Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate

The aim of the present study was to improve the solubility and oral bioavailability of a poorly water-soluble drug, 3-bis(4-methoxyphenyl) methylene-2-indolinone (TAS-301), by its melt-adsorption on a porous calcium silicate, Florite RE (FLR), without any solvents. The melt-adsorbed products were prepared by two methods: the small-scale batch method and the twin screw extruder method. The drug was melted and adsorbed on FLR (i.e., "melt-adsorption"), above its melting point. Crystallinity of the drug in the melt-adsorbed product was estimated by differential scanning calorimetry (DSC) and powder X-ray diffraction analysis. The dissolution test was conducted by the JP XIII paddle method. Oral absorption of the melt-adsorbed product was studied in fasted and fed dogs. The melt-adsorbed products prepared by the two methods were in powder forms. The drug existed in an amorphous state in the product and hardly recrystallized even after storing at a stressed condition (60 degrees C/80% RH for 3 days). The TAS-301 dissolution rate from the melt-adsorbed product was markedly enhanced compared with drug crystals. The area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) values of the drug after dosing the melt-adsorbed product were significantly greater than those after dosing the drug crystals. The solubility and bioavailability of TAS-301 were improved by its melt-adsorption on FLR. The present findings suggest melt-adsorption is a useful technique for improving solubility and bioavailability of poorly water-soluble drugs.     

High-dose-rate intracavitary brachytherapy: results of analyses of late rectal complications

: To examine the incidence of radiation-induced late rectal complications by analyzing the data of measured rectal doses in patients with cancer of the uterine cervix treated with high-dose-rate intracavitary brachytherapy.

: We measured doses to the rectum in 105 patients with cancer of the cervix during high-dose-rate intracavitary brachytherapy with a semiconductor dosimeter that can measure five points in the rectum simultaneously. On the basis of these measurements, equivalent doses, to which the biologically equivalent doses were converted as if given as fractionated irradiation at 2 Gy/fraction, were calculated as components of the cumulative dose at five rectal points in intracavitary brachytherapy combined with the external whole pelvic dose.

: The calculated values of equivalent doses for late effects at the rectum ranged from 15 to 100 Gy (median 60 Gy for patients who did not develop complications and 76 Gy for patients who subsequently developed Grade II or III complications). When converted to a graph of absolute rectal complication probability, the data could be fitted to a sigmoid curve. The data showed a very definite dose-response relationship, with a threshold for complications at approximately 50 Gy and the curve starting to rise more steeply at approximately 60 Gy. The steepest part of the curve had a slope equivalent to approximately 4% incidence/1 Gy increase in equivalent doses.

: The radiation tolerance dose, 5% and 50% complication probability, was about 64 and 79 Gy, respectively. Our data almost agree with the prescribed dose for the rectum for the radiation tolerance doses on the basis of the recorded human and animal data. The probability of rectal complications increased drastically after the maximal rectal dose was >60 Gy.     

Increased expression of sialyl Lewis(x) antigen in penetrating growth type A early gastric cancer

Early gastric cancer can be divided morphologically into two categories, penetrating growth type-A (Pen-A type) and other growth types (non-Pen-A types). Sialyl Lewis(x) antigen has been demonstrated to play an important role in tumor metastasis by serving as a functional ligand in the cell adhesion system. The aim of this study is to ascertain whether or not sialyl Le(x) antigen expression correlates with tumor growth patterns of early gastric carcinoma. An immunohistochemical assay was performed using monoclonal antibody CSLEX1 in 12 Pen-A type and 79 non-Pen-A type cancers. Scoring was based on the percentage of immunoreactive cells: negative, low expression (< or = 25%), and high expression (> 25%). Lymph node metastasis was found more frequently in Pen-A type than non-Pen-A type cancers (P=0.0004). Furthermore, sialyl Le(x) antigen high expression was detected more often in Pen-A type cancers (7 out of 12; 58.3%) than non-Pen-A type cancers (13 out of 79; 16.5%) (P=0.0036). Multivariate logistic regression analysis showed that these variables are related independently to the Pen-A type and the non-Pen-A type tumor growth patterns. These data suggest that the difference in sialyl Le(x) antigen expression between the Pen-A type and non-Pen-A type tumor growth patterns of early gastric cancer may, at least partially, reflect different biological behavior during tumor progression.     

Difference in prognostic value between sialyl Lewis(a) and sialyl lewis(x) antigens in blood samples obtained from the drainage veins of the colorectal tumors

Subtraction values, (i.e. values obtained by subtracting the serum titer of sialyl Lewis(a) (CA19-9) and sialyl Lewis(x) (SLX) antigens in peripheral venous blood from the serum titer of the same antigen in the tumor's drainage venous blood) were determined in order to clarify whether or not such values for these specific antigens (d-CA19-9 and d-SLX) are prognostic factors after resection for colorectal cancer. The blood samples were obtained from 144 colorectal cancer patients during surgical excisions of the tumors. Univariate and multivariate analyses revealed that d-SLX level was an independent prognostic factor, separate from stage, while d-CA19-9 level did not have any additional prognostic value. In conclusion, a high d-SLX level is a predictor of poor outcome after surgery.     

