Clinical trials ongoing.....; ......IFPMA........., another address

What are the treatment options?

There is presently no cure for Alzheimer's disease, but vaccination could change all that. However, treatments are already available to help manage the symptoms. Tacrine was prescribed to improve the memory impairment in Alzheimer's disease, but it had to be administered under close medical supervision because of side effects. New products with less side effects are now at disposal (Aricept, Exelon, Memantine, Reminyl). Research is ongoing, and other experimental treatments are currently being tested in multicenter clinical drug trials. These treatments are designed either to improve cognition or to slow the rate of decline. There are also many medications available for the behavioral symptoms associated with Alzheimer's disease, including antidepressants and drugs to control the agitation, anxiety and delusions. Antidepressants must be administrated by skillfull neurologists, because some of these drugs provoke catastrophic side effects.

AIT-082 (NeoTherapeutics Inc, Phase II ) It can cross the blood-brain barrier and enhance nerve cell function by increasing levels of neurotrophic factors.

Purine derivative. Named "Neotrophin". http://www.clinicalstudies.net/releases/neothera.html ><http://www.pslgroup.com/dg/3362e.htm

alpha-tocopherol, an anti-oxidant

ALZHEMED (see tramiprosate)

Anti-oxidants

Apomorphine HCl Pentech Pharmaceuticals Phase II

Aricept (E-2020) (DONEPEZIL) Eisai Co Ltd. Acetylcholine inhibitor.Phase III finished. Commercialized. Molecular mechanism

ATG-Z1

CoMentis BACE1 inhibitor Preclinical

AVIVA (linopirdine)

Du Pont Merck cognition enhancement Phase III

AXURA http://www.merz.com/    http://www.memantine.com

see Memantine

AZD-103 T

ransition Therapeutics/Elan Inhibits Aβ fibrillization and disassembles preformed amyloid fibrils Phase I

BC-PS (phosphatidylserine) Fidia Pharmaceutical Phase II

beta sheet breakers: anti-amyloid. See the litterature from Ghizo.

Besipiridine HCl (HP 749) Hoechst-Roussel Phase II/III 

cevimeline (AF-102B) Snow Brand Milk Products M1 agonist Phase III 

Cholinesterase inhibitor Marion Merrell Dow Phase II 

Clioquinol

11 April 2005. Sometimes it is not the drug that scuppers a clinical trial. Prana Biotechnology announced today that it is halting the much anticipated phase II/III clinical trial of its Alzheimer drug PBT1—before it even starts (see statement on Prana website).

Cl-979 (see Milameline) 

A) Cognex (tacrine) Acetylcholine inhibitor. Warner-Lambert . Commercialized for hospitals

B) Cognex. The point of view of Parke-Davis     Molecular mechanism

CX516 

DAD 2000. " Dapsone in Alzheimer Disease 2000" (DAD2000) Phase II clinical trial. Company Contact: Rupinder Bagri, Corporate Communications
Immune Network Ltd. 3650 Wesbrook Mall, Vancouver, BC, Canada V6S 2L2

DHEA. Neuroscience Pharma Inc. Neurosteroid. Phase III clinical  See Beaulieu and Forette, 

Donepezil (E2020) (Aricept). Acetylcholine inhibitor. Eisai. Commercialized

Donepezil on an other site ...........About Eisai  Molecular mechanism

E2012 Eisai γ-Secretase inhibitor Phase I

E-2020 (see Aricept or Donepazil). Acetylcholine inhibitor. Eisai  Molecular mechanism

EHT202 from ExonHit Therapeutics: Phase II in preparation. Action on the stimulation of the secretion of sAPPalpha, a neuroprotectant.

Eldepryl (Selegiline), an anti-oxidant 

ENS-163 Sandoz Phase I 

ENA-713 (Exelon) Novartis Phase III. Sandoz. ....Acetylcholine inhibitor. Commercialized Molecular mechanism

Eptastigmine (MF-201) Mediolanum Pharmaceuticals Phase III 

Estrogens : Could be a neuroprotector, but therapeutic trials are not that good.
Des espoirs, mais non confirmés actuellement. 

Exelon (ENA-713, Rivastigmine) Acetylcholine inhibitor. Novartis. Commercialized. Molecular mechanism

FK-508 Fujisawa Pharmaceutical Co Ltd Phase II 

FLURIZAN:(from Myriad) MPC-7869 ((R)-flurbiprofen) is a single enantiomer of flurbiprofen, which has been shown to lower brain levels of a toxic form of beta amyloid (Aß42) in a model of Alzheimer's. Clinical phase II done and now clinical trial Phase III

FLURBIPROFEN: MPC-7869 ((R)-flurbiprofen) is a single enantiomer of flurbiprofen, which has been shown to lower brain levels of a toxic form of beta amyloid (Aß42) in a model of Alzheimer's.

Lowers Aβ42 production by selectively modulating, but not inhibiting, γ-secretase activity to shift cleavage of amyloid precursor protein (APP) away from Aβ42 production toward shorter, less toxic peptide fragments. Selective modulation allows for γ- secretase to maintain activity on other biologically essential substrates. Flurizan is the R-enantiomer of flurbiprofen, and lacks significant COX-inhibiting activity. It is therefore well-tolerated at a high dose, without substantial gastro-intestinal or other side effects.

