Yoshizawa K

References (4)

Title : Long-term effect of galantamine on cognitive function in patients with Alzheimer's disease versus a simulated disease trajectory: an observational study in the clinical setting - Nakagawa_2017_Neuropsychiatr.Dis.Treat_13_1115
Author(s) : Nakagawa R , Ohnishi T , Kobayashi H , Yamaoka T , Yajima T , Tanimura A , Kato T , Yoshizawa K
Ref : Neuropsychiatr Dis Treat , 13 :1115 , 2017
Abstract : BACKGROUND: Long-term maintenance of cognitive function is an important goal of treatment for Alzheimer's disease (AD), but evidence about the long-term efficacy of cholinesterase inhibitors is sparse. To evaluate the long-term efficacy and safety of galantamine for AD in routine clinical practice, we conducted a 72-week post-marketing surveillance study. The effect of galantamine on cognitive function was estimated in comparison with a simulated disease trajectory. PATIENTS AND
METHODS: Patients with mild-to-moderate AD received flexible dosing of galantamine (16-24 mg/day) during this study. Cognitive function was assessed by the mini mental state examination (MMSE) and the clinical status was determined by the Clinical Global Impression-Improvement (CGI-I). Changes of the MMSE score without treatment were estimated in each patient using Mendiondo's model. Generalized linear mixed model analysis was performed to compare the simulated MMSE scores with the actual scores.
RESULTS: Of the 661 patients who were enrolled, 642 were evaluable for safety and 554 were assessed for efficacy. The discontinuation rate was 46.73%. Cognitive decline indicated by the mean change of actual MMSE scores was significantly smaller than the simulated decline. Individual analysis demonstrated that >70% of patients had better actual MMSE scores than their simulated scores. Significant improvement of CGI-I was also observed during the observation period. Adverse events occurred in 28.5% of patients and were serious in 8.41%. The reported events generally corresponded with the safety profile of galantamine in previous studies. CONCLUSION: These findings support the long-term efficacy of galantamine for maintaining cognitive function and the clinical state in AD patients. Treatment with galantamine was generally safe. Importantly, this study revealed that galantamine improved cognitive function above the predicted level in >70% of the patients.
ESTHER : Nakagawa_2017_Neuropsychiatr.Dis.Treat_13_1115
PubMedSearch : Nakagawa_2017_Neuropsychiatr.Dis.Treat_13_1115
PubMedID: 28458553

Title : The comparative efficacy and safety of cholinesterase inhibitors in patients with mild-to-moderate Alzheimer's disease: a Bayesian network meta-analysis - Kobayashi_2016_Int.J.Geriatr.Psychiatry_31_892
Author(s) : Kobayashi H , Ohnishi T , Nakagawa R , Yoshizawa K
Ref : Int J Geriatr Psychiatry , 31 :892 , 2016
Abstract : BACKGROUND: Comparative evidence for efficacy and safety of second-generation cholinesterase inhibitors (ChEIs) is still sparse. OBJECTIVES: The purpose of this research is to compare three ChEIs, donepezil, galantamine and rivastigmine, in patients with mild-to-moderate Alzheimer's disease (AD).
METHODS: We conducted a systematic review for published articles and included randomised, double-blind, placebo-controlled trials and head-to-head randomised trials evaluating the efficacy and safety of ChEIs in patients with AD. We examined Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-Cog), Neuropsychiatric Inventory (NPI), Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC+) and Clinical Global Impression of Change (CGIC) as efficacy endpoints. Withdrawals due to adverse events and number of patients experiencing nausea, vomiting, diarrhoea and dizziness were examined as safety profiles. Network meta-analyses were sequentially performed for efficacy and safety outcomes based on drug/dose treatment conditions.
RESULTS: Among the 21 trials included, network meta-analysis showed that all treatments were significantly more efficacious than placebo in cognition measured by ADAS-Cog. All treatments except galantamine were significantly more efficacious than placebo in global change in CIBIC+ or CGIC. Across all conditions, no significant efficacy was observed in neuropsychiatric symptoms measured by NPI. Derived hierarchies in the efficacy of treatment conditions were variables across efficacy and safety.
CONCLUSIONS: Our analysis is the first attempt to incorporate available direct and indirect evidence. The results suggest that ChEIs should have significant efficacy for cognition and global change assessment, but the efficacy on neuropsychiatric symptoms is questionable in patients with mild-to-moderate AD.
ESTHER : Kobayashi_2016_Int.J.Geriatr.Psychiatry_31_892
PubMedSearch : Kobayashi_2016_Int.J.Geriatr.Psychiatry_31_892
PubMedID: 26680338

