Enz A


Full name : Enz Albert

First name : Albert

Mail : Novartis Pharma Inc., Preclinical Research, Bldg. 386 762, CH-4002 Basel

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Country : Switzerland

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Phone : 61-324-4705

Fax : 61-324-4787

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References (25)

Title : Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients - Lefevre_2008_Clin.Pharmacol.Ther_83_106
Author(s) : Lefevre G , Sedek G , Jhee SS , Leibowitz MT , Huang HL , Enz A , Maton S , Ereshefsky L , Pommier F , Schmidli H , Appel-Dingemanse S
Ref : Clinical Pharmacology & Therapeutics , 83 :106 , 2008
Abstract : A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).
ESTHER : Lefevre_2008_Clin.Pharmacol.Ther_83_106
PubMedSearch : Lefevre_2008_Clin.Pharmacol.Ther_83_106
PubMedID: 17522596

Title : N1phenethyl-norcymserine, a selective butyrylcholinesterase inhibitor, increases acetylcholine release in rat cerebral cortex: a comparison with donepezil and rivastigmine - Cerbai_2007_Eur.J.Pharmacol_572_142
Author(s) : Cerbai F , Giovannini MG , Melani C , Enz A , Pepeu G
Ref : European Journal of Pharmacology , 572 :142 , 2007
Abstract : The effects of (-)-N(1)phenethyl-norcymserine (PEC, 5 mk/kg, i.p.) on acetylcholine release and cholinesterase activity in the rat cerebral cortex were compared with those of donepezil (1 mg/kg, i.p.), a selective acetylcholinesterase inhibitor, and rivastigmine (0.6 mg/kg, i.p.), an inhibitor of acetylcholinesterase and butyrylcholinesterase. Acetylcholine extracellular levels were measured by microdialysis coupled with HPLC; acetylcholinesterase and butyrylcholinesterase activity were measured with colorimetric and radiometric methods. It was found that comparable 2-3 fold increases in cortical extracellular acetylcholine level, calculated as areas under the curve, followed the administration of the three drugs at the doses used. At the peak of acetylcholine increase, a 27% acetylcholinesterase inhibition and no butyrylcholinesterase inhibition was found after donepezil (1 mg/kg, i.p) administration. At the same time point, rivastigmine (0.6 mg/kg, i.p.) inhibited acetylcholinesterase by 40% and butyrylcholinesterase by 25%. After PEC (5 mg/kg, i.p.) administration, there was a 39% butyrylcholinesterase inhibition and no effect on acetylcholinesterase. Since in the present study it was also confirmed that in the brain butyrylcholinesterase activity is only about 10% of acetylcholinesterase activity, it is surprising that its partial inhibition is sufficient to increase extracellular acetylcholine levels. The importance of butyrylcholinesterase as a "co-regulator" of synaptic acetylcholine levels should thus be reconsidered.
ESTHER : Cerbai_2007_Eur.J.Pharmacol_572_142
PubMedSearch : Cerbai_2007_Eur.J.Pharmacol_572_142
PubMedID: 17643410

Title : Targeting acetylcholinesterase and butyrylcholinesterase in dementia - Lane_2006_Int.J.Neuropsychopharmacol_9_101
Author(s) : Lane RM , Potkin SG , Enz A
Ref : Int J Neuropsychopharmacol , 9 :101 , 2006
Abstract : The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.
ESTHER : Lane_2006_Int.J.Neuropsychopharmacol_9_101
PubMedSearch : Lane_2006_Int.J.Neuropsychopharmacol_9_101
PubMedID: 16083515

