Comparison of Phosphate Binding Capacities of PA21, A Novel Phosphate Binder, with those of other Phosphate Binders in vitro and in vivo.

PURPOSE: The phosphate binding capacity of PA21, a novel phosphate binder, was compared with those of other phosphate binders in vitro and in vivo. METHODS: 1) For in vitro studies, PA21, sevelamer hydrochloride, lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate were incubated with a phosphate solution at 37°C for 2 h. Phosphate binding capacity was assessed at simulated gastrointestinal tract pH levels of 2, 5, and 8 for estimation of clinical effects, and the quantity of phosphate adsorbed by each phosphate binder was determined. 2) For in vivo studies, rats were orally administered various phosphate binders after the oral administration of phosphate solution (100 mg/kg) adjusted to pH 2, 5, or 8, and the effects of PA21 and other phosphate binders on the serum phosphorus level of the rats were investigated. RESULTS: 1) The in vitro studies revealed that PA21 and sevelamer hydrochloride adsorbed phosphate better at all tested pH levels than lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate, and PA21 showed the most potent phosphate binding capacity among the tested compounds. 2) The in vivo studies showed that PA21 dose-dependently inhibited the increase in the serum phosphorus level after the administration of phosphate solution and no difference in the extent of inhibition by PA21 was observed at the different pH levels (in contrast to other phosphate binders). CONCLUSION: These results indicated that PA21 has a phosphate binding capacity over the entire pH range of the GI tract.

Efficacy of Mitiglinide Combined with Dapagliflozin in Streptozotocin-nicotinamide-induced Type 2 Diabetic Rats and in Zucker Fatty Rats.

The efficacy of the combination of the rapid-acting insulin secretagogue mitiglinide and the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin was explored in streptozotocin-nicotinamide-induced type 2 diabetic (STZ-NA) rats and in Zucker fatty (ZF) rats. The STZ-NA rats were prepared at 8 weeks of age. At 9 weeks of age, the combination study was conducted by oral glucose tolerance test (OGTT). At 13 weeks of age, ZF rats were dosed orally with dapagliflozin once daily up to the 22(nd) day. At days 15 and 22, the combination study was conducted by OGTT. In 2 different animal models, plasma glucose levels were strongly suppressed by the combination of mitiglinide and dapagliflozin as compared with either drug alone. The urinary glucose excretion was drastically elevated in the dapagliflozin group, but the combination with mitiglinide suppressed it about 50%. In STZ-NA rats, the plasma insulin secretion by the combination of both drugs was about at the same level as in the mitiglinide group. In ZF rats, the plasma insulin secretion by the combination of both drugs was less than mitiglinide group. Thus, in 2 different animal models, the combination of mitiglinide and dapagliflozin showed stronger antihyperglycemic action accompanied by less insulin secretion than mitiglinide alone, and reduced the urinary glucose excretion as compared with dapagliflozin used alone. These results indicate that the combination of mitiglinide and dapagliflozin can be a promising combination for the treatment of diabetic patients.

Basic study on a lower-energy defibrillation method using computer simulation and cultured myocardial cell models.

Computer simulation and myocardial cell models were used to evaluate a low-energy defibrillation technique. A generated spiral wave, considered to be a mechanism of fibrillation, and fibrillation were investigated using two myocardial sheet models: a two-dimensional computer simulation model and a two-dimensional experimental model. A new defibrillation technique that has few side effects, which are induced by the current passing into the patient's body, on cardiac muscle is desired. The purpose of the present study is to conduct a basic investigation into an efficient defibrillation method. In order to evaluate the defibrillation method, the propagation of excitation in the myocardial sheet is measured during the normal state and during fibrillation, respectively. The advantages of the low-energy defibrillation technique are then discussed based on the stimulation timing.

Platelet function in sepsis.

