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PubMed2003

Prepubertal administration of estradiol valerate disrupts cyclicity and leads to cystic ovarian morphology during adult life in the rat: role of sympathetic innervation.

Administration of estradiol valerate (EV) to adult rats leads to anovulation and cystic ovarian morphology. Sympathetic ovarian nerve denervation (SONX) overcomes this disruption. In this study, we determined whether EV administration to juvenile rats prevents achievement of reproductive competence, disrupts cyclicity, and whether this programming is facilitated via activation of the sympathetic nerve input to the ovary. Prepubertal rats were administered 2 mg EV in corn oil or corn oil alone. One half of the animals from each group underwent SONX on d 71 of life. Rats were euthanized on d 91 for determination of serum gonadotropins, progesterone, Delta4 androstenedione, and estradiol concentrations, ovarian norepinephrine (NE), and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activities and ovarian dynamics. Results revealed that EV administration during juvenile period advanced pubertal onset, suppressed circulating LH, FSH, and Delta4 androstenedione, increased ovarian NE, estradiol, and 3beta-HSD activities, disrupted ovarian dynamics evidenced as absent corpus luteum and presence of ovarian cysts and culminated in anovulation. SONX restored cyclicity in these animals, normalized LH, estradiol, ovarian 3beta-HSD activities, and ovarian dynamics as evidenced by the disappearance of ovarian cysts and appearance of corpus luteum and restored corpus luteum function. These findings provide evidence that EV exposure during juvenile life leads to long-lasting deleterious reproductive consequences via activation of the sympathetic ovarian nerve.

Aging↗
PubMed1978

Effects of a single injection of estradiol valerate on the hypothalamic arcuate nucleus and on reproductive function in the female rat.

Young adult cyclic female rats were each injected with 2 mg estradiol valerate (EV) in sesame oil. Controls received an equivalent volume of sesame oil. Within 2 months after injection, most of the EV-treated animals showed persistent vaginal estrus and small polyfollicular ovaries as well as pathological changes in the hypothalamic arcuate nucleus. This pathological process was gradually progressive such that by 6 months after EV injection, the basal lateral region of the nucleus contained numerous reactive microglia, astrocytes, and degenerating elements of the neuropil. The experimental rats had elevated plasma PRL and GH concentrations which gradually diminished. Plasma estradiol concentration remained elevated 2 months after injection, while plasma LH and FSH concentrations stayed within the high and low normal range, respectively. The pituitary glands of injected animals weighed significantly more than those of controls 5.5 months after injection, but the enlarged glands did not cause hypothalamic compression. As mechanical anterior deafferentation of the medial basal hypothalamus has previously been shown to produce similar endocrine and reproductive alterations, it may be that estradiol treatment results in a functional-anatomical disconnection of the arcuate nucleus from the more anterior hypothalamic areas that regulate cyclicity. Whether this type of functional-anatomical phenomenon underlies other varieties of induced or secondary acyclicity in females remains to be determined.

Animals↗
PubMed1988

[Croton oil-induced hemorrhoid model in rat: comparison of anti-inflammatory activity of diflucortolone valerate with other glucocorticoids].

A hemorrhoid model was prepared by means of application of croton oil onto the recto-anus of rats. Cotton swab soaked with the inducer, which consisted of water, pyridine, diethylether and 6% croton oil in diethylether, was inserted into the anus. The following conditions were found to be optimal for preparing the model: cotton swab containing 0.16 ml of the inducer solution was applied to the anus of a 6 week-old rat (body wt. about 140 g) for 10 sec. The edema developed linearly until 7-8 hr after application, and the severity of the edema was sustained almost constantly for more than 24 hr. Macroscopic observations at 6 hr p. a. revealed homogeneous and consistent inflammation in the recto-anus applied region. Histological observation showed appearance of edema, infiltration of fibrin, inflammatory cells, vasodilation, blood congestion and medium to high degrees of necrosis in the mucosal epithelium. Thus this model was useful for evaluating the effect of anti-hemorrhoidal drugs on intumescence and vasodilatation. The efficacy of diflucortolone valerate, hydrocortisone caproate and hydrocortisone was evaluated in this model. Wet weight and vasopermeability increased by the inducer was suppressed strongly by simultaneous application of the corticoids, and the degree of suppression was parallel with the potency of the glucocorticoid activity. Compared to Scheriproct, Posterisan forte, Posterisan and Borraginol N, Neriproct showed the strongest effects in the protection against and treatment of the experimental hemorrhoid. Scheriproct, which was less active than Neriproct, was also found to have higher efficacy than the others.