Title : Rivastigmine as a modulator of the neuronal glutamate transporter rEAAC1 mRNA expression - Andin_2005_Dement.Geriatr.Cogn.Disord_19_18
Author(s) : Andin J , Enz A , Gentsch C , Marcusson J
Ref : Dementia & Geriatric Cognitive Disorders , 19 :18 , 2005
Abstract : Alzheimer's disease is a neurodegenerative disorder that affects the cholinergic, glutamatergic and monoaminergic systems in the neocortex and hippocampus. Today, the major pharmacological treatment involves the use of acetylcholinesterase inhibitors (AChEIs). In this study, an in situ hybridisation technique (using digoxigenin-labelled cRNA probes) was used to elucidate changes in mRNA expression of the neuronal glutamate transporter, rat excitatory amino carrier 1 (rEAAC1), after treatment with the AChEI rivastigmine. Compared with saline-treated rats, the rats subchronically (3 days) and chronically (21 days), but not acutely, treated with rivastigmine showed a significant increase in rEAAC1 mRNA expression in the hippocampal areas cornu anterior 1 (CA1), CA2, CA3 and dentate gyrus (p < 0.01), but not in the cortical areas. These results provide the first evidence that the glutamatergic system is modulated following acetylcholinesterase inhibition by rivastigmine, a finding, which is likely to be of importance for the clinical effects.
ESTHER : Andin_2005_Dement.Geriatr.Cogn.Disord_19_18
PubMedSearch : Andin_2005_Dement.Geriatr.Cogn.Disord_19_18
PubMedID: 15383741

Title : Cholinesterases: roles in the brain during health and disease - Ballard_2005_Curr.Alzheimer.Res_2_307
Author(s) : Ballard CG , Greig NH , Guillozet-Bongaarts AL , Enz A , Darvesh S
Ref : Curr Alzheimer Res , 2 :307 , 2005
Abstract : The cholinergic hypothesis of decline in dementia, whereby deficits in learning, memory and behavior are caused, at least in part, by decreased levels of acetylcholine (ACh) in the brain, first emerged more than 20 years ago. The role for acetylcholinesterase (AChE) and its inhibition in this scheme has long been accepted, but findings from preclinical experiments and clinical trials have placed butyrylcholinesterase (BuChE) alongside AChE as an important contributor to the occurrence, symptoms, progression and responses to treatment in dementia. A number of new lines of evidence suggest that both cholinesterase inhibitors (ChEs) may have broader functions in the CNS than previously thought, which relate to both 'classical' esterase activities of the enzymes as well as non-classical actions unrelated to their enzymatic function. Data suggest involvement of the ChEs in modulating glial activation, cerebral blood flow, the amyloid cascade, and tau phosphorylation. It has therefore been speculated that some actions of the ChEs could affect the underlying disease processes in Alzheimer's disease (AD), and that pharmacological manipulation with ChE inhibitors may affect long-term disease progression. Focusing on new findings relating to BuChE, we review recent evidence that has extended knowledge into the roles of ChEs in health, disease and aging.
ESTHER : Ballard_2005_Curr.Alzheimer.Res_2_307
PubMedSearch : Ballard_2005_Curr.Alzheimer.Res_2_307
PubMedID: 15974896

Title : A simple, rapid and sensitive method for simultaneous determination of rivastigmine and its major metabolite NAP 226-90 in rat brain and plasma by reversed-phase liquid chromatography coupled to electrospray ionization mass spectrometry - Enz_2004_Biomed.Chromatogr_18_160
Author(s) : Enz A , Chappuis A , Dattler A
Ref : Biomedical Chromatography , 18 :160 , 2004
Abstract : A simple and sensitive reversed-phase liquid chromatography coupled with electrospray-mass spectrometry was developed and validated for the simultaneous determination of rivastigmine, a cholinesterase inhibitor, and its major metabolite NAP 226-90 in rat plasma and brain homogenates. Rivastigmine and NAP 226-90 were extracted from plasma and brain by ethyl acetate and, after drying under nitrogen, re-dissolved in acetonitrile and separated isocratic by HPLC on a C(18) column and quantified by single ion monitoring mass spectrometer. The mean (+/-SD) extraction efficiency for rivastigmine in plasma and brain was 93 +/- 2 and 95 +/- 2% (n = 5) of NAP 226-90 in a drug range of 10-100 pmol/mL or pmol/g. The method proved to be linear within the tested range (regression coefficient, r = 0.9999, n = 5). Intra- and inter-day precision coefficients of variation and accuracy bias were acceptable (within 15%, n = 5) over the entire range for both compounds using plasma or brain samples. The limits of quantification were 0.5 pmol/mL plasma and 2.5 pmol/g brain for rivastigmine and 1 pmol/mL plasma and 5 pmol/g brain for NAP 226-90, respectively. The analytical technique was used to determine the concentrations of rivastigmine and its metabolite NAP 226-90 in rat plasma and brain after oral drug administration. The concentrations of the parent drug and its major metabolite were compared to a pharmacodynamic parameter, the ex vivo inhibition of acetylcholinesterase.
ESTHER : Enz_2004_Biomed.Chromatogr_18_160
PubMedSearch : Enz_2004_Biomed.Chromatogr_18_160
PubMedID: 15103701

