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The therapeutic effect of sustained-release microspheres of a potent LHRH agonist (leuprorelin acetate) on experimental endometriosis in female rats was examined histologically. Endometriosis was produced in rats by autotransplantation of endometrial tissue obtained from the left uterine horn into the renal subcapsular space. In the nontreated rats, the transplants were well established and had formed large cysts containing fluid. The walls of the cysts were composed of epithelium and stroma resembling that of normal endometrium. In the rats which received the microspheres of leuprorelin acetate, growth of the transplant was markedly suppressed as evidenced by the reduced size of the cystic cavity and the flattened and pyknotic epithelium. Also, the uterine and ovarian weight decreased significantly. In the ovariectomized rats, growth of the transplant was also markedly suppressed, and the uterine weight decreased. The present results clearly indicate that a single injection of the sustained-release microspheres of leuprorelin acetate markedly suppresses growth of the transplant and produces uterine and ovarian atrophy in the rats.

The effect on guinea pig airways of the inhalation of leukotrienes, histamine or antigen was investigated by measuring changes in lung volume and analyzing the airway area on bronchograms with the Zeiss interactive image analysis system (IBAS). LTC 4 , LTD 4 , LTE 4 and histamine inhaled through an ultrasonic nebulizer caused inflation of the lung: LTD 4 was the most potent of the leukotrienes and was 100 times more potent than histamine on a molar basis. The results of analyses of areas of large and small bronchi and bronhioles on the bronchograms indicated that LTD 4 selectively decreased the area of the peripheral airways. Inhalation of an antigen in actively sensitized animals resulted in inflation of the lung and in a selective decrease in the area of the peripheral airways. Anaphylactic bronchoconstriction provoked by antigen inhalation was clearly inhibited by AA-861, a 5-lipoxygenase inhibitor but not significantly by mepyramine, an antihistamine. These observations indicate that LTD 4 is a potent constrictor of the peripheral airways in guinea pigs and that the anaphylactic bronchoconstriction provoked by antigen inhalation could be mediated by LTD 4 in actively sensitized guinea pigs.

The results of toxicity studies on sulbenicillin (SB-PC) in rats, dogs and monkeys as well as distribution and excretion patterns in these animals and humans were reviewed and, taking into account the results of its clinical trials in 6376 patients, the following conclusion was obtained. 1. There was marked species difference in excretion and distribution of SB-PC. In dogs, unlike other animals including humans, excretion of SB-PC into bile was larger than that into urine, and its distribution in the liver at an extraordinarily high concentration was observed. When SB-PC was intravenously injected to dogs at various dosages, transient but dose-related hepatotoxic signs appeared, and a few animals died at 1500 mg/kg/day. 2. There were no abnormalities in rats treated intramuscularly with 2500 mg/kg/day of SB-PC for 6 months except for a local irritation at the injection site. The excretion pattern of SB-PC in cynomolgus monkeys was quite similar to that in humans, and they tolerated daily intravenous injections at 1500 mg/kg/day for one month well. None of the animals showed any significant changes in hematological, biochemical and histological examinations. 3. In clinical trials of SB-PC, intravenous infusion at 30 g (15 gx 2)/day/man did not affect the normal function of the liver and kidneys in the patients. The above results were compared with those reported for carbenicillin (CB-PC) and it was indicated that SB-PC is less toxic than CB-PC in humans.

A phenotypically male Wistar rat having reduced body-weight and small penis is investigated histologically and cytogenetically. Left and right gonads are represented by ovotestes.Chromosome studies demonstrate the occurrence of two cell-lines, one line showing 41 chromosomes without the Y and the other having 42 chromosomes with an additional minute chromosome. Morphological and Giemsa-banding analyses indicate that the minute chromosome is resulted from a deletion of the long arm of the Y. Thus, a true hermaphroditism characterized by the 41, X/42, XYq- mosaic complex is established in this rat.

The effects of fluoride on the developing enamel and dentin of rat incisors were investigated. Rats were treated orally with the anti-neoplastic agents, Tegafur and ethyl t-6-butoxy-5-fluorohexahydro-2, 4-dioxopyrimi-dine-r-5-carboxylate (TAC-278), and NaF at different doses for eight weeks. These anti-neoplastic agents contain fluorine (F) and appeared to release 5-fluorouracil after the treatment. Tegafur and TAC-278 induced mottled enamel characterized by pigment-free and chalky white areas. Histo-pathologically, ameloblasts, at the secretory to maturation stage, showed degeneration and necrosis, and formed a cystic irregular array. In the dentin, there were focal or diffuse hypoplastic defects resulting from degeneration and atrophy of odontoblasts. Microradiographically, calcio-traumatic lines resulting from damage to secretory ameloblasts, and calcio-traumatic zones resulting from damage to ameloblasts at the maturation stage were observed in the enamel. These changes were essentially the same as the abnormality resulting from NaF treatment. The F concentration in the incisors was highest in the NaF treated rats, and lowest in the TAC-278 treated rats. The severity of gross lesion of the incisors and the F concentration in the incisors were well correlated. From these results, it is suggested that, like NaF, an excessive dose of Tegafur or TAC-278 affects the developing enamel and dentin of rat incisors.