Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial.

We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by -0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (-0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

Bone-bonding ability of a hydroxyapatite coated zirconia-alumina nanocomposite with a microporous surface.

Using a combination of hydroxyapatite (HA) coating and microporous surface treatment, bone-bonding ability was given to composites of ceria-stabilized tetragonal zirconia and alumina (CZA), which possesses excellent mechanical and wear properties and phase stability. Four types of CZA plates (2 x 10 x 15 mm3) were prepared for this study, which were CZA with a polished surface (group 1), a microporous surface prepared by hydrofluoric acid and heat treatment (group 2), a microporous surface with a submicron HA coating prepared by alternately soaking the plate from group 2 in aqueous CaCl2/HCl and Na2HPO4 solutions (group 3), and a microporous surface with a 4-microm HA coating prepared by the biomimetic method, where the plates from group 3 were soaked in simulated body fluid (group 4). Plates were implanted into rabbit tibia, and after 4, 8, and 16 weeks, tensile testing and histological examination of the bone-implant interface were conducted. At 4 weeks, group 4 had superior bone-bonding ability compared with other implants, which was maintained at the later postimplantation times. This HA-coated CZA with a microporous surface has the possibility of clinical use as a bearing material in cementless joint prostheses or as a load-bearing bone substitute.

Development of a phantom compatible for MRI and hyperthermia using carrageenan gel--relationship between dielectric properties and NaCl concentration.

A phantom has previously been developed containing carrageenan, agarose and gadolinium chloride (called CAG phantom) for MRI with 1.5 T. T(1) and T(2) relaxation times of this phantom are independently changeable by varying concentrations of relaxation-time modifiers to simulate relaxation times of the various types of human tissues. The CAG phantom has a T(1) value of 202-1904 ms and a T(2) value of 38-423 ms, when the GdCl(3) concentration is varied from 0-140 micromol/kg and the agarose concentration is varied from 0-1.6%. A new phantom has now been developed (called CAGN phantom), made by adding an electric conductive agent, NaCl, to the CAG phantom for use in the areas of MRI and hyperthermia research. Dielectric properties of the CAGN phantom were measured and the results of experiments were expressed by the Cole-Cole equation in the frequency range of 5-130 MHz. The relationship between the conductivity of the CAGN phantom and the concentration of NaCl was expressed by a linear function in the frequency range of 1-130 MHz. The linear function involves a parameter of frequency and, when the frequency is 10 MHz, the conductivity of the CAGN phantom can be changed from 0.27-1.26 Sm(-1) by increasing the NaCl concentration from 0-0.7%. The CAGN phantom developed can be employed in basic experiments for non-invasive temperature measurement using MRI and as a loading phantom for MRI with up to 3 T.

The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours.

It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3), a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5 degrees C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.

Cepharanthin enhances thermosensitivity without a resultant reduction in the thermotolerance of a murine mammary carcinoma.

Cepharanthin (Ce) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. The results of our previous in vitro study indicated that Ce reduces thermotolerance by enhancing thermosensitivity. In the present study, we investigated the in vitro and in vivo effects of Ce on thermosensitivity and thermotolerance using a murine mammary carcinoma, MCa, and C3H/HeN mice. Ce enhanced the thermosensitivity of MCa cells for heating at 44 degrees C not only in vitro but also in vivo. The in vivo enhancement ratio +/- SD of Ce at 100 mg/kg for heating at 44 degrees C was 1.3+/-0.3. The fractionated heat treatments at 44 degrees C for 30 and 60 min with an interval time of 0-6 days resulted in the development of remarkable thermotolerance and the expression of heat shock protein 70 in MCa tumors after the first heating. Ce at 100 mg/kg given immediately after the first heating increased the expression of heat shock protein 70 in MCa tumors, and did not reduce the development of thermotolerance. Ce given immediately before the first or second heating also did not inhibit the thermotolerance. The results of this study suggest that Ce enhances the thermosensitivity of MCa tumors as a thermosensitizer, but that this mild thermosensitizing property of Ce might be insufficient to conquer the remarkable thermotolerance in MCa tumors that develops after the first heating.

A new treatment for penile conservation in penile carcinoma: a preliminary study of combined laser hyperthermia, radiation and chemotherapy.

OBJECTIVE: To investigate the role of laser hyperthermia in penis-conserving therapy for penile carcinoma. PATIENTS, MATERIALS AND METHODS: Penile carcinoma KPK-1 cells were transplanted into nude mice to induce tumour; the effects of laser hyperthermia, the chemotherapeutic agent peplomycin, or their combination on the inhibition of KPK-1 tumour growth were assessed. In a clinical study, two patients with well-differentiated, stage T2 penile tumours with corporeal involvement were treated to conserve the penis using concurrent radiation, laser hyperthermia and peplomycin. They had no pathologically identified regional lymph node metastasis. Radiation was given for 5 days a week for 3 weeks at a total dose of 30 Gy. Nd:YAG laser hyperthermia was administered at 42-43 degrees C for 15 min twice a week for 3 weeks immediately after radiation. Peplomycin (10 mg per day) was administered intravenously over 24 h together with the laser hyperthermia. RESULTS: The combined treatment with laser hyperthermia and peplomycin completely inhibited KPK-1 tumour growth, but the treatment with either laser hyperthermia or peplomycin alone had little effect. The results were also corroborated by the histopathological findings; the necrotic area in mice treated with combined therapy was much larger than that in those treated with laser hyperthermia alone. Both patients given combined laser hyperthermia, radiation and peplomycin were treated successfully, with the penis and sexual function conserved, and both survived for > 7 years with no evidence of any local or regional recurrence. There were no major complications related to the combined treatment. CONCLUSIONS: This preliminary study showed that combined treatment with laser hyperthermia, radiation and peplomycin might be a promising therapy for conserving the penis in some patients with stage T2 penile tumours.

Effect of oral adsorbent AST-120 on cyclosporin absorption in rats.

The oral adsorbent AST-120 is used to inhibit the progression of renal failure by adsorbing uraemic toxins in the gastrointestinal tract. When AST-120 is administered to patients receiving immunosuppressive medicines, it is important to study the effect of AST-120 on the amount of these and other drugs absorbed. We have, therefore, studied the in-vitro adsorption of cyclosporin by AST-120 and investigated the effect of oral administration of AST-120 on the absorption of cyclosporin in rats. The in-vitro adsorption ratios of AST-120 for cyclosporin were more than 80%. When pure cyclosporin powder was administered with AST-120, blood cyclosporin concentrations were significantly higher than when cyclosporin was administered alone. When cyclosporin dissolved in medium-chain triglyceride was administered to rats by intramuscular injection there was no significant difference in the blood cyclosporin concentration of rats given combined AST-120 and cyclosporin and those given cyclosporin alone. There was no significant difference between the serum concentration of total bile acids, in rats receiving combined oral AST-120 and cyclosporin dissolved in olive oil, and those receiving orally solely a solution of cyclosporin dissolved in olive oil. These results suggest that oral administration of AST-120 accelerates the absorption of orally administered cyclosporin from the gastrointestinal tract and does not affect the metabolism of cyclosporin. When a solution of cyclosporin in olive oil is administered orally, however, oral administration of AST-120 has no influence on cyclosporin absorption and does not affect the enterohepatic circulation of bile acids.