Improvement of oligoasthenozoospermia in epileptic patients on switching anti-epilepsy medication from sodium valproate to phenytoin

We present two cases of infertile male patients with oligoasthenozoospermia who were receiving anti-epilepsy medication. Complete reversal of the spermatic dysfunction followed by a successful conception was achieved after discontinuation of sodium valproate, suggesting that the drug was responsible for spermatic dysfunction in these individuals.     

Capillary angiogenesis and remodeling induced in rat limb by arteriovenous shunting

Capillary angiogenesis and remodeling induced by arteriovenous (AV) shunting in rat hind limb was investigated by evaluating changes in capillary density and diameter in the skeletal muscle subject to retrograde flow and high pressure. Wistar rats were used, and an AV anastomosis was created in the hind limb. Two weeks after AV shunting, the microvasculature in the limb was visualized by GS-lectine, and the samples were observed using confocal laser microscopy. The capillary density were increased by approximately 150% for small vessels (<13 microm in diameter) under retrograde flow condition, but no change appeared for large vessels (>13 microm in diameter). The capillary diameters were not significantly different between control and chronic condition. In conclusion, retrograde flow produced by AV shunting increased capillary density but it did not change the capillary diameter significantly.     

Heterogeneity of capillary flow in the retrograde microcirculation induced in rat limb by arteriovenous shunting

Arteriovenous (AV) fistulas have been used clinically for improving adjunctive bypass patency. Such AV shunting induces retrograde flow in the microvascular network, which may induce microvascular remodeling and angiogenesis at the chronic phase. This paper was aimed to examine heterogeneity of blood flow among capillaries in the retrograde microcirculation induced by AV shunting. An AV anastomosis was created in rat hind limb. Using a dual window method or frame-by-frame technique on the fluorescence microscopic video images, we measured velocities of red blood cells (RBCs) flowing in the capillary network in three flow conditions: control (normal flow), arterial occlusion, and AV shunting (retrograde flow). For each flow condition, RBC velocities were obtained in 155 capillaries of 6 rats. By classifying all the capillaries into four groups based on the levels of RBC velocity in the occlusion state, we evaluated the mean velocities, coefficient of variation (CV), and histograms for each group of capillaries. The mean velocity and CV in each group changed significantly from the control to AV shunting states. Especially, most significant changes appeared in capillary groups where the superficial femoral artery or its collateral arteries might have a direct influence. Though the AV shunting improved capillary perfusion in the mean level, major parts of capillaries still remained at low perfusion.     

Effective antigen-retrieval method for immunohistochemical detection of abnormal isoform of prion proteins in animals

For immunohistochemistry of the prion diseases, several pretreatment methods to enhance the immunoreactivity of human and animal abnormal proteinase-resistant prion protein (PrP^Sc) on the tissue sections have been employed. The method of 121°C hydrated autoclaving pretreatment or the combination method of 121°C hydrated autoclaving with a certain chemical reagent (formic acid or proteinase K, etc) are now widely used. We found that an improved hydrated autoclaving method at 135°C, more effectively enhanced PrP^Sc immunoreactivity for the antibodies recognizing the linear epitope. In addition, this method was more effective for the long-term fixation samples as compared with other previous methods. However, this modified method could not retrieve PrP^Sc antigenic epitopes composed of conformational structures or several discontinuous epitopes. We describe the comparative studies between our improved method and other antigen-retrieval procedures reported previously. Based on the differences of reaction among the antibodies, we also discuss the mechanisms of the hydrated autoclaving methods to retrieve PrP^Sc immunoreactivity.     

Apparent diffusion coefficient of human brain tumors at MR imaging

PURPOSE: To determine if apparent diffusion coefficient (ADC) can be used to differentiate brain tumors at magnetic resonance (MR) imaging. MATERIALS AND METHODS: Institutional review board approval or informed patient consent was not required. MR images were reviewed retrospectively in 275 patients with brain tumors: 147 males and 128 females 1-81 years old, treated between September 1997 and July 2003. Regions of interest were placed manually in tumor regions on MR images, and ADC was calculated with a five-point regression method at b values of 0, 250, 500, 750, and 1000 sec/mm2. ADC values were average values in tumor. All brain tumor subgroups were analyzed. Logistic discriminant analysis was performed by using ADC, age, and patient sex as independent variables to discriminate among tumor groups. RESULTS: A significant negative correlation existed between ADC and astrocytic tumors of World Health Organization grades 2-4 (grade 2 vs grades 3 and 4, accuracy of 91.3% [P < .01]; grade 3 vs 4, accuracy of 82.4% [P < .01]). ADC of dysembryoplastic neuroepithelial tumors (DNTs) was higher than that of astrocytic grade 2 tumors (accuracy, 100%) and other glioneuronal tumors. ADC of malignant lymphomas was lower than that of glioblastomas and metastatic tumors (accuracy, 83.6%; P < .01). ADC of primitive neuroectodermal tumors (PNETs) was lower than that of ependymomas (accuracy, 100%). ADC of meningiomas was lower than that of schwannomas (accuracy, 92.4%; P < .01). ADC of craniopharyngiomas was higher than that of pituitary adenomas (accuracy, 85.2%; P < .05). ADC of epidermoid tumors was lower than that of chordomas (accuracy, 100%). In meningiomas, ADC was not indicative of malignancy grade or histologic subtype. CONCLUSION: ADC is useful for differentiation of some human brain tumors, particularly DNT, malignant lymphomas versus glioblastomas and metastatic tumors, and ependymomas versus PNETs.