Cardiac functions were evaluated by echocardiography in dogs treated with doxorubicin. The dogs were administered 1.5 mg/kg body-weight doxorubicin intravenously at intervals of 3 weeks. Two-dimensional echocardiography of several sections of the heart was taken and fractional shortenings of chordal and papillary muscle levels were measured from M-mode echocardiogram to assess the left ventricular contractile function. And color Doppler and pulse Doppler examinations of mitral flow velocity were performed. Concomitantly, electrocardiogram (ECG) was also examined. The animals with decreased cardiac function were euthanized and the hearts were examined histologically. Fractional shortening was reduced gradually in the dogs treated with doxorubicin. And mitral regurgitation during systolic phase and changes of mitral flow velocity during diastolic phase were also revealed in the dogs with severe reduction of fractional shortening. These changes might indicate the reduction of cardiac functions, both of contractility and diastolic filling functions. ECG abnormalities, which were small changes, revealed only in the dogs that had severe reduction of fractional shortening and mitral regurgitation. In histological examination, myocardial degeneration was observed. And, the degree of myocardial damage might be relative to alteration of fractional shortening. Thus, the result demonstrates that the early alteration of cardiac function induced with doxorubicin can be detected by echocardiography in dogs. The result also indicates that cardiac function predicted by fractional shortening measured from M-mode echocardiogram might be correlated with histological changes of myocardium.
The fraction (venom B) of spine venom from the crown-of-thorns starfish (Acanthaster planci) caused contractions of the uterus of rats and enhanced vascular permeability in rabbits. The venom B-induced contraction of the smooth muscle was depressed by inhibitors of prostaglandin synthesis such as indomethacin or aspirin, but not by the anticholinergic agent, atropine. The fraction with the uterus contractile action was partially purified from venom B through column chromatography. This fraction contains phospholipase and proteinase activities and was different from the lethal factor in the venom. These results suggest that the uterine contractile action caused by venom B is mediated by prostaglandins and partly contributed by the activity of phospholipase in the venom.
The toxicological significance of the placental metallothionein (MT) was studied from the viewpoint of cadmium (Cd) intoxication. The Cd concentration was higher in the placenta than the kidneys until 8 hr after a single injection of <109>CdCl2, but was very low after administration of <109>Cd-MT. Compared with lower doses, fetal Cd began to increase at the dose of 2 mg/kg. Alkaline phosphatase activity in the placenta was significantly decreased, and dead fetuses appeared at this dose. The MT concentration was not increased by the Cd injection but the ratio of Cd/Zn in MT increased proportionally to the dose up to 2 mg/kg. MT was detected in the placenta during all stages of pregnancy, and its concentration was higher in the earlier stage. The metal bound to MT was mainly Zn, and very little Cu was bound. In the mice that became pregnant after <109>Cd accumulation, redistribution of <109>Cd was not observed. MT-I and -II in the placenta were identified by column chromatography and immuno-blotting methods. These findings suggest that the placental MT might play a protective role against Cd toxicity by trapping of the metal.
N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390) and 5'-deoxy-5-fluorouridine (5'-DFUR) are 5-fluorouracil (5-FU) derivatives developed as anti-tumor pharmaceuticals. To evaluate immunotoxicities of these compounds, BDF1 mice were administered vehicle, 300-2700 mg (0.68-6.14 mmol)/kg/day of Ro 09-1390, or 100/900 mg (0.41-3.66 mmol)/kg/day of 5'-DFUR for 1 to 7 days, and effects on cellularity in lymphoid organs were assessed by immunohistochemistry as well as general toxicologic paranleters. To distinguish compound-specific direct action from nonspecific indirect action caused by dietary reduction, dietary restriction groups were also included as control groups. Final body weight, thymus weight, bone marrow cell number (BMC), and leukocyte number were reduced with high dose of both compounds. Reduction of BMC in groups administered with Ro 09-1390 or 5'-DFUR was more severe than in dietary restriction groups given comparative amount of diet with compound-administered groups. Diffuse thymic cortical hypoplasia was observed in the highest dose of both compounds and more apparent in the Ro 09-1390 than in the 5'-DFUR. Focal nodular thymocyte hyperplasia was observed especially in the lower dose of 5'-DFUR. The results indicate that immunotoxic profiles of Ro 09-1390 and 5'-DFUR are very similar and characterized primarily by myelotoxicity and Ro 09-1390 is approximately two-times less toxic than 5'-DFUR on a molar basis in BDF1 mice.
Effect of antioxidants on humoral immune responses, such as butylated hydroxytoluene (BHT), n-propyl gallate (PG) and dimethyl sulfoxide (DMSO) is suppression in in vitro antibody production. These antioxidants all inhibited T-dependent B cell response, not T-independent and polyclonal B cell response. These data suggest that antioxidants suppress humoral immunity by suppression of regulation of T cells or action of macrophages on B cells, not by direct suppression of B cells. The other possible explanation for antioxidant action is the lack of T-B cell contact required for the triggering of the B cell response with T-dependent antigens.