Effects of the synthetic estrogen 17 alpha-ethinylestradiol on the life-cycle of the fathead minnow (Pimephales promelas).

A fish full life-cycle (FFLC) study was conducted for 17 alpha-ethinylestradiol (EE2) using the fathead minnow, Pimephales promelas. Newly fertilized embryos (< 24 h old) were exposed to five concentrations of EE2 (0.2, 1.0, 4.0, 16, and 64 ng/L nominal) in continuous flow-through conditions for 305 d at 25 +/- 1 degrees C. Exposure concentrations were verified by 14C-EE2 radiochemistry, supported by radioimmunoassay, and mean measured values were > or = 70% of nominal. For the F0 adult phase until 301 d posthatch, the no-observed-effect concentrations (NOECs) for growth, survival, and reproduction (as egg production) were all > or = 1.0 ng/L. The NOEC values for F1 embryo hatching success and larval survival (at 28 d posthatch) were both > or = 1.0 ng/L. While statistically detectable changes in F1 growth were evident at 0.2 ng/L, these were not considered to be biologically significant when compared with historical control data. Male fish exposed to EE2 at 4.0 ng/L failed to develop normal secondary sexual characteristics; on the other hand, assumed females exposed to this level of EE2 were able to breed when paired with males that had not been exposed to EE2. Histology of F0 control, 0.2-, and 1-ng/L exposed fish at 56 d posthatch indicated an approximate female-to-male (F:M) sex ratio of 50:50 (with no ovatestes observed in the control), while fish exposed to EE2 at 4.0 ng/L for 56 d posthatch had a F:M sex ratio of 84:5 (with ovatestes in 11% of fish). After 172 d posthatch, no testicular tissue was observed in any fish exposed to EE2 at 4.0 ng/L. At the same time point, plasma vitellogenin levels were significantly higher in fish exposed to EE2 at 16 ng/L. A lack of sexual differentiation occurred in males at concentrations > or = 4.0 ng/L. Taking into account these data, the overall no-observed-adverse-effect concentration was considered to be 1.0 ng/L.

Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.

The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease.

Effect of three non-ionic contrast media on rats and rabbits with regard to renal changes. Interspecies comparison.

The effect of three non-ionic contrast media (iosimide, iopamidol and iopromide) was investigated in rabbits and rats after single i.v. application up to high doses with regard to renal changes. Determinations of serum urea nitrogen and creatinine and urinary enzymes (lactate dehydrogenase, gamma-glutamyl-transpeptidase and N-acetyl-beta-D-glucosaminidase) as well as histological examinations of the kidneys were performed. The results obtained demonstrate that rabbit as an experimental animal was more sensitive than rat in exhibiting renal changes to contrast media. Furthermore, determinations of urinary enzymes demonstrated that gamma-GT in rabbits and LDH in rats were the most sensitive indicators for detection of early kidney damage. With regard to the high dose levels required, these kidney changes do not indicate any risk to humans at diagnostic dose levels.

Pharmacology and toxicology of azelaic acid.

The results of general pharmacological studies on metabolism, smooth muscles, renal function, cardiovascular and neurotropic effects do not contra-indicate the specific surface use of azelaic acid. From specific pharmacologic studies it is assumed that azelaic acid exerts its therapeutic effect in acne by an antimicrobial, probably bacteriostatic, effect on acne-relevant microorganisms such as Propioni bacerium acnes and, in addition, by a strong comedolytic effect. In numerous studies it has been demonstrated that azelaic acid is not toxic.

Nonsteroidal antiinflammatory agents. 14. Synthesis and pharmacological profile of 6-chloro-5-(cyclopentylmethyl)indan-1-carboxylic acid.

The preparation of 6-chloro-5-(cyclopentylmethyl)indan-1-carboxylic acid is described. This acid has good anti-inflammatory and analgesic activities without producing irritation in the gastrointestinal tract up to the highest tested dose.

Corticosteroid-like effects after high doses of compound (5-methoxy-2-thienyl)-thioacetic acid sodium salt in rats.

During a systemic tolerance study in rats with compound (5-methoxy-2-thienyl)-thioacetic acid sodium salt (MTTA), which is known to decrease the lipolytic process and platelet aggregation, effects after high doses were observed which are similar to the well-known findings after corticosteroid administration. The oral application of MTTA in a dose range from 10 to 1000 mg/kg over a period of 4 weeks resulted in a decrease in total lipids and free fatty acids from 100 mg/kg onwards and an increase in total glycerin and triglycerides after 1000 mg/kg, supplemented with an increased excretion of keto-bodies in urine at all dose levels. The hematological examinations revealed a reduction of blood eosinophils and lymphocytes in males at doses from 10 mg/kg, whereas the eosinophilic granulocytopoiesis was decreased only at the 1000 mg/kg level in both sexes. Determinations of organ weights showed a decrease in thymus weight from 300 mg/kg onwards with an involution at the highest dose levels, being confirmed by histological examination, whereas the adrenal glands' weights were decreased only at the dose level of 1000 mg/kg. Since the endogenous corticosterone level remained unaltered at all doses, it is suggested that these corticosteroid-like effects are directly attributable to MTTA.

