S-Adenosylhomocysteine Analogue of a Fairy Chemical, Imidazole-4-carboxamide, as its Metabolite in Rice and Yeast and Synthetic Investigations of Related Compounds.

During the course of our investigations of fairy chemicals (FCs), we found S-ICAr-H (8a), as a metabolite of imidazole-4-carboxamide (ICA) in rice and yeast (Saccharomyces cerevisiae). In order to determine its absolute configuration, an efficient synthetic method of 8a was developed. This synthetic strategy was applicable to the preparation of analogues of 8a that might be biologically very important, such as S-ICAr-M (9), S-AICAr-H (10), and S-AICAr-M (11).

Metal ion binding of modified pyrimidine-base pairs in DNA duplexes.

We report the synthesis and metal ion-binding properties of DNA duplexes containing 5-substituted uracil ((X)U) pairs, such as 5-bromouracil, 5-fluorouracil and 5-cyanouracil pairs. Thermal denaturation studies of these modified DNA duplexes revealed that the DNA duplexes were stabilized in the presence of Hg(II) ions in acidic and neutral solutions. On the other hand, the duplexes were stabilized in the presence of Hg(II) and Ag(I) ions. These results indicated that (X)U-Hg(II)-(X)U complex was formed in the acidic and neutral solutions, then, in the basic solutions (X)U-Ag(I)-(X)U complex as well as the (X)U-Hg(II)-(X)U complex were formed. ESI-TOF MS analysis also indicated formation of the metal ion-DNA complexes.

Metal-ion selectivity of chemically modified uracil pairs in DNA duplexes.

DNA duplexes containing 5-modified uracil pairs (5-bromo, 5-fluoro, and 5-cyanouracil) bind selectivity to metal ions. Their selectivity is sensitive to the pH value of the solution (see picture), as the acidities of the modified uracil bases vary according to the electron-withdrawing properties of the substituents.

Synthesis of DNA duplexes containing complexes of 5-modified pyrimidine bases and metal ions.

DNA duplexes carrying metal ions at the 5-position of uracil residues were synthesized by mixing oligodeoxyribonucleotides (ODNs) containing 5-formyl uracils, metal ions, and amines. A metal ion binding site may form from the 5-formyl residue and amines.

Study of nateglinide in Japan: long-term treatment of patients with type 2 diabetes.

Nateglinide is an oral antidiabetic medication that acts through rapid, short-term stimulation of insulin production. This study undertook to identify the nature of any adverse effects of nateglinide and to assess its clinical efficacy in long-term use in clinical practice. Patients (n=1014) were recruited from centers in Japan and were followed over a 15-month treatment period. Pretreatment and posttreatment values were obtained for fasting blood glucose, postprandial blood glucose, hemoglobin A1c (HbA1c), triglycerides, and total cholesterol. All adverse reactions were noted, along with standard laboratory blood variables. The efficacy value was rated as 78.76% by the treating physicians; this was indicated by a postprandial glucose decrease of 53.2 mg/dL (from 223.8+/-61.1 mg/dL to 170.6+/-40.7 mg/dL), a fasting glucose decrease of 9.3 mg/dL (from 155.1+/- 40.0 mg/dL to 145.4+/-35.1 mg/dL), and an HbA1c decrease of 0.68% (from 7.51+/- 1.36% to 6.83+/-1.09%). In patients previously treated with sulfonylurea, a decrease in HbA1c was not observed. Changes in HbA1c had no association with age, body mass index (BMI), duration of diabetes, or concomitant disease. No change in BMI was noted after 15 months of nateglinide treatment. Adverse reactions occurred at an incidence of 10.07% (100/993 cases), with hypoglycemic symptoms being the most prevalent (1.91%). Adverse reactions were sometimes associated with extant renal dysfunction, a condition about which the physician had to be aware. No problems such as increased incidences of adverse reactions or deterioration in severity were detected in this long-term study. This study showed the efficacy and safety of long-term treatment with nateglinide of patients with diabetes from various backgrounds.

Postmarketing surveillance study of nateglinide in Japan.

Nateglinide is an oral antidiabetic medication that acts through rapid, short-term stimulation of insulin production. This study was undertaken to identify the incidence and nature of adverse effects of nateglinide and to assess its efficacy in clinical practice. Patients (n = 3254) were recruited from 606 centers in Japan with a 12-week observation period. Pretreatment and posttreatment values were obtained for fasting blood glucose, postprandial blood glucose, hemoglobin A1c (HbA1c), triglycerides, cholesterol, and body mass index. All adverse events were reported, along with standard laboratory blood variables. The incidence of adverse events was 7.40%; hypoglycemia, including hypoglycemic symptoms, was reported as the most prevalent (1.62%). Adverse events were observed more frequently in patients with hepatic or renal dysfunction; no significant findings were noted in the remaining patient population. The efficacy rating determined by the treating physicians was 76.40%. HbA1c decreased by 0.81% from 7.70+/-1.53% to 6.89+/-1.22%, postprandial glucose decreased by 54.05 mg/dL from 228.91+/-73.69 mg/dL to 174.86+/-62.86 mg/dL, and fasting glucose decreased by 23.73 mg/dL from 164.15+/-51.42 mg/dL to 140.43+/-42.63 mg/dL. These effects were most marked in patients who were previously medication naïve or who had been diagnosed with diabetes for a short period. Mean body mass index decreased, and nateglinide was equally effective in obese patients. Nateglinide showed good therapeutic effect when used as the first choice in patients with a short duration of diabetes, and in those with no history of previous treatment. Moreover, nateglinide seemed to be useful for the treatment of elderly patients and obese patients.