Title : Co-administration of memantine has no effect on the in vitro or ex vivo determined acetylcholinesterase inhibition of rivastigmine in the rat brain - Enz_2004_Neuropharmacol_47_408
Author(s) : Enz A , Gentsch C
Ref : Neuropharmacology , 47 :408 , 2004
Abstract : Rivastigmine, a cholinesterase inhibitor, is successfully used for the symptomatic therapy of Alzheimer's disease (AD) in the clinic. The drug has a very low potential for drug-drug interactions, as has been demonstrated within large clinical trials. Memantine, recently approved by the FDA for the treatment of moderate to severe AD, acts as a low affinity, non-competitive NMDA-antagonist, on a completely different neurotransmitter system, the glutamatergic system. Given the different sites of action, the possibility to combine a cholinergic with a glutamatergic intervention as potentially superior AD therapy has recently been proposed. In vitro studies have demonstrated that memantine, when added to reversible AChE inhibitors, such as tacrine, donepezil or galantamine, did not interfere with the inhibitory action of any of these drugs. The results from the present study provide evidence that rivastigmine as a pseudo-irreversible (or slow-reversible) AChE inhibitor shares this property described for reversible inhibitors, since memantine (1-100 microM), irrespective of whether given prior to or after rivastigmine did not influence rivastigmine's AChE inhibition in vitro. A similar observation was also made under in vivo conditions (ex vivo measurements): following a 21 day chronic, oral administration of 6 micromol/kg rivastigmine alone or of a combination of rivastigmine plus memantine (6 micromol/kg p.o. of either of the two compounds), an identical degree of AChE inhibition was observed. The concentrations of rivastigmine, its metabolite NAP 226-90 and memantine were measured in the brain of the same animals. Following an equimolar oral dose (6 micromol/kg) of both compounds, the brain level of memantine exceeded that of rivastigmine + metabolite, by a factor of around 30, when measured 2 h after the final dosing, irrespective of the duration of treatment (acute, for 3 or 21 days). This indicates that neither of the two drugs showed accumulation but also, and more importantly, that memantine does not modulate the prime therapeutic action of rivastigmine (AChE inhibition) in vitro or in vivo. Clinical trials using a combination of both drugs will provide a final proof of whether a combination therapy would lead to an increased efficacy in AD patients.
ESTHER : Enz_2004_Neuropharmacol_47_408
PubMedSearch : Enz_2004_Neuropharmacol_47_408
PubMedID: 15275830

Title : Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit - Giacobini_2002_J.Neural.Transm.(Vienna)_109_1053
Author(s) : Giacobini E , Spiegel R , Enz A , Veroff AE , Cutler NR
Ref : J Neural Transm (Vienna) , 109 :1053 , 2002
Abstract : Cholinesterase (ChE) inhibition represents the most efficacious treatment approach for Alzheimer's disease (AD) to date. This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon). In 18 patients with mild to moderate AD, CNTB scores, activities of AChE and BuChE in the CSF, and plasma BuChE activity were determined prior to treatment with rivastigmine. Doses of rivastigmine were then titrated (1 mg b.i.d./week) to final doses of 1, 2, 3, 4, 5 or 6 mg b.i.d. (n = 3 per dose). Following treatment with the target dose of rivastigmine for at least 3 days, CNTB scores were re-determined. CSF samples were continuously collected together with plasma samples prior to and for 12 hours after the final dose of rivastigmine, and AChE and BuChE activities determined.AChE in CSF and BuChE in plasma were dose-dependently inhibited by rivastigmine treatment. The inhibition of BuChE in CSF was not clearly dose-dependent. A statistically significant correlation was observed between the change in CNTB summary score and inhibition of AChE activity (r = -0.56, p < 0.05) and BuChE activity (r = -0.65, p < 0.01) in CSF. Improvement in speed-, attention- and memory-related subtests of the CNTB correlated significantly with inhibition of BuChE but not AChE activity in CSF. Weak or absent correlation with change in cognitive performance was noted for inhibition of plasma BuChE. These results indicate that cognitive improvement with rivastigmine in AD is associated with central inhibition of ChEs and support a role for central BuChE in addition to AChE inhibition in modulating cholinergic function in AD.
ESTHER : Giacobini_2002_J.Neural.Transm.(Vienna)_109_1053
PubMedSearch : Giacobini_2002_J.Neural.Transm.(Vienna)_109_1053
PubMedID: 12111443

Title : Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine - Bar-On_2002_Biochemistry_41_3555
Author(s) : Bar-On P , Millard CB , Harel M , Dvir H , Enz A , Sussman JL , Silman I
Ref : Biochemistry , 41 :3555 , 2002
Abstract : Rivastigmine, a carbamate inhibitor of acetylcholinesterase, is already in use for treatment of Alzheimer's disease under the trade name of Exelon. Rivastigmine carbamylates Torpedo californica acetylcholinesterase very slowly (k(i) = 2.0 M(-1) min(-1)), whereas the bimolecular rate constant for inhibition of human acetylcholinesterase is >1600-fold higher (k(i) = 3300 M(-1) min(-1)). For human butyrylcholinesterase and for Drosophila melanogaster acetylcholinesterase, carbamylation is even more rapid (k(i) = 9 x 10(4) and 5 x 10(5) M(-1) min(-1), respectively). Spontaneous reactivation of all four conjugates is very slow, with <10% reactivation being observed for the Torpedo enzyme after 48 h. The crystal structure of the conjugate of rivastigmine with Torpedo acetylcholinesterase was determined to 2.2 A resolution. It revealed that the carbamyl moiety is covalently linked to the active-site serine, with the leaving group, (-)-S-3-[1-(dimethylamino)ethyl]phenol, being retained in the "anionic" site. A significant movement of the active-site histidine (H440) away from its normal hydrogen-bonded partner, E327, was observed, resulting in disruption of the catalytic triad. This movement may provide an explanation for the unusually slow kinetics of reactivation.
ESTHER : Bar-On_2002_Biochemistry_41_3555
PubMedSearch : Bar-On_2002_Biochemistry_41_3555
PubMedID: 11888271
Gene_locus related to this paper: torca-ACHE

Title : Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis - Boncristiano_2002_J.Neurosci_22_3234
Author(s) : Boncristiano S , Calhoun ME , Kelly PH , Pfeifer M , Bondolfi L , Stalder M , Phinney AL , Abramowski D , Sturchler-Pierrat C , Enz A , Sommer B , Staufenbiel M , Jucker M
Ref : Journal of Neuroscience , 22 :3234 , 2002
Abstract : Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.
ESTHER : Boncristiano_2002_J.Neurosci_22_3234
PubMedSearch : Boncristiano_2002_J.Neurosci_22_3234
PubMedID: 11943824

