Name:	AF 102B
Other Names:	cevimeline HCL, Evoxac™
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Approved by FDA in 2000 for treatment of dry mouth in Sjogren's syndrome.
Role in Alzheimer's Disease:	Improve neuronal responsiveness to neurotrophic factors.
Pharmacological Role:	A M1 selective agonist from the AF series, via m1 muscarinic receptors, can activate distinct signal transductions and enhance amyloid precursors proteins secretion from transfected cells and primary cell cultures. It shows neurotrophic effects and is beneficial in a variety of animal models for Alzheimer's disease. AF102B blocks production of A-beta by increasing the activity of alpha-secretase and possibly also by inhibiting gamma-secretase.
Side Effects:	Gastrointestinal symptoms, diaphoresis, and confusion have been related to therapy in patients with probable Alzheimer's disease. Nausea, rhinitis, diarrhea, sialorrhea, polyuria, asthenia, and flushing have also been reported.
Evidence pro its efficacy:	AF102B reversed cognitive impairments at significantly lower doses than those needed to induce side-effects. Tested in 19 Alzheimer patients, AF102B was found to reduce CSF A-beta levels by 22 percent in 14 patientsAlzheimer patients -- the first drug ever shown to have such an effect in human patients.
Evidence con its efficacy:	n/a
Dosage:	40 or 60 milligrams (mg) three times daily were investigated in Alzheimer-type dementia.
Companies:	SnowBrand Pharmaceuticals Inc.

References

Beach TG, Walker DG, Potter PE, Sue LI, Fisher A. Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Res. 2001 Jun 29;905(1-2):220-3. Abstract

Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. 2000 Dec;48(6):913-8. Abstract

Fisher A, Michaelson DM, Brandeis R, Haring R, Chapman S, Pittel Z. M1 muscarinic agonists as potential disease- modifying agents in Alzheimer's disease. Rationale and perspectives. Ann N Y Acad Sci. 2000;920:315-20. Abstract

Fitten LJ, Ortiz F, Siembieda DW, O'Neill J, Halgren E, Fisher A. Reduction of motoric agitation and restlessness by AF102B and tacrine in the macaque. J Neuropsychiatry Clin Neurosci. 1999 Winter;11(1):79-85. Abstract

Fisher A, Brandeis R, Haring R, Eshhar N, Heldman E, Karton Y, Eisenberg O, Meshulam H, Marciano D, Bar-Ner N, Pittel Z. Novel m1 muscarinic agonists in treatment and delaying the progression of Alzheimer's disease: an unifying hypothesis. J Physiol Paris. 1998 Oct-Dec;92(5- 6):337-40. Abstract

Gurwitz D, Haring R, Pinkas-Kramarski R, Stein R, Heldman E, Karton Y, Fisher A. NGF-dependent neurotrophic-like effects of AF102B, an M1 muscarinic agonist, in PC12M1 cells. Neuroreport. 1995 Feb 15;6(3):485-8. Abstract

Fisher A, Brandeis R, Karton I, Pittel Z, Gurwitz D, Haring R, Sapir M, Levy A, Heldman E. (+-)-cis-2-methyl- spiro(1,3-oxathiolane-5,3')quinuclidine, an M1 selective cholinergic agonist, attenuates cognitive dysfunctions in an animal model of Alzheimer's disease. J Pharmacol Exp Ther. 1991 Apr;257(1):392-403. Abstract

Togashi H, Matsumoto M, Yoshioka M, Saito Y, Saito H. Effects of a novel cholinergic M1 agonist, AF102B, on ambulation and water drinking behavior in rats. Hokkaido Igaku Zasshi. 1991 Jan;66(1):59-66. Abstract