GABA inverse agonist Marion Merrell Dow (also depression) Phase II 

inverse GABA agonist Marion Merrell Dow (also depression) Phase II 

Galanthamine Galantamine ...Acetylcholinesterase inhibitor.....J Pharmacol Exp Ther 1996 May;277(2):728-738. Phase III (Jansen Pharmaceutica & Shire Pharmaceuticals) Molecular mechanism. Commercialized

Galanthamine derivatives Hoechst Marion Roussel; Waldheime Pharmazeutika AChE inhibitor. Phase III 

Ginkgo biloba .Amélioration mise en évidence par plusieurs essais thérapeutiques: JAMA 1997 Oct 22;278(16):1327-1332 

HuperzineA ....Exhibits anticholinesterase activity and is now under investigation as potential Alzheimer disease medication. 

Ibuprofen 

Idebedone. Takeda Chemical Industries Ltd. Lipid peroxidase inhibitor, nootropic agent. Awaiting approval 

Lazabemide Hoffmann- La Roche (also Parkinson's) . MAO-B inhibitor.Awaiting approval 

Levacecarnine Hoffman-La Roche Phase III 

LY 246078 Eli Lilly Phase II (see Xanomeline) 

LY450139 Eli Lilly γ-Secretase inhibitor Phase II

MAO-B inhibitor Marion Merrell Dow (also Parkinson's) Phase II 

mAb (monoclonal antibodies): 1) bapineuzumab (Elan/Wyeth)
  2) LY2062430 (Eli Lilly) in Phase II trials,
  3) RN1219 (Pfizer) in Phase I.

MDL 26,479 (see 26,479) 

MDL 73,745 (see 73,745)

Memantine: Sold in Germany. Antagonist of NMDA receptors. Decreases the deleterious entry of calcium generated by excitotoxic glutamatergic neurons. Good results on moderately to severe Alzheimer patients:  
Vendu en Allemagne. Donne des résultats significatifs pour les démences Alzheimer modérées et sévères. Voir Mémantine

Memolog (nebracetam) Boehringer Ingelheime Gmbh Waiting approval Improving mental performance in Alzheimer's disease

Metrifonate. Bayer AG. Acetylcholine inhibitor. Awaiting approval. Problems.

Site Alzheimer Research Forum                Molecular mechanism

Mentane (velnacrine maleate) Hoechst-Roussel Phase III application submitted 

MF-201 (see Eptastigmine) 

Milameline (CI-979) Warner-Lambert Co. Phase III M1 agonist 

Montirelin Gruenenthal Gmbh ACh release stimulator, TRH agonist Phase III 

MPC-7869 ((R)-flurbiprofen) is a single enantiomer of flurbiprofen, which has been shown to lower brain levels of a toxic form of beta amyloid (Aß42) in a model of Alzheimer's.

NBI-4001 Neurocrine Biosciences Phase II 

Nebracetam Boehringher Ingelheim Corp Non-NMDA antagonist Awaiting approval 

Nefiracetam Daiichi Seiyaku Co Ltd Ach agonist, Ca channel opener: acting on presynaptic nicotinic Acetylcholine receptors. Awaiting approval 

Neotrophin (AIT-082) purine derivative that enhances Nerve Growth Factor.: Websites see AIT 082

TorreyPines Therapeutics

M1 muscarinic agonist, α-secretase activator Phase I

NSAIDs nonsteroidal antiinflammatory drugs 

NS-105 Nippon Shinyaku Co Nootropic agent, ACh/GABA modulator 

Oestrogènes (estrogenes) 

NEM Cephalon Inc. preclinical 

NeoTrofin see AIT-082 

Nimotop (nimodipine) Miles Inc. Pharmaceutical Division Phase III 

Ondanserion Glaxo Phase III 

P10358, a novel, orally active acetylcholinesterase inhibitor J Pharmacol Exp Ther, 1997, 280:710-720 

Phenserine from Axonyx

2 September 2005. The New York-based biopharmaceutical company Axonyx announced Tuesday that its experimental acetyl cholinesterase inhibitor drug Phenserine was ineffective in two curtailed phase 3 trials.

Physostigmine (see Synapton) 

Propentofylline Hoechst Marion Roussel Alzheimer and vascular dementia. PDE inhibitor. Awaiting approval. Some problems. 

Reminyl ( galantamine) Acetylcholinesterase inhibitor.....J Pharmacol Exp Ther 1996 May;277(2):728-738. Phase III (Jansen Pharmaceutica & Shire Pharmaceuticals). Commercialized.