Title : Synthesis and acetylcholinesterase inhibition of 5-desamino huperzine A derivatives - Hogenauer_2001_Bioorg.Med.Chem.Lett_11_2627
Author(s) : Hogenauer K , Baumann K , Enz A , Mulzer J
Ref : Bioorganic & Medicinal Chemistry Lett , 11 :2627 , 2001
Abstract : (E)- and (Z)-5-Desamino huperzine A derivatives have been synthesized using a new synthetic strategy towards the huperzine A skeleton. These derivatives showed AChE inhibition constants in the low micromolar range and thus display better activity than all previously synthesized C5 derivatives.
ESTHER : Hogenauer_2001_Bioorg.Med.Chem.Lett_11_2627
PubMedSearch : Hogenauer_2001_Bioorg.Med.Chem.Lett_11_2627
PubMedID: 11551765

Title : Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans - Kennedy_1999_J.Clin.Psychopharmacol_19_513
Author(s) : Kennedy JS , Polinsky RJ , Johnson B , Loosen P , Enz A , Laplanche R , Schmidt D , Mancione LC , Parris WC , Ebert MH
Ref : J Clin Psychopharmacol , 19 :513 , 1999
Abstract : This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal rivastigmine plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after rivastigmine administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after rivastigmine than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after rivastigmine than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE.
ESTHER : Kennedy_1999_J.Clin.Psychopharmacol_19_513
PubMedSearch : Kennedy_1999_J.Clin.Psychopharmacol_19_513
PubMedID: 10587286

Title : Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease - Cutler_1998_Acta.Neurol.Scand_97_244
Author(s) : Cutler NR , Polinsky RJ , Sramek JJ , Enz A , Jhee SS , Mancione L , Hourani J , Zolnouni P
Ref : Acta Neurologica Scandinavica , 97 :244 , 1998
Abstract : INTRODUCTION: This study evaluates the activity of SDZ ENA 713, a centrally-selective acetylcholinesterase (AChE) inhibitor, in the cerebral spinal fluid (CSF) of patients with Alzheimer's disease (AD), and its relationship to central and peripheral pharmacokinetic parameters.
METHODS: Eighteen AD patients were enrolled in this open-label, multiple-dose study. Patients were titrated in 1 mg bid/week increments to target doses of 1, 2, 3, 4, 5, or 6 mg bid SDZ ENA 713. After patients had been maintained at their target dose for at least 3 days, continuous CSF samples were obtained via a lumbar catheter for 12.5 h, beginning 0.5 h prior to the final dose of SDZ ENA 713.
RESULTS: Dose-dependent inhibition of CSF AChE was significantly correlated (P < 0.05) with plasma drug and metabolite concentrations. The 6 mg bid treatment group showed a maximum mean inhibition of 62% at 5.6 h post-dose. CONCLUSION: Rapid, sustained, dose-dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.
ESTHER : Cutler_1998_Acta.Neurol.Scand_97_244
PubMedSearch : Cutler_1998_Acta.Neurol.Scand_97_244
PubMedID: 9576639

Title : Kinetic and X-Ray Crystallographic Studies of the Binding of ENA-713 to Torpedo Californica Acetylcholinesterase -
Author(s) : Bar-On P , Harel M , Millard CB , Enz A , Sussman JL , Silman I
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :373 , 1998

Title : Kinetic and structural studies on the interaction of the anti-Alzheimer drug, ENA-713, with Torpedo californica acetylcholinesterase -
Author(s) : Bar-On P , Harel M , Millard CB , Enz A , Sussman JL , Silman I
Ref : Journal de Physiologie (Paris) , 92 :406 , 1998

Title : Acetylcholinesterase Inhibitors (AChE-I) as a Potential Use for Alzheimers Disease (AD) Therapy -
Author(s) : Enz A
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :475 , 1995

