Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin.

An integrated analysis was performed with data from 4 phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10 -transformed urinary N-acetyl-ß-D-glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 and 24 weeks in multivariate analysis (respectively, P < .0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c > 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decreased in patients with moderate HbA1c levels.

In vivo release and gene expression of plasmid DNA by hydrogels of gelatin with different cationization extents.

The objective of this paper is to investigate the in vivo release and gene expression of lacZ plasmid DNA (pSV-lacZ) by the hydrogels of cationized gelatin. Gelatin with different cationization extents was prepared by changing the amount of ethylenediamine added to aminize the carboxyl groups of gelatin with a water-soluble carbodiimide. The cationized gelatin prepared was crosslinked by various concentrations of glutaraldehyde (GA) to obtain cationized gelatin hydrogels with different cationization extents as the release carrier of plasmid DNA. When the cationized gelatin hydrogels incorporating 125I-labeled pSV-lacZ were implanted into the femoral muscle of mice, the radioactivity remaining decreased with time and the retention period was prolonged with an increase in the concentration of GA used for hydrogel preparation. In vivo experiments with 125I-labeled cationized gelatin hydrogels revealed that the higher the GA concentration, the longer the in vivo retention period of radioactivity remaining for every cationized gelatin hydrogel. Only for the hydrogels prepared from gelatin with the aminized percentages of 29.7, 41.6, and 47.8 mol.%, the time profile of pSV-lacZ retention correlated well with that of hydrogel retention. The gene expression by the cationized gelatin hydrogels incorporating pSV-lacZ depended on the aminized percentage of gelatin and was significant at the percentage of 41.6 mol.% or higher. It is possible that the pSV-lacZ was complexed with the degraded fragments of cationized gelatin and released with a positive charge, resulting in enhanced gene expression. We conclude that gelatin with a cationization extent of at least 41.6 mol.% is needed for the enhanced in vivo gene expression of plasmid DNA by the hydrogel release system.

A trial on regeneration therapy of rat liver cirrhosis by controlled release of hepatocyte growth factor.

This paper is an investigation of therapeutic trial on the liver cirrhosis by the controlled release of hepatocyte growth factor (HGF). Biodegradable microspheres were prepared from gelatin for the controlled release of HGF. Rats with liver cirrhosis were prepared by the intraperitoneal injection of thioacetamide at a dose of 0.2 g/kg every other day for 10 weeks. The rats received single intraperitoneal injection of gelatin microspheres incorporating 2 or 0.4 mg of HGF, 2 or 0.4 mg of free HGF, and HGF-free, empty gelatin microspheres 3 weeks after the last thioacetamide injection. Histological observation of the rat liver revealed that injection of gelatin microspheres incorporating HGF effectively allowed to recovery from the liver fibrosis, inducing liver regeneration. When the histological score, the area of fibrous linkage, and the hydroxyproline content in the liver were evaluated, all values were significantly smaller than those of the free HGF and empty gelatin microspheres injection, irrespective of the HGF dose. It is concluded that the gelatin microspheres incorporating HGF are a promising therapeutic method of inducing successful liver regeneration by fibrosis digestion in rats with cirrhosis.

Controlled release of plasmid DNA from cationized gelatin hydrogels based on hydrogel degradation.

This paper shows achievement of the in vivo controlled release of a plasmid DNA from a biodegradable hydrogel and the consequent regulation of gene expression period. Cationization of gelatin was preformed through introduction of ethylenediamine and the gelatin prepared was crosslinked by various concentrations of glutaraldehyde to obtain cationized gelatin (CG) hydrogels as the carrier of plasmid DNA. In vivo release of plasmid DNA from the CG hydrogels was compared with the in vivo degradation of hydrogels. When CG hydrogels incorporating 125I-labeled plasmid DNA were implanted into the femoral muscle of mice, the plasmid DNA radioactivity remaining decreased with time and the retention period prolonged with a decrease in the water content of hydrogels used. The higher the water content of 125I-labeled CG hydrogels, the faster the hydrogel radioactivity remaining decreased with time. The time profile of plasmid DNA remaining in the hydrogels was in good accordance with that of hydrogel radioactivity, irrespective of the water content. Intramuscular implantation of plasmid DNA-incorporated CG hydrogels enhanced significantly expression of the plasmid DNA around the implanted site. The retention period of gene expression became longer as the hydrogel water content decreased. Fluorescent microscopic study revealed that the plasmid DNA-CG complex was detected around the hydrogel implanted even after 7-day implantation in marked contrast to the injection of plasmid DNA solution. It was concluded that in our hydrogel system, active plasmid DNA was released accompanied with the in vivo degradation of hydrogel, resulting in extended gene expression. The time profile of plasmid DNA release and the consequent gene expression was controllable by changing the water content of hydrogels.