8 research outputs found
Influence of substituent modifications on the binding of 2-amino-1,8-naphthyridines to cytosine opposite an AP site in DNA duplexes: thermodynamic characterization
Here, we report on a significant effect of substitutions on the binding affinity of a series of 2-amino-1,8-naphthyridines, i.e., 2-amino-1,8-naphthyridine (AND), 2-amino-7-methyl-1,8-naphthyridine (AMND), 2-amino-5,7-dimethyl-1,8-naphthyridine (ADMND) and 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND), all of which can bind to cytosine opposite an AP site in DNA duplexes. Fluorescence titration experiments show that the binding affinity for cytosine is effectively enhanced by the introduction of methyl groups to the naphthyridine ring, and the 1:1 binding constant (106 Mā1) follows in the order of AND (0.30) < AMND (2.7) < ADMND (6.1) < ATMND (19) in solutions containing 110 mM Na+ (pH 7.0, at 20Ā°C). The thermodynamic parameters obtained by isothermal titration calorimetry experiments indicate that the introduction of methyl groups effectively reduces the loss of binding entropy, which is indeed responsible for the increase in the binding affinity. The heat capacity change (ĪCp), as determined from temperature dependence of the binding enthalpy, is found to be significantly different between AND (ā161 cal/mol K) and ATMND (ā217 cal/mol K). The hydrophobic contribution appears to be a key force to explain the observed effect of substitutions on the binding affinity when the observed binding free energy (ĪGobs) is dissected into its component terms
Effects of insulin degludec and insulin glargine on day-to-day fasting plasma glucose variability in individuals with type 1 diabetes: a multicentre, randomised, crossover study
Association of dipeptidyl peptidaseā4 inhibitor use and risk of pancreatic cancer in individuals with diabetes in Japan
ABSTRACT Aims/Introduction This study was designed and carried out to investigate the association of dipeptidyl peptidaseā4 inhibitor (DPPā4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. Materials and Methods The JMDC Claims Database, which contains the medical and prescription information of Japanese employmentābased health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPPā4is or other oral glucoseālowering agents (GLAs). Results Individuals with diabetes who received DPPā4is (nĀ =ā61,430) or other oral GLAs (nĀ =ā83,304) were analyzed. Followāup periods (median [interquartile range]) were 17āmonths (8ā33) for DPPā4is and 14āmonths (7ā28) for other oral GLAs. KaplanāMeier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (logārank test: all, PĀ =ā0.7140; hospitalized, PĀ =ā0.3446). Cox proportional hazards models showed that use of DPPā4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8ā1.3, PĀ =ā0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8ā1.4, PĀ =ā0.6662). Similar results were obtained when individuals with ā„2āyears oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. Conclusion This database study shows that there is not a significant PC risk due to DPPā4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings