In vitro and in vivo release properties of brilliant blue and tumour necrosis factor-alpha (TNF-alpha) from poly(D,L-lactic-co-glycolic acid) multiphase microspheres

The dissolution properties of two model compounds, brilliant blue and tumour necrosis factor (TNF-alpha), from poly(D,L-lactic-co-glycolic acid) (PLGA) multiphase microspheres were investigated. In addition, the in vivo release of TNF-alpha from the microspheres, in mice, was studied. The microspheres were prepared by an anhydrous multiple emulsion solvent evaporation method. Multiphase microspheres containing brilliant blue exhibited a three phase release profile in vitro, and displayed a significantly lower level of dye released during the initial phase compared to conventional matrix-type microspheres. Slow release of the dye was observed during the second phase, which was followed by a disintegration of the polymer wall during the third phase of the release process. In vitro dissolution profiles of TNF-alpha were calculated by compensation for the simultaneous degradation of the protein in the dissolution medium. The initial burst release of TNF-alpha was significantly reduced with the multiphase microspheres. The three phase release profile, as seen with the dye, was not observed for the microspheres containing the TNF-alpha. The rate of release of the protein from the microspheres was determined in vivo by analysing the residual level of TNF-alpha remaining in the particles following intraperitoneal administration of the microspheres to mice. The release of the protein from the microspheres in vivo was significantly faster than predicted from the results of the in vitro studies. The absence of an initial burst release of TNF-alpha from the multiphase microspheres was reflected in a significant reduction in the plasma level of TNF-alpha when compared to the matrix-type microspheres and a solution of the protein. The controlled release property of the multiphase microspheres is expected to overcome the adverse reactions due to dose dumping that occurs following the local administration of TNF-alpha.     

Effects of pirarubicin,an antitumor antibiotic,on the cardiovascular system

Summary In the present study we examined the effects of pirarubicin [(2R)-4-0-tetrahydropyranyladriamycin, THP] on a cardiovascular system. An injection of THP (0.39–3.13 mg/kg, i. v.) reduced the mean blood pressure and caused an increase in the respiratory air rate in anesthetized rats. At 1.5×10^–6–1.5×10^–5 m, THP markedly relaxed a contraction induced by 10^–7 m norepinephrine in rat aorta with endothelium but not in that without endothelium. At a dose of 0.02–0.5 mg, THP produced an increase in the contractile force and the perfusion flow of isolated perfused guinea pig hearts. At a higher concentration (4.5×10^–5–1.5×10^–4 m), it produced a slight increase in the contractile force of the left atria in guinea pigs. This positive inotropic action of THP was inhibited by diphenhydramine (10^–6–5×10^–5 m), chlorpheniramine (3×10^–7–3×10^–5 m), and tripelennamine (3×10^–7–3×10^–5 m) but not by propranolol (10^–6 m), cimetidine (10^–5 m), diltiazem (10^–6 m), or ryanodine (10^–8 m). THP given i. v. at 2.5 mg/kg elevated the plasma histamine level in anesthetized dogs. From these data, we conclude that THP mainly relaxed the rat aorta in the presence of endothelium and that at higher concentrations, it increased the contractile force in the cardiac muscle, probably mediated through the release of histamine.     

Hand-arm vibration syndrome and its prevalence in the present status of private forestry enterprises in Japan

Summary Currently there are no limitations on age of employment on private forestries in Japan. Hence, it was hypothesized that in these kind of enterprises, elderly chain saw operators, or those with long-term exposure, might be at higher risk of developing hand-arm vibration syndrome (HAVS). We consequently investigated the prevalence of HAVS in 447 chain saw workers on private forestries in Gifu Prefecture, Japan, with particular reference to age and exposure period. Of this population, 43 (9.6%) had signs and symptoms of vibration-induced white finger (VWF), and among these workers the severity of finger blanching was significantly correlated (P < 0.01) with the exposure period. Classification of all subjects by exposure period showed that workers with 30 years' exposure had higher prevalences of VWF (20.9%) and numbness of the hands (25.4%) compared to other groups. Significant differences (P < 0.01) were found between the functional capacities of workers with VWF and those of control subjects. We concluded that (a) the elderly chain saw operators and those with longer exposure should be moved to other jobs with a lower or no risk of exposure to vibration, and (b) the results of screening tests, even without cold water immersion (which we did not employ, in order to protect workers' hands), could be helpful for the identification of workers with VWF.     

Induction of active melanocytes in mouse skin by carcinogens: a new method for detection of skin carcinogens

Application of potent skin carcinogens, such as 7, 12-dimethylbenz[a]anthracene,3-methylcholanthrene, benzo[a]pyrene and 4-nitroquinoline-1-oxide,induced numerous dihydroxyphenylalanine (dopa)-positive cellsin the interfollicular epidermis of C57BL/6 mice in a dose-and time-dependent fashion. Chrysene, a weak skin carcinogen,and croton oil, a tumor promoter, also induced 3–4 timesmore dopa-positive cells than acetone. Liver carcinogens, suchas 3'-methyl-4-di-methylaminoazobenzene and N-2-acetylaminofluorene,and non-carcinogenic aromatic hydrocarbons, such as anthracene,fluoranthene, fluorene and pyrene, did not induce increase inthese cells. These results indicate that increase in the numberof dopa-positive cells after application of chemicals is wellcorrelated with the abilities of these compounds to induce skincarcino-genesis and suppress sebaceous glands.     

Current advances in rhinomanometry

Current advances in rhinomanometry were reviewed in this paper. Active posterior rhinomanometry with a “head-out” body plethysmograph may be the least invasive method currently available for measuring nasal patency. In general, active anterior rhinomanometry with a face mask or a nasal nozzle has been employed in various studies throughout the world. Nasal resistance as calculated from the equationR = 0.78 (ΔP/V)^1.33 at any points on a pressure/flow curve, or averaged nasal resistance may be the most suitable expression for nasal patency. Values for nasal resistance at ΔP 100 Pa in Japanese patients or ΔP 150 Pa in Caucasians have been widely employed as standard objective data for nasal obstruction, although rhinomanometric results sometimes do not agree with subjective evaluation of nasal obstruction. Nasal airflow acceleration or peak flow index during nasal breathing at rest can be applied as warranted to confirm an objective diagnosis of symptomatic nasal obstruction. Further, nationality and anthropological characteristics can be related to the severity and type of stuffiness.     

A 5 year follow-up study on the relationship between changes in serum lipids and blood pressure, and changes in exercise habits in subjects 30 years of age

A 5 year follow-up study was conducted to investigate the relationships between %changes in serum lipids and blood pressure and corresponding changes in exercise habits in the middle-aged. The subjects were 152 males and 169 females who received a health check-up at 30-years-old during the period between 1990-1992 and then at 35-years-old during the period between 1995-1997. The results are as follows: 1. In multiple regression analysis, % delta toriglyceroid (TG) and % delta AI(atherogenic index) ratio were associated significantly with changes in exercise habits in males (P < 0.05) and % delta high density lipoprotein cholesterol (HDLC) was associated with changes in exercise habits in females (P < 0.05). % delta TG and % delta HDLC were affected by changes in exercise habits adjusted for BMI, smoking, and drinking. But changes in TC and blood pressure were not affected by changes in exercise habits. 2. In males, % delta TG was significantly lower in those subjects who started their exercise habit than in the no exercise group and than in those within the ceased exercise group who ceased their exercise during the study period (P < 0.05). % delta AI was significantly lower in the started exercise group than in the no exercise group. Also, the continued exercise group had a significantly (P < 0.05) lower % delta AI as compared to the ceased exercise group. In females, % delta TG was significantly lower in the started exercise group than in the no exercise group (P < 0.05). % delta HDLC was higher significantly in the continued exercise group than in the ceased exercise group (P < 0.05). From the results obtained, it is recommended that the no exercise subjects should have exercise more than once time per week and those with more than 1 time per week maintain their exercise habits.     

Tumor-specific Activation of Mitogen-activated Protein Kinase in Human Colorectal and Gastric Carcinoma Tissues

To search for the signaling events in colorectal carcinoma relevant to its tumorigenesis, we investigated the activity of mitogen-activated protein kinase (MAPK) in human colorectal carcinoma tissues and paired normal tissues. Of 64 cases examined, approximately 75% (48 cases) showed tumor-specific activation of MAPK by in situ kinase renaturation assay, as well as in vitro kinase assay with immunoprecipitated MAPK. In addition, tumor-specific activation of MAPK was associated with the activation of MAPK kinase in the cases we examined. However, no clear correlation of MAPK activation with lymph node involvement, metastatic rate, stage, histological classification, age or sex was observed. These results suggest that the MAPK pathway is involved in colorectal tumor development, but its activation alone is not sufficient for malignant conversion. In contrast to colorectal carcinoma, gastric carcinoma tissues showed a lower rate of MAPK activation, suggesting that the signaling pathway activated in colorectal carcinoma tissues may differ in part from that of gastric carcinoma.