Kohji Yano

Long‐term deprivation of oestrogens by ovariectomy potentiates β‐amyloid‐induced working memory deficits in rats

In the present study, we examined whether deprivation of oestrogens by ovariectomy could modify learning and memory deficits caused by a continuous intracerebroventricular (i.c.v.) infusion of amyloid β‐peptide (Aβ), the major constituent of senile plaques in AD. Neither long‐term (3 months) nor short‐term (1 month), deprivation of oestrogens by ovariectomy caused a significant impairment in spatial learning and memory in a water maze and spontaneous alternation behaviour in a Y‐maze. A continuous i.c.v. infusion of Aβ‐(1‐42) caused spatial learning and memory deficits in both ovariectomized and sham‐operated rats. The Aβ‐induced working memory deficits were significantly potentiated in ovariectomized rats compared with sham‐operated rats when mnemonic ability was examined 3 months after ovariectomy. These results suggest that long‐term deprivation of oestrogens induced by ovariectomy increases susceptibility to memory deficits produced by Aβ‐(1‐42) in rats.

Oral mucosal adhesive film containing local anesthetics: In vitro and clinical evaluation

In vitro and in vivo studies were conducted to gauge the effectiveness of a novel oral mucosa adhesive, moderately water-soluble, pliant polymer artificial dentifrice (AD) film containing dibucaine (DC) for relief of pain due to oral erosion. The film was prepared from a hydroxypropyl cellulose-M (HPC-M) ethanol solution containing varying amounts of DC, as well as polyethylene glycol. In the in vitro experiments, the disintegration of HPC-M showed a lag time of about 50 min, a much lower rate than that of drug release, which more or less leveled off after 50 min. Twenty-five percent of the DC was released from the film (0.113 and 0.225 mg/cm2) after the initial 5 min, which then reached about 80% after 50 min, the time at which the polymer began to break up. In the in vivo study, the local anesthetic effect of the film was evaluated in 23 patients (10 males, 13 females) suffering from the adverse effects of chemotherapy. When applied to the wet surface of the mucosa, the AD film absorbed moisture and showed excellent adhesion. Pain relief in patients lasted 2.2 +/- 0.21 and 4.3 +/- 0.25 h at DC doses of 0.113 and 0.225 mg/cm2, respectively. These results suggest that the AD film may cover mucositis sites of oral mucosa long enough to allow DC release and bring relief from pain arising from chemotherapy and/or radiotherapy.

Distribution and serum concentration of sisomicin released from fibrin glue-sealed dacron graft in the rat and human.

We investigated whether or not fibrin glue (FG) used as a sealant in vascular prostheses to prevent leakage might be useful as a carrier of antibiotics for the prevention of local graft infection. Sisomicin (SISO) was incorporated into fibrin glue (SISO-FG) and evaluated as to its safety and pharmacokinetics. SISO (1.75 mg) -FG Dacron grafts were implanted subcutaneously in the anterior abdominal region of Sprague-Dawley rats, and then the changes in SISO concentrations in the serum and in the tissue around the implantation sites were compared with those same sites in rats that had had intravenous injection of SISO (1.75 mg). The serum SISO concentrations were significantly lower in the SISO-FG Dacron graft group than they were in the intravenous injection group. However, until 4 h after implantation the SISO concentrations in the tissues around the implantation sites were significantly higher in the SISO-FG Dacron group than they were in the iv injection group, and the peak concentrations during that time were 5.8 times higher for the SISO-FG Dacron group than they were for the intravenous injection group. The ratio of the area under the tissue concentration time curve of SISO (AUC tissue) after implantation of the SISO-FG Dacron graft to that after intravenous injection of SISO was 13.08. Therefore, FG was considered to control the release of SISO into the serum and to maintain a high SISO concentration in the tissue around the implantation site. Clinically, SISO (45 mg) -FG was applied directly to the Dacron grafts implanted in 10 patients who underwent prosthetic vascular reconstruction. No graft infection was observed in any of the patients who received SISO-FG Dacron grafts. The mean serum concentration of SISO was 0.65+/-0.17 microg/mL after 1 h and 0.33+/- 0.21 microg/mL after 3 h. The results of these clinical applications are in close correlation with those of the animal experiment and suggest that FG is useful as a carrier of SISO, allowing its controlled release for the prevention of local infection.

Prevention of Vascular Graft Infection by Sisomicin Incorporated into Fibrin Glue

To examine the efficacy of sisomicin (SISO) incorporated into fibrin glue (FG) for the prevention of graft infection in animal models, the susceptibility to infection of Dacron grafts (control) and SISO‐FG Dacron grafts following the inoculation of Staphylococcus aureus or S. epidermidis was compared. The results showed that SISO‐FG Dacron grafts displayed resistance to graft infection.

The Latent Risk of Acidosis in Commercially Available Total Parenteral Nutrition (TPN) Products: a Randomized Clinical Trial in Postoperative Patients

To evaluate the latent risk of acidosis in commercially available total parenteral nutrition (TPN) products, three types of commercially available TPN products were compared in postoperative patients. Sixty-four hospitalized patients with gastro-intestinal disease who undertook curative gastro intestinal resection were studied prospectively and administered with TPN solutions. Three types of commercially available TPN products were assigned randomly to eligible patients. Serial studies of blood acid-base status, serum electrolytes, and urinary acid-base status were conducted in the three groups administered with different TPN solutions. Patients received appropriate electrolytic solutions on the operation day and TPN solution from 2 to 7 days after operation. There were no differences among any of the serum electrolytes in the three groups. In one group, urinary pH decreased slightly and urinary net acid excretion (NAE) increased significantly after administration. This TPN product contains about 40 mEq/L of non-metabolizable acid to avoid the Maillard reaction that produces a complex of glucose and amino acids. Urinary NAE did not change in the other two groups. These TPN products do not use non-metabolizable acid to adjust pH. The present results suggest that the non-metabolizable acid may be a risk factor of metabolic acidosis.