Animals↗
PubMedDate not supplied

Changes in psychic and somatic well-being and cognitive capabilities of peri- and postmenopausal women after the use of a hormone replacement drug containing estradiol valerate and levonorgestrel.

A multicenter, prospective, open-label postmarketing surveillance study examined to what extent 2-month oral hormone replacement therapy (estradiol valerate and levonorgestrel; Klimonorm) could produce changes in psychosomatic well-being, self esteem and cognitive capabilities in 78 peri- and postmenopausal women. The women included were 42-58 years of age and had approached the physician due to climacteric symptoms. The following tests were used: Kupperman index, Menopause Rating Scale (MRS II), General Depression Scale (ADS), Zerssen's Symptom List (B-L), Frankfurt Self-Concept Scales (FSAL, FSAP, FSEG, FSSW), Digit Symbol Substitution Test (DSST), d2 Test of Attention and Number Square Test. The results showed a clear improvement in subjective psychosomatic well-being and improvements to a lesser extent in the concentration and cognitive capabilities in women in the third treatment cycle.

Administration, Oral↗
PubMed1983

A double-blind cross-over study on the effects of ORG OD14 compared to oestradiol valerate and placebo on lipid and carbohydrate metabolism in oophorectomized women.

ORG OD14 is a synthetic steroid which in traditional bioassays has been shown to have oestrogenic and progestogenic as well as very weak androgenic-anabolic properties. As judged from earlier studies, this steroid seems suitable for continuous treatment of climacteric deficiency symptoms. The aim of this study was to evaluate the effects induced by OD14 on lipid, lipoprotein and carbohydrate metabolism, as compared to E2V and placebo. Twenty-two women, oophorectomized as part of the treatment of cervical carcinoma in clinical stage IB or IIA, were given ORG OD14 2.5 mg/day, oestradiol valerate (E2V) 2 mg/day and a placebo for 6 weeks each, in a double-blind cross-over study. There was a marked decrease in all lipid components of HDL (high density lipoprotein), i.e. total and free cholesterol, triglycerides and phospholipids (P less than 0.001), after OD14. The oral glucose tolerance test showed higher values after OD14 compared to both E2V and placebo (P less than 0.05), indicating a slightly impaired glucose tolerance. The lipid metabolic changes induced by OD14 indicate a rather strong androgenic influence in this respect.

Adult↗
PubMed1981

Effect of oestradiol valerate on the rat blood--testis and blood--epididymal barriers to [3H]inulin.

Micropuncture samples were taken from rats treated with 2.9 mg oestradiol valerate/day for 14 days, sham injected or untreated. Oestradiol valerate treatment reduced testicular weight and serum testosterone concentrations (P less than 0.05), but did not alter the movement of [3H]inulin into seminiferous tubules or those of the cauda epididymidis. [3H]Inulin concentrations in the seminiferous tubule fluids were always less than 8% of blood isotope concentrations, and those in cauda epididymal tubuule fluid were always less than 5% of blood isotope concentrations. It was concluded that the maintenance of the anatomical component of the blood--testis and blood--epididymal barriers (cell--cell tight junctions) is not androgen-dependent.

Animals↗
PubMed1987

Plasma patterns of LH, FSH and prolactin in rats with a polycystic ovarian condition induced by oestradiol valerate.

The patterns of plasma LH, FSH and prolactin concentrations were investigated in rats with a polycystic ovary condition (PCO). The condition was induced by treatment with oestradiol valerate 9 weeks before blood sampling. Serial blood samples were taken at 10-min intervals for 4 h from ten rats with PCO. All samples were assayed for LH, those from five animals for FSH and those from the remaining five animals for prolactin. In addition, five control animals with normal oestrous cycles were sampled during oestrus and the samples assayed for LH. Mean concentrations of LH, FSH and prolactin in rats with PCO were 140 ng/l, 76 micrograms/l and 7.6 micrograms/l respectively. All three hormones exhibited an episodic pattern. The mean peak amplitudes of LH, FSH and prolactin were 120 ng/l, 25 micrograms/l and 3.5 micrograms/l respectively. All three hormones exhibited a similar mean frequency of four or five episodes per 4 h. The LH and FSH patterns were closely synchronized; nearly all FSH peaks coincided with LH peaks. The prolactin pattern did not, however, correlate with that of the gonadotrophins. Despite the persistent oestrous condition of the animals with PCO, it was clear that their pattern of LH did not resemble that of cyclic animals in normal oestrus; in the normally cyclic animals in oestrus the pulse period was nearly twice as long and the pulse amplitude was more than sixfold greater than those in animals with PCO. We conclude that the unique episodic patterns of gonadotrophins are more important than mean blood concentrations of these hormones in establishing and maintaining the polycystic ovary syndrome.