Title : Pharmacological evaluation of phenyl-carbamates as CNS-selective acetylcholinesterase inhibitors - Weinstock_1994_J.Neural.Transm.Suppl_43_219
Author(s) : Weinstock M , Razin M , Chorev M , Enz A
Ref : J Neural Transm Suppl , 43 :219 , 1994
Abstract : The pharmacological and clinical properties of a novel phenyl carbamate acetylcholinesterase (AChE) inhibitor, SDZ ENA 713 are described. In animals and human subjects this compound showed superior chemical stability, oral bioavailability and a longer duration of action than physostigmine. SDZ ENA 713 produced a 10-fold greater inhibition of AChE in the hippocampus and cortex than in the heart and skeletal muscle, which explains its relatively low toxicity and freedom from cholinergic side effects. The selective effect in the cortex and hippocampus may be due to its preferential inhibition of the G1 form of the enzyme, which is present in relatively higher concentrations in these brain areas. Evidence of a selective hippocampal action was obtained in normal human subjects in whom REM sleep density was increased at doses that had no effect on plasma cholinesterase. If memory impairments in AD are related to a lack of cholinergic activity in cortical and hippocampal brain areas, SDZ ENA 713 should produce significant symptomatic improvement.
ESTHER : Weinstock_1994_J.Neural.Transm.Suppl_43_219
PubMedSearch : Weinstock_1994_J.Neural.Transm.Suppl_43_219
PubMedID: 7884403

Title : SDZ ENS 163 a novel pilocarpine like drug: pharmacological in vitro and in vivo profile - Enz_1993_Life.Sci_52(5-6)_513
Author(s) : Enz A , Boddeke HW , Sauter A , Rudin M , Shapiro G
Ref : Life Sciences , 52 :513 , 1993
Abstract : The thiolactone analogue of pilocarpine, SDZ ENS 163, acts in vitro and in vivo as a partial agonist at M1/M3 and as an antagonist at M2 muscarinic receptors. In vitro, the properties of SDZ ENS 163 have been investigated in several functional models for muscarinic receptors: it is a full agonist at M1 (rat superior cervical ganglion, carbachol = 100%) and a partial agonist at M3 receptors (guinea pig ileum). However, the drug shows antagonistic properties at M2 receptors (rat atria). Radioligand binding studies with 3H-N-methylscopolamine (3H-NMS) using CHO cells expressing m1 or m3 receptors indicate that SDZ ENS 163 does not discriminate between m1 and m3 receptors (Ki 1.5 and 2.4 microM respectively). Regarding phosphoinositide (PI) turnover in A9L cells, SDZ ENS 163 is a partial agonist at m1 receptors. In ex vivo neurochemical studies in rats SDZ ENS 163 displays effects characteristic of muscarinic antagonists regarding the turnover of ACh which is increased in the brain. At a similar dose-range SDZ ENS 163 accelerates PI metabolism in the rat brain in vivo and increases the energy of the low frequency band (2-5 Hz) in the rat hippocampal EEG. These effects observed in vivo are consistent with postsynaptic M1 agonistic and presynaptic M2 antagonistic activities. Since SDZ ENS 163 at centrally active doses exerts no peripheral cholinergic effects, it may be useful for the symptomatic treatment of Alzheimer's disease.
ESTHER : Enz_1993_Life.Sci_52(5-6)_513
PubMedSearch : Enz_1993_Life.Sci_52(5-6)_513
PubMedID: 8382766

