Deep learning shows the capability of high-level computer-aided diagnosis in malignant lymphoma.

A pathological evaluation is one of the most important methods for the diagnosis of malignant lymphoma. A standardized diagnosis is occasionally difficult to achieve even by experienced hematopathologists. Therefore, established procedures including a computer-aided diagnosis are desired. This study aims to classify histopathological images of malignant lymphomas through deep learning, which is a computer algorithm and type of artificial intelligence (AI) technology. We prepared hematoxylin and eosin (H&E) slides of a lesion area from 388 sections, namely, 259 with diffuse large B-cell lymphoma, 89 with follicular lymphoma, and 40 with reactive lymphoid hyperplasia, and created whole slide images (WSIs) using a whole slide system. WSI was annotated in the lesion area by experienced hematopathologists. Image patches were cropped from the WSI to train and evaluate the classifiers. Image patches at magnifications of ×5, ×20, and ×40 were randomly divided into a test set and a training and evaluation set. The classifier was assessed using the test set through a cross-validation after training. The classifier achieved the highest levels of accuracy of 94.0%, 93.0%, and 92.0% for image patches with magnifications of ×5, ×20, and ×40, respectively, in comparison to diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia. Comparing the diagnostic accuracies between the proposed classifier and seven pathologists, including experienced hematopathologists, using the test set made up of image patches with magnifications of ×5, ×20, and ×40, the best accuracy demonstrated by the classifier was 97.0%, whereas the average accuracy achieved by the pathologists using WSIs was 76.0%, with the highest accuracy reaching 83.3%. In conclusion, the neural classifier can outperform pathologists in a morphological evaluation. These results suggest that the AI system can potentially support the diagnosis of malignant lymphoma.

Quantitative analysis of the effect of supersaturation on in vivo drug absorption.

The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.

A theoretical-empirical analysis on the initial dissolution rate of drugs from polydispersed particles.

The purpose of this work is to clarify the relationship of mean particle size to the dissolution rate of polydispersed particles for Biopharmaceutical Classification System (BCS) Class II drugs. An equation for the initial dissolution rate of polydispersed particles relative to mean particle diameter was theoretically derived from the Noyes-Whitney equation assuming spherical particles and sink conditions. To verify the relationship of dissolution to the mean particle diameters, the dissolution rates of 6 types of hypothetically-generated log-normal polydispersed particles and 3 different sized particles of aprepitant, a designated BCS class II drug, were compared with known mean diameters calculated according to surface area-weighted mean diameter (D(3,2), commonly referred to as the Sauter mean diameter), length-weighted mean diameter (D(3,1)) and number-weighted mean diameter (D(3,0)). The results confirmed that the initial dissolution rates of polydispersed particles reflect the mean diameter and correlated best with the reciprocal of D(3,2) at the start of dissolution, in accord with our theoretical conclusions. The particle size required for sufficient dissolution of aprepitant was also investigated by examining the relationship between D(3,2) and oral absorption predicted using a physiological-based model.

Slow release of tetracycline from a mucoadhesive complex with sucralfate for eradication of Helicobacter pylori.

Treatment composed of a gastric mucoadhesive antibiotic with slow release drug delivery is expected to be effective for the eradication of Helicobacter pylori (H. pylori). In this study, we evaluated the slow release property of the tetracycline-sucralfate acidic complex. Tetracycline was the antibiotic selected because of its complexation capacity with sucralfate. Sustained release was tested using two different dissolution test methods: paddle and flow-through cell. The adhesive paste formed from the acidic complex displayed a longer sustained release profile of tetracycline using flow-through cell method. The milder conditions of the flow-through cell method better mimicked the fasted state of the stomach, suggesting that the oral administration with fasting is appropriate for the acidic complex. Furthermore, the paste formation protected the tetracycline from decomposition under an acidic condition, which apparently contributes to long-term release. Change in the zeta potential of the acidic complex particles was helpful in clarifying the release mechanisms of the tetracycline. The data indicated that the immediate release of tetracycline in the early stage of the test was indispensable to the subsequent paste formation that enables slow release. If administrated orally with fasting, the acidic complex rapidly adheres to the gastric mucosa and sustains long-term release of the tetracycline to the gastric lumen or mucus layer. This antibiotic delivery mechanism, which requires only a minimum dosage, may be effective for efficient eradication of H. pylori.

The acidic complexation of tetracycline with sucralfate for its mucoadhesive preparation.

The complex of antibiotics with sucralfate (SF) was prepared with acid. The mechanism of the complexation and some factors concerning the preparation, which influence the mucoadhering property, were studied. The complexation was confirmed by the change in color and instrumental analysis. The acidic complex appeared to be produced by reagglomeration of SF preliminary particles. It was suggested that the amide or amine groups of tetracycline (TC) and aluminum moieties of SF serve as the binding sites. The potential of multiple binding sites and a priority in them were suggested by the Scatchard plot analysis. The additional amounts of acid and the increase in the surface area increased the number of sites. The amount of the additional acid appeared to be the most important factor during the preparation of the acidic complex. The appropriate amount of acid added appeared to produce a complex rich in TC. However, an excess amount might cause the excess dissociation of aluminum moieties, which destroys the mucoadhesive paste-forming property.