Animals↗
PubMed1991

Luteal function, estrous response, and pregnancy rate after treatment with Norgestomet and various dosages of estradiol valerate in suckled cows.

Two experiments were conducted to determine whether dosage of estradiol valerate (EV) or day of estrous cycle when treatment was administered affected response to Syncro-Mate-B (SMB). Suckled beef cows received a 6-mg Norgestomet (NOR) ear implant (in situ 9 d) and a 3-mg NOR i.m. injection. In Exp. 1, 74 cows received NOR treatments concurrently with either 5 or 6 mg of EV administered i.m. on either d 1, 3, or 5 of an estrous cycle (estrus = d 1). In Exp. 2, 169 cows received NOR treatments concurrently with either 5, 7, or 9 mg of EV administered i.m. on either d 3 or 9 of an estrous cycle. In Exp. 1, 67, 50 and 92%, respectively, of cows receiving 5 mg of EV on d 1, 3, or 5 had functional corpora lutea (CL) at implant removal, whereas 42, 75, and 77%, respectively, of cows receiving 6 mg of EV had functional CL at implant removal (dosage P greater than .10; day P less than .05). Synchronized estrous responses were 50, 33, and 23%, respectively, when cows received 5 mg of EV on d 1, 3, or 5, and 67, 33, and 38%, respectively, when cows received 6 mg of EV (dosage P greater than .10; day P less than .05). First-service pregnancy rate was decreased (P less than .05) in cows treated on d 5 (33%) compared with cows treated on d 1 (63%), but dosage of EV had no effect on pregnancy rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Luteal function and reproductive response in suckled beef cows after metestrus administration of a norgestomet implant and injection of estradiol valerate with various dosages of injectable norgestomet.

In an experiment replicated over 2 yr, 149 suckled beef cows were administered Syncro-Mate-B (SMB), a 6-mg Norgestomet (NOR) ear implant (in situ 9 d) in conjunction with an i.m. injection of 5 mg of estradiol valerate (EV), and either 3.0, 4.5, or 6.0 mg of NOR, 2 d after estrus. All cows were artificially inseminated at 48 h (timed insemination; TI) after implant removal (IR) and cows were reinseminated at any estrus subsequent to 24 h of TI through 30 d. Blood samples collected before treatment, every 3 d through IR, and at TI were assayed for progesterone (P4). At TI, 44, 39, and 12% of cows treated with 3.0, 4.5, or 6.0 mg of NOR, respectively, had serum concentrations of P4 greater than 1 ng/mL (3.0 and 4.5 mg vs 6.0 mg, P less than .01). Fifty-eight, 63, and 84% of cows treated with 3.0, 4.5, or 6.0 mg of NOR, respectively, exhibited a synchronized (within 5 d of IR) estrus (3.0 and 4.5 mg vs 6.0 mg, P less than .05). Pregnancy rates for the 5-d synchronized period were 38, 45, and 66% for cows treated with 3.0, 4.5, or 6.0 mg of NOR, respectively (3.0 and 4.5 mg vs 6.0 mg, P less than .05). First-service pregnancy rates were 66, 71, and 79% for cows treated with 3.0, 4.5, or 6.0 mg of NOR, respectively (P greater than .10).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of metestrous administration of a norgestomet implant and injection of norgestomet and estradiol valerate on luteinizing hormone release and development and function of corpora lutea in suckled beef cows.