BACKGROUND: Coagulation abnormalities and thrombocytopenia are common in severe sepsis, but sepsis-related alterations in platelet function are ill-defined. OBJECTIVES: The purpose of this study was to elucidate the effect of sepsis on platelet aggregation, adhesiveness, and growth factor release. PATIENTS AND METHODS: Agonist-induced platelet aggregation was measured in platelet-rich plasma separated from blood samples collected from 47 critically ill patients with sepsis of recent onset. Expression of platelet adhesion molecules was measured by flow cytometry and the release of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) was measured by ELISA in the supernatant of platelet aggregation. RESULTS: Septic patients had consistently decreased platelet aggregation compared with controls, regardless of the platelet count, thrombin generation, or overt disseminated intravascular coagulation (DIC) status. The severity of sepsis correlated to the platelet aggregation defect. Adhesion molecules, receptor expression (CD42a, CD42b, CD36, CD29, PAR-1), and alpha-granule secretion detected by P-selectin expression remained unchanged but the release of growth factors was differentially regulated with increased VEGF and unchanged PDGF after agonist activation even in uncomplicated sepsis. CONCLUSIONS: Sepsis decreases circulating platelets' hemostatic function, maintains adhesion molecule expression and secretion capability, and modulates growth factor production. These results suggest that sepsis alters the hemostatic function of the platelets and increases VEGF release in a thrombin-independent manner.

[Complications in home treatment of patients with severe disturbances of consciousness].

We have been providing home treatment for patients with severe disturbance of consciousness requiring various medical treatments for about 10 years. In the 65 cases we have encountered, we studied complications during the course of the home treatment. The proportions of infections, decubiti and convulsions were found to be very high. With infections in particular, conditions worsened rapidly in many cases, so we made it a principle to have the patients hospitalized early. We also investigated changes in serum albumin levels, peripheral blood lymphocyte count and prognostic nutritional index (PNI). Patients who develop infections repeatedly and succumb to early death often show low values for PNI and lymphocyte count. The low values are considered useful as one indicator of the general conditions of patients under home treatment. For the management of patients with severe disturbances of consciousness, it is important to keep a close liaison with other departments or hospitals and strengthen home nursing sections.

Efficacy of oral fluconazole in tinea pedis of the hyperkeratotic type. Stratum corneum levels.

In this study, in addition to studying the efficacy and safety of the once-daily administration of 100-mg capsules of fluconazole over an 8-week administration period with six patients with hyperkeratotic-type tinea pedis, we also measured the serum and horny layer concentrations of fluconazole to study the mobility into the horny layer in diseased areas of the sole skin. The final overall efficacy and overall safety were both 100% (six out of six), and no side-effects, including abnormal laboratory changes, were observed in any of the patients. The drug mobility study revealed that in the horny layer of the skin a steady state was reached after 4 weeks of administration, with the mean concentration being 12.8 micrograms g-1. This concentration was a high concentration that was no less than 13 times the geometric mean MIC (0.972 microgram ml-1) for fresh clinical isolates of Trichophyton rubrum. Based on the above results, fluconazole is considered to be highly useful for treating various kinds of dermatomycosis, including hyperkeratotic-type tinea pedis.

Lichen planus annularis: an immunohistochemical study.

Lichen planus annularis is a relatively rare skin manifestation of lichen planus. The mechanisms in the formation of annular lesions are not fully understood. We reported here a 57-year-old female with this disease. The eruption initially occurred as lichen-papules, then enlarged (bean-sized, umbilicated small plaques), and finally developed annular manifestations. We performed immunohistochemical examinations of specimens taken from different types of eruptions. In all specimens, HLA-DR was expressed in the focal keratinocytes adjacent to the dermal HLA-DR positive cell infiltration. Both in the initial papule and in the final annular lesion, expression of ICAM-1 was present only in the keratinocytes above the dermal cell infiltration, similar to HLA-DR. It is of interest that, in the umbilicated small plaques, the peripheral epidermis other than the central site extensively reacted to ICAM-1. LFA-1 expression was most prominent in the mononuclear cells impinging on the dermo-epidermal junction in all specimens. In addition, in the periphery of the umbilicated small plaques, which showed no bandlike dense cell infiltration nor degeneration of basement membrane, TNF-alpha, but not LFA-1, was positive in the infiltrated cells of the upper dermis. These results suggest that expressions of ICAM-1 and TNF-alpha in the peripheral keratinocytes and dermal infiltrated cells are important molecular events in the mechanisms of formation of the annular lesions.

Significance of monocytosis in varicella and herpes zoster.

Percent ratios and absolute numbers of peripheral blood monocytes in patients with varicella and herpes zoster were determined and compared with those in patients with herpes simplex virus infection, measles and rubella. Monocytosis during the acute stage (p less than 0.01) was statistically significant in varicella and generalized and localized herpes zoster, compared with the levels in herpes simplex virus infection, measles and rubella. Absolute monocyte counts in varicella and HZ were significantly increased (p less than 0.02) beyond those of measles and rubella. The high % ratios of monocytes in varicella and herpes zoster during the acute stage decreased to normal ranges with cure.