Title : Substrate specificity of fluoroacetate dehalogenase: an insight from crystallographic analysis, fluorescence spectroscopy, and theoretical computations - Nakayama_2012_Chemistry_18_8392
Author(s) : Nakayama T , Kamachi T , Jitsumori K , Omi R , Hirotsu K , Esaki N , Kurihara T , Yoshizawa K
Ref : Chemistry , 18 :8392 , 2012
Abstract : The high substrate specificity of fluoroacetate dehalogenase was explored by using crystallographic analysis fluorescence spectroscopy and theoretical computations. A crystal structure for the Asp104Ala mutant of the enzyme from Burkholderia sp FA1 complexed with fluoroacetate was determined at 1.2 A resolution. The orientation and conformation of bound fluoroacetate is different from those in the crystal structure of the corresponding Asp110Asn mutant of the enzyme from Rhodopseudomonas palustris CGA009 reported recently J Am Chem Soc 2011 133 7461. The fluorescence of the tryptophan residues of the wild-type and Trp150Phe mutant enzymes from Burkholderia sp FA1 incubated with fluoroacetate and chloroacetate was measured to gain information on the environment of the tryptophan residues. The environments of the tryptophan residues were found to be different between the fluoroacetate and chloroacetate-bound enzymes this would come from different binding modes of these two substrates in the active site. Docking simulations and QM/MM optimizations were performed to predict favorable conformations and orientations of the substrates. The F atom of the substrate is oriented toward Arg108 in the most stable enzyme-fluoroacetate complex. This is a stable but unreactive conformation in which the small O-C-F angle is not suitable for the S(N)2 displacement of the F ion. The cleavage of the C-F bond is initiated by the conformational change of the substrate to a near attack conformation NAC in the active site The second lowest energy conformation is appropriate for NAC the C-O distance and the O-C-F angle are reasonable for the S(N 2 reaction. The activation energy is greatly reduced in this conformation because of three hydrogen bonds between the leaving F atom and surrounding amino acid residues. Chloroacetate cannot reach the reactive conformation due to the longer C-Cl bond this results in an increase of the activation energy despite the weaker C-Cl bond.
ESTHER : Nakayama_2012_Chemistry_18_8392
PubMedSearch : Nakayama_2012_Chemistry_18_8392
PubMedID: 22674735
Gene_locus related to this paper: bursp-deha

Title : The catalytic mechanism of fluoroacetate dehalogenase: a computational exploration of biological dehalogenation - Kamachi_2009_Chemistry_15_7394
Author(s) : Kamachi T , Nakayama T , Shitamichi O , Jitsumori K , Kurihara T , Esaki N , Yoshizawa K
Ref : Chemistry , 15 :7394 , 2009
Abstract : The biological dehalogenation of fluoroacetate carried out by fluoroacetate dehalogenase is discussed by using quantum mechanical/molecular mechanical (QM/MM) calculations for a whole-enzyme model of 10 800 atoms. Substrate fluoroacetate is anchored by a hydrogen-bonding network with water molecules and the surrounding amino acid residues of Arg105, Arg108, His149, Trp150, and Tyr212 in the active site in a similar way to haloalkane dehalogenase. Asp104 is likely to act as a nucleophile to attack the alpha-carbon of fluoroacetate, resulting in the formation of an ester intermediate, which is subsequently hydrolyzed by the nucleophilic attack of a water molecule to the carbonyl carbon atom. The cleavage of the strong C-F bond is greatly facilitated by the hydrogen-bonding interactions between the leaving fluorine atom and the three amino acid residues of His149, Trp150, and Tyr212. The hydrolysis of the ester intermediate is initiated by a proton transfer from the water molecule to His271 and by the simultaneous nucleophilic attack of the water molecule. The transition state and produced tetrahedral intermediate are stabilized by Asp128 and the oxyanion hole composed of Phe34 and Arg105.
ESTHER : Kamachi_2009_Chemistry_15_7394
PubMedSearch : Kamachi_2009_Chemistry_15_7394
PubMedID: 19551770
Gene_locus related to this paper: bursp-deha