Sixteen suckled beef cows were used to determine effects of Syncro-Mate-B (SMB) on the development and function of corpora lutea (CL) and LH release. Twelve cows were treated 2 d after estrus with the standard SMB treatment regimen, a 6-mg Norgestomet ear implant (in situ 9 d) and a 2-mL i.m. injection of 3 mg of Norgestomet and 5 mg of estradiol valerate at time of implant insertion. Four cows served as untreated controls. In cows treated with SMB with subsequently nonfunctional CL (n = 5), mean concentrations of progesterone (P4) were lower on d 9, 12 (implant removal), and 14 of the treated cycle than in control cows or in those cows treated with SMB that developed functional CL (P < .01). In cows treated with SMB that developed functional CL (n = 7), mean concentrations of P4 were lower only on d 12 of the treated cycle than those in control cows (P < .01). In cows treated with SMB with subsequently nonfunctional CL, CL were smaller from d 9 through 14 of the treated cycle than in control cows or in those cows treated with SMB that developed functional CL (P < .01). In cows treated with SMB that developed functional CL, CL were smaller on d 9 and 11 of the treated cycle than in control cows (P < .01). Regardless of subsequent CL function, mean concentrations of LH and numbers of LH pulses were lower in cows treated with SMB than in control cows on d 3 and 4 of the treated cycle (P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Endogenous hormone response and fertility in dairy heifers treated with norgestomet and estradiol valerate.

Seventy postpuberal dairy heifers were assigned to remain untreated (n = 26) or to receive the Syncro-Mate-B (SMB) treatment (n = 44). Untreated heifers were inseminated at 12 hr after detection of estrus, while SMB-treated heifers were inseminated either at 48 hr after implant removal (group 1) or at 12 hr after detection of estrus (group 2). Jugular blood was collected at regular intervals from four untreated heifers and from 20 SMB heifers. In untreated heifers, estradiol-17 beta (E) was unchanged throughout the estrous cycle. Progesterone (P) reached maximum concentrations during the luteal phase and then declined to less than 2 ng/ml before estrus. Follicle stimulating hormone (FSH) ranged between 50.1 and 100.2 ng/ml during the estrous cycle, then reached a peak (P less than .05) concentration of 516.2 ng/ml coincident with peak luteinizing hormone (LH) concentration at 12 hr after the detection of estrus. In SMB-treated heifers, plasma E increased by 12 hr after injection of estradiol valerate and then declined throughout the rest of the sampling period. P declined to less than 2 ng/ml by 24 hr after administration of the SMB treatment and remained low throughout the sampling period. FSH declined in response to SMB treatment, then reached a peak (P less than .05) concentration coincident with peak LH 40 hr after implant removal. First service pregnancy rates among the untreated, group 1 and group 2 heifers, were 65, 58 and 38%, respectively, and did not differ (P greater than .05). SMB treatment was effective in inducing luteolysis and in suppressing estrus and peak gonadotropin release. Intervals from implant removal until estrus and from implant removal until peak gonadotropin release were highly variable among SMB-treated animals.

Animals↗
PubMed1988

Timing of preovulatory endocrine events, estrus and ovulation in Brahman x Hereford females synchronized with norgestomet and estradiol valerate.

The purpose of these studies was to investigate the pattern and timing of preovulatory endocrine events, estrus and ovulation in Brahman X Hereford (F1) heifers synchronized with norgestomet and estradiol valerate. In Exp. 1, 66 nulliparous and 191 primiparous Brahman X Hereford (F1) heifers were used to estimate the interval from norgestomet implant removal to onset of estrus. The mean interval from implant removal to onset of estrus was 29.8 +/- .5 h, with 80.9% exhibiting estrus within 48 h. Endocrine and reproductive characteristics were examined in detail during Exp. 2 with 37 primiparous heifers. Continuous observation for estrus, 6-h or 2-h blood sampling and ovarian palpation per rectum were employed. All animals were artificially inseminated 48 h after implant removal. Mean interval from implant removal to onset of estrus and to onset of the luteinizing hormone (LH) surge were closely related (r = .91; P less than .0001). Mean intervals from implant removal to ovulation, onset of estrus to ovulation and onset of LH surge to ovulation were 59.1 +/- 2.5 h, 23.3 +/- 1.4 h and 23.1 +/- 1.6 h, respectively. Approximately 73% of heifers exhibited estrus within 54 h after implant removal (optimal timing); conception rate was 59.3% in this subgroup. Conception rate of heifers that did not exhibit estrus within 54 h after implant removal or exhibited an LH surge later than 12 h after estrus (delayed timing) was 10%. Assessment of plasma estradiol-17 beta concentrations suggested that retarded selection and(or) maturation of the preovulatory follicle following implant removal delayed estrus and lowered conception in up to 28% of females timed-inseminated at 48 h.