Title : Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer's disease - Enz_1993_Prog.Brain.Res_98_431
Author(s) : Enz A , Amstutz R , Boddeke H , Gmelin G , Malanowski J , Boddeke HW
Ref : Prog Brain Res , 98 :431 , 1993
Abstract : It could be argued that clinical experience with cholinergic drugs in the therapy of AD has not yet shown relevant symptomatic improvements. The main reasons for this might be attributed to peripheral cholinergic effects and the liver toxicity of some of these drugs, which limit their use and prevent confirmation of the cholinergic hypothesis (Gray et al., 1989). The main disadvantages of the cholinesterase inhibitors used in clinical trials are the short duration of action in the case of physostigmine and the potential for liver toxicity seen with the aminoacridine derivatives. The results presented with SDZ ENA 713 indicate that the disadvantages of AChE inhibitors might be overcome by improving CNS selectivity and thereby decreasing the peripheral cholinergic effects and toxicity. Clinico-pharmacological studies with SDZ ENA 713 have been performed in healthy volunteers; while central activity was clearly demonstrated in an EEG-sleep study (Holsboer et al., 1992), no prohibitive peripheral side effects were seen, confirming in humans the results obtained in experimental animals (Enz et al., 1991). A multicentre clinical investigation in AD patients has been performed in Europe and is currently being evaluated.
ESTHER : Enz_1993_Prog.Brain.Res_98_431
PubMedSearch : Enz_1993_Prog.Brain.Res_98_431
PubMedID: 8248533

Title : SDZ ENS 163 is a selective M1 agonist and induces release of acetylcholine - Enz_1992_Naunyn.Schmiedebergs.Arch.Pharmacol_345_282
Author(s) : Enz A , Shapiro G , Supavilai P , Boddeke HW
Ref : Naunyn Schmiedebergs Arch Pharmacol , 345 :282 , 1992
Abstract : In the present study some pharmacological properties of the new muscarinic agonist SDZ ENS 163; (+)-(3S,cis)-3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl) methyl-2(3H)-thiophenonedihydrogenphosphate] have been investigated. In the rat superior cervical ganglion, a model for M1 muscarinic receptors, SDZ ENS 163 induced concentration-dependent depolarizations (pD2 = 6.5 +/- 0.3; efficacy = 128 +/- 4.2% compared to carbachol). SDZ ENS 163 was a very weak partial agonist with respect to M2 receptor-induced decrease in contractile force in rat left atria (efficacy = 14 +/- 2.9%). In addition, SDZ ENS 163 competitively antagonized the effect of carbachol in rat left atria (pA2 = 5.8 +/- 0.2). In the guinea-pig ileum SDZ ENS 163 was a partial agonist with respect to force of contraction mediated by M3 receptors (pD2 = 5.3 +/- 0.1; efficacy = 72 +/- 4.2%). The oxotremorine-induced inhibition of the electrically stimulated release of acetylcholine (ACh) in rat hippocampal slices was reversed by SDZ ENS 163 (pA2 = 5.5 +/- 0.1). In addition after oral administration SDZ ENS 163 (3-10 mumol/kg) reduced brain ACh levels, which is indicative of increased ACh turnover. Finally, increases in energy of the low frequency band (2-5 Hz) were observed in rat hippocampal EEG after intraperitoneal administration of SDZ ENS 163 (0.3-30 mumol/kg). We conclude that SDZ ENS 163 is a selective M1 agonist in vitro with an additional M2 antagonistic effect. The in vivo effects of SDZ ENS 163 may result both from postsynaptic M1 agonistic as well as M2 receptor antagonistic activity. The unique pharmacological profile of SDZ ENS 163 may prove clinically favourable for treatment of cognitive deficits.
ESTHER : Enz_1992_Naunyn.Schmiedebergs.Arch.Pharmacol_345_282
PubMedSearch : Enz_1992_Naunyn.Schmiedebergs.Arch.Pharmacol_345_282
PubMedID: 1620233