[Anti-allergic action effect of Pseudolarix amabilis Rehd. extract and its efficacy on atopic dermatitis].

Pseudolarix amabilis Rehd. extract was examined in vitro for antibacterial effects, anti-inflammatory effects, and inhibitory effects on histamine release. Pseudolarix amabilis Rehd. extract was also examined for efficacy on dermatitis in atopic dermatitis model mice (NC mice) and effects on keratinous moisture level and transepidermal water loss in miniature pigs. Pseudolarix amabilis Rehd. extract had antibacterial effects on Staphylococcus aureus, Candida albicans, and Streptococcus pyogenes; however this antibacterial effect varied with the temperature at which and conditions under which Pseudolarix amabilis Rehd. was extracted. Pseudolarix amabilis Rehd. extract at the final concentration of 2 mg/mL significantly inhibited the hyaluronidase activity; and at 0.005, 0.05, and 0.5 mg/mL, it also significantly inhibited the histamine release. In the mice in which atopic dermatitis had been induced, 28-day administration of Pseudolarix amabilis Rehd. extract at 4 and 400 mg/mL significantly inhibited aggravation of dermatitis without having effects on body weight. In the dorsal skin of miniature pigs, Pseudolarix amabilis Rehd. extract at 4 and 400 mg/mL significantly increased keratinous moisture level with the increase in the number of dosing days, and caused no changes in transepidermal water loss. From the above results, it is clear that Pseudolarix amabilis Rehd. extract inhibits both proliferation of bacteria and inflammation caused by antigens. Furthermore, it is suggested that Pseudolarix amabilis Rehd. extract will serve as a medicinal drug which effectively moistens the skin and prevents and heals dermatitis.

A novel evaluation method of gastric mucoadhesive property in vitro and the mucoadhesive mechanism of tetracycline-sucralfate acidic complex for eradication of Helicobacter pylori.

PURPOSE: The gastric mucoadhesive property of tetracycline-sucralfate acidic complex (CO) was evaluated by using a novel method in vitro to compare with the in vivo test. The mucoadhesive mechanism of the acidic complex was also studied. METHODS: The gastric mucosa removed from a rat was placed covering the end of a plunger and secured in a disposable syringe. The acidic test medium was gradually infused in and then flowed out. Two different kinds of CO, tetracycline, or a physical mixture (PM) were introduced into the device to compare their mucoadhesive properties. The tetracycline content in the residue on the mucosa was measured. The results were compared with those of the in vivo test. The acidic response of CO and the protein binding capacity of a sucrose octasulfate group (SOS) in sucralfate or CO were evaluated. RESULTS: The mucoadhesive properties of CO were clearly superior to those of PM. The remaining amounts of tetracycline in each test sample, determined by the in vitro test, were in agreement with those of the in vivo test. The excellent mucoadhesive property of CO appeared to be caused by the rapid response to the acid and resulting mucoadhesive gel formation. Furthermore, the binding capacity of SOS to the protein was clearly greater than that of PM. The excessive acid treatment during the preparation of CO tended to decrease the mucoadhesive property. CONCLUSIONS: CO appeared to be potentially useful for the eradication of Helicobacter pylori because of the direct delivery of tetracycline to the gastric mucosa for an extended period of time.

[Analysis of scratching behavior in a picryl chloride induced atopic dermatitis model in mice].

To elucidate the actual state of scratching behavior of NC mice noted when PiCl-induced dermatitis occurs, the circadian rhythm in scratching behavior of this mouse model was examined, and the time when scratching behavior, which is useful to evaluate the severity of itch, occurs was assessed. A steroid drug (Prednisolone ointment), which has been confirmed to inhibit dermatitis from worsening, was used to examine whether or not, or how it inhibits scratching behavior in this mouse model. It became clear that scratching behavior increased during a period from the evening to the night in the animals which had not been sensitized (normal animals); compared with the day time, scratching behavior occurred more often in the nighttime. It also became clear that scratching behavior increased in the animals with PiCl-induced dermatitis increase in the frequency of induction of dermatitis, and Prednisolone ointment significantly inhibited scratching behavior in the animals in which dermatitis had been induced with PiCl six times. From these results, it can be said that scratching behavior increases in PiCl-induced mouse atopic dermatitis models correlatively with the increase in the frequency of induction of dermatitis, and steroid drugs decrease the frequency of the scratching behavior. In conclusion, it is strongly suggested that this mouse model is useful for development of therapeutic methods and novel medicinal drugs for atopic dermatitis.