Animals↗
PubMed1981

Changes in central circulation in premenopausal women during application of an estradiol valerate-norgestrel combination (Cyclabil).

The orthostatic circulatory reaction, the physical working capacity on a bicycle ergometer, the indirectly measured blood pressure at rest and after the ergometer test, the total hemoglobin content, blood volume and the heart volume in supine position were all determined on three separate occasions in the 17 premenopausal women who were taking an estrogen-progestogen combination as premenopausal substitution (2 mg estradiol valerate and 0.5 mg norgestrel, CyclabilR, Schering AG). Twelve women not receiving steroid treatment served as controls. The examinations were performed once prior to the commencement of the medication and 6 and 12 months thereafter. The orthostatic pulse reaction, the physical working capacity, the total amount of hemoglobin and heart volume did not change during the 12 months. Heart volume increased in both groups but there was no difference between the groups. Systolic and diastolic blood pressure increased slightly in the treated group during the first months but returned towards the initial values at 12 months. The transitory blood pressure increase when using the estrogen-progestogen combination in the premenopause during 12 months is similar to that earlier reported in younger women taking low-dose steroid contraceptives (8). It is conceivable that an adaptative mechanism in the vascular system will work in both situations.

Adult↗
PubMed1986

Clinical experience with a low-dose combination of estradiol valerate and levonorgestrel. Double-blind comparative study between SH D 386 F and Cyclabil. Effects on symptoms, lipids and endometrial condition.

In a double blind study of the effects of hormone replacement therapy in climacteric women, two different dosages of estradiol--17 beta valerate and levonorgestrel, with the same ratio between the amounts of the two steroids (Cyclabil and the trial preparation having the code number SH D 386 F respectively), were compared. The differences in effects on symptoms, certain humoral parameters including serum lipids, and endometrial histology before and after 12 months of therapy were evaluated. The study population consisted of 120 healthy women in the age range 41-63 years, many of whom had undergone previous estrogen treatment. All had typical climacteric symptoms and were peri- or postmenopausal. There were no significant differences between the two preparations as regards the effects on symptoms--except for episodes of hot flushes and depression (loss of confidence), which were more frequent during treatment with the higher dosage. One of the main objects of the study was to determine whether the lower dosage would be sufficient to prevent the development of endometrial hyperplasia. To this end, endometrial samples were collected before and after 12 months of treatment, using "Mi-markTM" disposable equipment for endometrial cytology/histology. No significant endometrial hyperplasia was found in either of the groups during the period of investigation. The serum lipid pattern was evidently more influenced in the group treated with Cyclabil. The drop-out rate was 20%, most of them being due to side effects of mild to moderate severity such as undesirable withdrawal bleedings or unsatisfactory relief of symptoms, which sometimes resulted in a wish to return to earlier treatment regimens.

Adult↗
PubMed1996

The effects of estradiol valerate plus medroxyprogesterone acetate and conjugated estrogens plus medrogestone on climacteric symptoms and metabolic variables in perimenopausal women.

BACKGROUND: Two sequential hormone replacement regimens, containing either estradiol valerate plus medroxyprogesterone acetate (E2V/MPA) or conjugated estrogens plus medrogestone (CE/MED), were compared with respect to effects on climacteric symptoms, lipid metabolism, and hemostasis. METHODS: In an open, multicenter study, 51 perimenopausal women were randomized to E2V/MPA and 50 to CE/MED. Assessment of climacteric complaints was performed at baseline and at months 1, 3, and 6. The effects on lipid and hemostatic variables were measured at baseline and at month 6. Quantitative data were analyzed using analysis of variance, the paired t-test or the chi2 Mantel-Hanszel test, where appropriate. RESILTS: Efficacy regarding treatment of climacteric symptoms was with E2V/MPA as good as with CE/MED, with a statistically significant reduction of most symptoms in both groups. After 6 months, total cholesterol and triglycerides had remained unchanged in both groups. High-density lipoprotein cholesterol showed no significant change with E2V/MPA, whereas an increase was noted in the CE/MED group (p<0.05). Low-density lipoprotein cholesterol was decreased with E2V/MPA (p<0.01) and was unchanged in the CE/MED group. Hemostatic parameters showed no significant changes after 6 months, with the exception of a decreased prothrombin time with E2V/MPA (p<0.05). Acceptability was excellent, expressed by the low incidence of treatment-related drop-outs in both groups. CONCLUSIONS: E2V/MPA is a one tablet per day sequential HRT regimen, which is as effective and acceptable as hormone replacement therapy with CE/MED regarding treatment of climacteric symptoms. Neither preparation had negative effects on lipid metabolism and hemostatic variables.