Rivastigmine (see Exelon) Molecular mechanism

S12024 ..........phase IIb Development stopped. Problems of toxicity 

sabcomeline SB 202026 SmithKline Beecham. Phase III. M1 partial agonist 

SB 202026 (sabcomeline) SmithKline Beecham. Phase III. M1 partial agonist 

Selegiline (Eldepryl) Somerset Inc MAO B inhibitor 

SR 46559 Sanofi S.A Phase II 

Suritozole (see 26,479 ) or MDL 26,479

talsaclidine

Boehringer Ingelheim Corp M1 agonist Phase III

Tarenflurbil

Myriad Genetics’ tarenflurbil — a modulator of γ-secretase activity — is the
most advanced agent in clinical development for preventing Aβ formation. In a Phase IItrial in patients with mild-to-moderate AD, tarenflurbil was safe and well tolerated, and demonstrated a reduced rate of cognitive decline compared with a placebo. Tarenflurbil is currently in an 18-month pivotal Phase III study. Final data from the US sites are anticipated in the second half of 2008.
Provided the trial is successful, tarenflurbil could be launched as soon as 2009/2010.

Tramiprosate (AlzheMed)

Tramiprosate is a glycosaminoglycan mimetic designed to bind to Aβ peptides, thereby stopping the formation of amyloid plaques. Owing to the short duration (3 months) of the tramiprosate Phase
II trial, no dramatic effects on cognition were observed. However, in an open-label extension study, tramiprosate showed clinically significant benefits on cognitive and global performance measures, with a stabilization of the disease in a proportion of patients with mild AD after
3 years of treatment. Tramiprosate is being investigated in two pivotal 18-month Phase III clinical trials with data expected in 2007 and 2008.

TTP488

TransTech Pharma/Pfizer

Blocks RAGE/Aβ interactions, reduces brain amyloid load

Phase IIa

Estrogens. The debate over whether postmenopausal women should take estrogen has been raging for years--long enough for some of these women to become old enough to get AD. Some studies suggest that estrogen, in addition to protecting against heart disease and bone loss, protects against AD.^[8] Estrogen also seems to slow the progression of AD in those who already have it. The mechanism underlying its possible prophylactic efficacy in AD is not known. Estrogen does serve as a trophic factor for ACh, and one study shows that patients on both estrogen and an AChE inhibitor fare better than do those on either treatment alone.^[9] Unopposed estrogen therapy may increase the risk of uterine cancer, whereas data on the effect of estrogen on the risk for breast cancer are less clear.

A review by Beverly N. Jones III, MD, John R. Absher, MD

Other drugs. Some data suggest that an antioxidant such as vitamin E, at a dosage of 2000 IU/day, slows AD progression.^[10] In addition, since levels of monoamine oxidase (MAO) rise with aging, an MAO inhibitor (MAOI) might logically serve as an anti-aging pill. In fact, preliminary evidence suggests that selegiline (Eldepryl), a selective MAOI that does not require a tyramine-free diet, can also be helpful in treating AD (N Engl J Med, 1997, 336:1216-1222. MAOIs should not be combined with selective serotonin reuptake inhibitors (SSRIs), meperidine, or general anesthetics.

AChE inhibitors are the only drugs that have been approved by the FDA for the treatment of AD. Although there are no data supporting the use of combined therapy, this author would consider adding vitamin E or estrogen to donepezil in some cases. The combination of an NSAID and an AChE inhibitor might cause GI problems.

Rev Neurol (Paris) 1997 Apr;153(3):185-192

Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area.

Orgogozo JM, Dartigues JF, Lafont S, Letenneur L, Commenges D, Salamon R, Renaud S, Breteler MB

Unite de Recherche Epidemiologique, INSERM U 330, Universite de Bordeaux II, France.

Alcoholism is a possible cause of dementia, mainly through associated nutritional deficiencies and, rarely, through acute direct toxicity. However alcohol consumption was not found to be a risk factor in previous epidemiologic studies. We prospectively studied 3,777 community residents aged 65 and over, in the districts of Gironde and Dordogne. Average daily alcoholic consumption was recorded at baseline. Incident cases of dementia and Alzheimer's disease were screened at follow-up with explicit criteria. At 3 years, 2,273 subjects not demented at baseline were still available for follow-up. Wine was the only alcoholic beverage reported by more than 95 p. 100 of regular drinkers. In the 318 subjects drinking 3 to 4 standard glasses per day (> 250 and up to 500 ml), categorized as moderate drinkers, the crude odds ratio (OR) was 0.18 for incident dementia (p < 0.01) and 0.25 for Alzheimer's disease (p < 0.03), as compared to the 971 non-drinkers. After adjusting for age, sex, education, occupation, baseline MMSE and other possible confounders, the ORs were respectively 0.19 (p < 0.01) and 0.28 (p < 0.05). In the 922 mild drinkers (< 1 to 2 glasses per day) there was a negative association only with AD, after adjustment (OR = 0.55; p < 0.05). The inverse relationship between moderate wine drinking and incident dementia was explained neither by known predictors of dementia nor by medical, psychological or socio-familial factors. Considering also the well documented negative associations between moderate wine consumption and cardiovascular morbidity and mortality in this age group, it seems that there is no medical rationale to advise people over 65 to quit drinking wine moderately, as this habit carries no specific risk and may even be of some benefit for their health. Advising all elderly people to drink wine regularly for prevention of dementia would be however premature at this stage.

PMID: 9296132, UI: 97441913