by Smith Kline and Beecham has alsobeen discontinued. The oral formula of xanomeline developed by Novo Nordiskand Lilly had a significant effect on the ADAS-Cog rating scale and onthe CIBC. SB-2026 was particularly and highly significantly effective onthe behavioral non-cognitive symptoms such as vocal outbursts, suspiciousness,delusions, agitation and hallucinations. Nevertheless, the developmentof its oral formulation has been discontinued, because of unacceptabletoxicity. There is still a transdermal formulation in development, whichmay be better tolerated. (26. Bodick, 1997) (27.Alzheimer Forum 2000)
Kayaku in Japan and Teva in Israel develop AF 102B. It is anA M1 selective agonist, which may increase secretion of amyloid precursorprotein in humans. It may also decrease the phosphorylation of the tauprotein. Therefore it may have disease-modifying properties. Some clinicalresults suggest that it is significantly effective on cognitive symptoms.But little clinical results have been published as yet. (Fisher 1996)(29.AlzheimerForum 2000)

2.3 Other drugs

Under the category other drugs, we will just briefly consider drugsprescribed for the cognitive symptoms of the elderly patients. They haveshown some benefits on the cognitive symptoms but with no definite proofof efficacy. If relevant, some of those drugs will be more thoroughly describedin a next paper because they have shown properties of slowing down thedisease progression.
Dihydroergotamine (HYDERGINE) from Novartis is an ergot alkaloid. It is available in many countries. It may improve the blood circulationin the brain and stimulate glucose metabolism. However, in the AmericanPhysician’s Desk Reference (30), there is a statement of only possiblymild efficacy of the drug, not definitely demonstrated, in the treatmentof cognitive performance in cerebrovascular diseases. Ergoloid mesylatesmight show activity in some psychometric and behavioral tests, the globaleffect did not reach statistical significance. Therefore, the efficacyof this drug may be questionable and it cannot be recommended for routinetreatment of demented patients. (31)
Gingko Biloba: is the name of a tree of Chinese origin, butgrowing in many countries with temperate climate. The active substancesreferred as Egb 761 are extracted from the leaves. Patients receiving 30mgtwice a day of this extract during 12 weeks have shown an improvement onthe ADAS-Cog score of 1.4 improvement, which is at the limit of significance.Better results were reached in daily activities and social conduct. (32.LeBars PL, 1997)
Nicergoline from Krewel is an ergot alkaloide with metabolic(i.e. stimulating oxygen consumption by mitochondria), antithrombotic andvasoactive action. Patients with Senile Dementia (Vascular Dementia, Alzheimer’s disease and mixed condition) were treated during 12 months with 30-mg nicergoline twice a day. Some benefits have been shown in cognition and the drug wasvery well tolerated. (33. Nappi G, 1997)
Memantine from Merz is the first NMDA-antagonist having provenefficacy in Senile Dementia with good tolerability. In two published trialsmemantine has show spectacular results in patients with severe dementia,improving cognitive and non-cognitive functions. The patients were lessaggressive, functioning better socially and requiring less care. (34. Winblad,1999) This drug will be more thoroughly discussed in a next paper presentingthe subject of neuroprotection and disease modifiers in Senile dementia.

3.Conclusions

Do we have a drug for the treatment of Alzheimer’s disease? Pryse-Philips (1., 1999) estimated that the efficacy criteria for a drug of 3 pointsimprovement on the ADAS-COG scale compared to placebo, usually selectedby clinical research statisticians, were not significant on a clinicalpoint of view. He estimated that a 7 points difference would be clinicallymore meaningful. Only 15% of patients treated by acetylcholinesterase inhibitorsversus 8% patients under placebo reached that level of response. He concluded,that it was premature to speak about an effective drug to treat the Alzheimer’sdisease.
Gauthier (4., 1999) considered other aspects on this issue. There werenotable improvement in some patients who returned to past activities, lessresponse in some other patients, the drugs stabilizing the condition ofthe patients for about 1 year. These improvements justified the use ofdrugs.

The author of this paper favors the opinion of Prof. Gauthier, because all the Alzheimer’s disease research open up new opportunities to better understand the memory and other cognitive functions. The knowledge willbuild up in a know- how of better brain management. As vision of the future,brain clinics will arise, where every person aged 50 years or more wouldbe recommended to go to and learn how to optimize one’s brain potential,and thus contributing to a better quality of life for a growing proportionof the aging populations.

References:

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