Adult↗
PubMed1999

Synchronization of estrus in beef cattle with norgestomet and estradiol valerate.

Fifty-six cows received a norgestomet implant and an injection of norgestomet and estradiol valerate; half (n = 28) received 500 IU equine chorionic gonadotrophin (eCG) at implant removal, 9 d later. A third group (n = 25) received 2 doses of cloprostenol (500 micrograms) 11 d apart. Estrous rate was higher (P < 0.05) for cows given norgestomet and estradiol plus 500 IU eCG (75.0%) than for those receiving cloprostenol (44.0%); for those receiving norgestomet and estradiol alone, it was intermediate (67.8%). Pregnancy rates to artificial insemination (after estrus or timed) were higher (P < 0.05) for cows given norgestomet and estradiol than for those given cloprostenol (23 of 28, 82.1% vs 13 of 25, 52.0%), and intermediate (67.8%) for those given norgestomet and estradiol plus eCG. In a second experiment, for heifers treated with norgestomet and estradiol plus eCG (n = 15) or with 2 doses of cloprostenol (n = 16), estrous rates were 66.7% vs 56.2% (P > 0.5), ovulation rates were 100.0% vs 81.2% (P = 0.08), intervals from implant removal or cloprostenol treatment to estrus were 48.0 +/- 4.4 hours vs 61.3 +/- 7.0 hours (P = 0.12) and to ovulation were 70.4 +/- 4.4 hours vs 93.2 +/- 7.5 hours (P < 0.01), respectively; pregnancy rates were 41.7 and 35.7%, respectively (P > 0.5). Norgestomet and estradiol were as good as (heifers) or superior to (cows) a 2-dose cloprostenol regimen. In cows given norgestomet and estradiol, injecting eCG at implant removal did not significantly improve estrous or pregnancy rates.

Analysis of Variance↗
PubMed1976

[Toxicological examination of pure diflucortolone valerate and its formulations as ointment, fatty ointment and cream in animal experiments (author's transl)].

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.

Administration, Oral↗
PubMed1976

[Pharmacokinetics and biotransformation of diflucortolone valerate in man (author's transl)].

Two male normal subjects were each given 1 mg of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione1,2,4-3H (3H-diflucortolone valerate, Nerisona) by i.v. injection. The pharmacokinetics and biotransformation of the corticoid were examined by measurement of the total activity in the blood, plasma, urine and faeces and by thin-layer chromatographic analysis of the spectrum of the metabolites in plasma and urine. The compound is very rapidly degraded. No more intact ester was identifiable in the plasma 5 min after injection while, at the same time, 6alpha,9-difluoro-11beta,21-dihydroxy-16alpha-methyl-1,4-pregnadiene-3,20-dione (diflucortolone), the product of hydrolysis, was present in a concentration of 6-8 ng/ml plasma. The half-life of diflucortolone in the plasma was 4-5 h, that of the total 3H-steroids about 9 h. 80-40% of the 3H-steroids in the plasma were in unconjugated form. Besides diflucortolone and two unidentified metabolites chromatographic comparison demonstrated the presence of 6alpha,9-difluoro-21-hydroxy-16alpha-methyl-1,4-pregnadiene-3,11,20-trione (11-keto-diflucortolone) as a further metabolite in the plasma. The elimination was rapid and complete: by 24 h after injection approximately 56% of the dose had been eliminated with the urine and by 7 days after administration 98 and 93% of the dose had been recovered in urine and faeces. The ratio of elimination urine to faeces averaged 3:1. Within 48 h after the injection about 30% of the dose was eliminated in the form of unconjugated 3H-steroids, about 20% as 3H-steroid-glucuronides and about 10% as 3H-steroid-sulphates. Diflucortolone was demonstrable both in the unconjugated form and as glucuronide and 11-keto-diflucortolone as glucuronide and as sulphate. A total of 7 metabolites were characterized in the urine by means of chromatography.

Adult↗