Effect of intratracheal and oral application of corticosteroids on the adrenal function test in beagle dogs after ACTH-stimulation.

The effect of synthetic corticosteroids given intratracheally or orally on the adrenal glands of beagle dogs was investigated. The adrenal function was evaluated using a standardized ACTH stimulation test. In addition, histological and morphometrical examinations of the adrenal cortex were performed at the end of the study. Beclomethasone dipropionate given intratracheally at daily dose levels of 0.05, 0.1 and 0.5 mg/kg body weight led to a dose dependent adrenal suppression on the basis of plasma cortisol concentration and eosinophil counts after ACTH stimulation and size of zona fasciculata and reticularis. A complete adrenal suppression was observed at the highest dose level of 0.5 mg/kg body weight. Also the oral administration of 0.1 mg/kg body weight/day of beclomethasone dipropionate had a definite adrenal suppressive effect comparaable to that of 0.1 mg/kg body weight given intratracheally. However, intratracheal administration of fluocortin butylester, a local antiinflammatory drug but systemically a nearly ineffective corticosteroid (2 X 8 mg/kg body weight/day) had no suppressive effect on the adrenal gland of the beagle dog, even after a 320 times higher dose.

Effect of fluocortin butylester and beclomethasone dipropionate on the adrenal gland in beagle dogs.

The effect of butyl-6 alpha-fluoro-11 beta-hydroxy-16 alpha-methyl-3,20-dioxo-1,4-pregnadien-21-oate (fluocortin butylester, Vaspit) administered intratracheally and of beclomethasone dipropionate given intratracheally or orally on the adrenal glands of beagle dogs was investigated. The adrenal function was evaluated using a standardized ACTH stimulation test including eosinophil counts 5 h after a single i.v. injection of 0.02mg (approximately 2 IU) ACTH/kg body weight were found as well as the histological and morphometrical examination of the adrenal cortex. The cortisol determination (with Clark's method) 1.5 h and eosinophil counts to be the optimum indices for the evaluation of adrenal function. Beclomethasone dipropionate given intratracheally at daily dose levels of 0.05; 0.1 and 0.5 mg/kg body weight lead to a dose dependent adrenal suppression on the basis of plasma cortisol concentration, eosinophil counts after ACTH stimulation and size of zona fasciculata and reticularis. A complete adrenal suppression was observed at the highest dose level of 0.5 mg/kg bw. Also the oral administration of 0.1 mg/kg bw./day of beclomethasone dipropionate had a definite adrenal suppressive effect comparable to that of 0.1 mg/kg bw. given intratracheally. However, intratracheal administration of fluocortin butylester even after a 320 times higher dose (2 X 8 mg/kg bw./day) had no suppressive effect on the adrenal gland of the beagle dog.

[Toxicological examination of pure diflucortolone valerate and its formulations as ointment, fatty ointment and cream in animal experiments (author's transl)]. / Tierexperimentelle Verträglichkeitsprüfung von Diflucortolonvalerianat als reiner Wirkstoff und als Salbe, Fettsalbe und Creme

On the basis of absolute DL50 values 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) is virtually non-toxic after single oral administration (mouse greater than 4 g/kg, rat ca. 3.1 g/kg, dog greater than 1 g/kg). Given s.c. (LD50 mouse ca. 180 mg/kg, rat ca. 13 mg/kg) and i.p. (LD50 mouse ca. 450 mg/kg, rat ca. 98 mg/kg) it is highly active and therefore produces also toxic effects. The formulations Nerisona ointment, fatty ointment and cream have proven practically non-toxic in rats after single oral gavage (LD50 greater than 33 g/kg). The daily s.c. administration over 6 weeks revealed systemic glucocorticoid effects in rats at 0.0004 mg/kg and in dogs at 0.04 mg/kg. Similar effects were seen in dogs after daily dermal treatment for 13-14 weeks with Nerisona ointment at 100 mg/kg body weight. On the skin of rabbits and dogs there were no differences in the reaction at the application site between Nerisona ointment, fatty ointment and cream and the corresponding ointment, or cream bases by daily dermal administration for 28 days. However, the 13-14 week dermal study in dogs with Nerisona ointment revealed atrophy of the epidermis at the application site in several cases. The daily dermal application of Nerisona ointment during organogenetic phases of pregnancy caused embryotoxic effects in rats at 500 mg/kg and in rabbits at 50 mg/kg. All of these findings are discusses as well-known glucocorticosteroid effects.