Title : M1 muscarinic receptors mediate intracellular calcium release in NB-OK1 human neuroblastoma cells - Boddeke_1992_Naunyn.Schmiedebergs.Arch.Pharmacol_346_255
Author(s) : Boddeke HW , Buttini M , Lichtsteiner M , Enz A
Ref : Naunyn Schmiedebergs Arch Pharmacol , 346 :255 , 1992
Abstract : Muscarine acetylcholine receptors were characterized in NB-OK1 cells using radioligand (3H-NMS) binding experiments and second messenger (calcium and phosphatidylinositol (PI) turnover) studies. In radioligand binding experiments the displacement curves of pirenzepine (KI = 1.3 x 10(-8) M), AF-DX 116 (KI = 8.2 x 10(-7) M), methoctramine (KI = 8.4 x 10(-8) M) and parafluorohexahydrosiladifenidol (pF-HHSiD) (KI = 1.8 x 10(-8) M) were monophasic and indicated the presence of M1 muscarinic receptors. Schild analysis with the muscarinic antagonists pirenzepine, AF-DX 116, methoctramine and pF-HHSiD yielded pA2 values of 8.40 +/- 0.13, 6.48 +/- 0.09, 7.61 +/- 0.12 and 7.22 +/- 0.08 in the calcium experiments and pA2 values of 8.13 +/- 0.30 and 6.26 +/- 0.26, 7.65 +/- 0.16 and 7.46 +/- 0.11, respectively, in the PI turnover experiments. These results indicate that both the carbachol-induced increase in intracellular calcium and the increase in PI turnover are mediated by M1 muscarinic receptors. In calcium free buffer, stimulation with carbachol induced similar responses to those seen under control conditions. From functional and radioligand binding experiments we conclude that the muscarinic receptor expressed in NB-OK1 cells is the M1 subtype. In addition, the M1 receptor-induced calcium response is related to PI turnover and is independent on extracellular calcium.
ESTHER : Boddeke_1992_Naunyn.Schmiedebergs.Arch.Pharmacol_346_255
PubMedSearch : Boddeke_1992_Naunyn.Schmiedebergs.Arch.Pharmacol_346_255
PubMedID: 1407011

Title : Different Influence of Inhibitors on Acetylcholinesterase Molecular forms G1 and G4 Isolated from Alzheimers Disease and Control Brains -
Author(s) : Enz A , Chappuis A , Probst A
Ref : In Multidisciplinary approaches to cholinesterase functions - Proceedings of Fourth International Meeting on Cholinesterases , (Shafferman, A. and Velan, B., Eds) Plenum Press, New York :243 , 1992

Title : Pharmacologic and clinicopharmacologic properties of SDZ ENA 713, a centrally selective acetylcholinesterase inhibitor -
Author(s) : Enz A , Boddeke H , Gray J , Spiegel R
Ref : Annals of the New York Academy of Sciences , 640 :272 , 1991
PubMedID: 1776750

Title : Poster: Muscarinic agonists for senile dementia, past experience and future trends -
Author(s) : Gray JA , Enz A , Spiegel R
Ref : Trends in Pharmacological Sciences , Suppl :98 , 1989

Title : Muscarinic agonists for senile dementia: past experience and future trends - Gray_1989_Trends.Pharmacol.Sci_Suppl_85
Author(s) : Gray JA , Enz A , Spiegel R
Ref : Trends in Pharmacological Sciences , Suppl :85 , 1989
Abstract : Clinical experience with muscarinic agonists in the symptomatic treatment of Alzheimer's disease includes studies of the effects of pilocarpine, arecoline, bethanechol, oxotremorine and RS 86. Although the results are somewhat conflicting, there is evidence that a subgroup of patients may respond with an improvement of cognitive and/or behavioural function. The existing agents tend to induce adverse effects due to the stimulation of peripheral muscarinic receptors. Furthermore they reduce (at least in vitro) acetylcholine release by an action on presynaptic receptors. Strategies to overcome these problems include the development of potent agonists with high blood-brain barrier penetration, the search for agents selective for muscarinic receptor subtypes (using cloned receptors as tools) and the identification of agents acting as presynaptic receptor antagonists, to increase acetylcholine release.
ESTHER : Gray_1989_Trends.Pharmacol.Sci_Suppl_85
PubMedSearch : Gray_1989_Trends.Pharmacol.Sci_Suppl_85
PubMedID: 2694530