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The administration of flumethasone, by three different routes, its measurement in the plasma and some effects on wool growth in Merino wethers.

Flumethasone was given to Merino wethers weighing 30-50 kg at rates of 0.62-1.35 mg/kg(0.75) by intravenous (experiments 1 and 2), intraruminal (experiment 4) and subcutaneous (experiment 5) routes over 8 days. In experiment 3, 1.2 mg flumethasone/kg(0.75) was given intravenously over 4, 5 or 6 days. The plasma concentration profiles showed concentrations in the order: intravenous greater than subcutaneous greater than intraruminal. Plasma concentration patterns usually were highest during the first 48 h of infusion followed by relatively stable values. This last feature was not evident in experiments when the rate of hormone infusion was increased. Estimates of the metabolic clearance rates for flumethasone in experiments 1, 2 and 5 were 200-700 ml/min during the equilibrium concentration periods. The effects of flumethasone on some aspects of wool growth revealed interactions between the routes of administration, the period of dosage and the rate of wool growth in the recipients. In experiments 1 and 2 intravenous infusion of 1.20-1.33 mg flumethasone/kg(0.75) caused the shedding of all wool fibres about 30 days after treatment. Some effects of dosing sheep with flumethasone at a time when wool growth was decreasing were also observed in experiment 2. Flumethasone given at a rate of 1.2 mg/kg(0.75) over 4, 5 or 6 days caused the shedding of only some wool fibres which were firmly retained on the sheep by the continuous fibres. Intraruminal and subcutaneous infusions of 0.62-1.35 mg flumethasone/kg(0.75) had similar results to the last in the majority of animals although in a few cases no discontinuity of wool fibres was observed. Recovery in wool growth was observed after treatment. Animals regained their pretreatment wool growth in experiments 1, 4 and 5 by 60 days after treatment and probably equalled at that time wool growth in controls. Recovery was retarded in some individuals in experiment 2 and in some groups in experiment 3. In experiment 1, 21 days wool growth was estimated to have been lost. Some aspects of complete versus partial shedding of wool fibres are discussed particularly with reference to wool harvesting. Some similarities in the appearance of fleeces of steroid-treated sheep and naturally shedding animals are also discussed. In some experiments, particularly when the infusion rate of flumethasone was increased (experiment 3), the sheep showed temporary but significant feed refusals during, but more commonly after, treatment. Speculative discussion as to the metabolic causes of this response is included.

Animals

Combination dermatological products: a comparison of betamethasone dipropionate/clotrimazole/gentamicin sulphate and flumethasone pivalate/clioquinol creams.

The combination creams, betamethasone dipropionate/clotrimazole/gentamicin sulphate and flumethasone pivalate/clioquinol, were compared in patients with corticosteroid responsive dermatoses and/or cutaneous fungal and/or bacterial infections. Medication was applied to affected areas twice daily for 28 days. Of 67 patients enrolled, 31 treated with betamethasone/clotrimazole/gentamicin and 33 given flumethasone pivalate/clioquinol were evaluated for efficacy and safety each week during therapy and once 14 days post-therapy. Disease signs and symptoms were less severe in the group given betamethasone/clotrimazole/gentamicin than in the comparative group at days 7 (P = 0.04), 21 (P = 0.02), 28 (P = 0.09), and 42 (P = 0.09) and at patients' last valid visit (P = 0.06). By the last valid visit, signs/symptoms had improved by 82% for patients treated with betamethasone/clotrimazole/gentamicin versus 68% for those treated with flumethasone pivalate/clioquinol. Patients given betamethasone/clotrimazole/gentamicin had statistically significantly better therapeutic responses than those given flumethasone pivalate/clioquinol at day 7 and, by the last valid visit, 19/31 (61%) patients given betamethasone/clotrimazole/gentamicin compared to 15/33 (45%) given flumethasone pivalate/clioquinol had a complete cure or an excellent therapeutic response. Median time of onset of relief of erythema and pruritus was approximately 2 days, regardless of treatment. No adverse reactions were reported.

Administration, Topical

Flumethason-induced calving is preceded by a period of myometrial inhibition during luteolysis.

The temporal relationship among changes of the concentrations of the 13,14-dihydro-15-keto metabolite of prostaglandin F2 alpha (PGFM), estrone (E1) and estrone sulphate (E1S) in maternal arterial plasma (MP) and amniotic fluid (AF), the prepartum progesterone (P4) decline in MP, and the evolution of uterine electromyographic (EMG) activity was investigated in 6 cows. Calving was induced by a single i.m. injection of 5 mg flumethason on Day 270 of gestation. The period under investigation was subdivided into four consecutive periods: Period 1 covered the last 2 days before flumethason treatment; Period 2 (mean +/- SEM duration: 16.1 +/- 2.5 h), Period 3 (8.8 +/- 1.1 h), and Period 4 (13.0 +/- 1.5 h) together included the interval between injection and the onset of the expulsive stage of induced parturition. Each was defined by its pattern of uterine EMG activity. During Periods 1 and 2, this activity occurred in long episodes (2-20 min; contractures) at a similar mean (+/- SEM) frequency (0.51 +/- 0.14/h and 0.42 +/- 0.07/h, respectively). No significant differences in hormonal concentrations in MP and AF between these two periods were detected. During Period 3, contractures nearly disappeared (freq: 0.09 +/- 0.05/h), and in MP mean P4 levels were significantly lower and PGFM levels were significantly higher than before. Mean PGFM concentrations in AF were not significantly changed during Period 3. Finally, during Period 4, EMG activity reappeared and a parturient EMG pattern gradually evolved in the presence of a further significant decline of P4 levels and significant increase of PGFM concentrations in MP.(ABSTRACT TRUNCATED AT 250 WORDS)

Amniotic Fluid

Stimulation of androgen and oestrogen concentrations in plasma of cows after administration of a synthetic glucocorticoid (flumethasone) at the end of gestation.

Administration of flumethasone (3.5 mg i.m.) to six cows on day 260 of pregnancy induced parturition in only one animal. In the other five cows circulating concentrations of epitestosterone and conjugated oestrogens increased to reach maximum values (epitestosterone, 13.73 +/- 2.81 nmol/l; conjugated oestrogens, 33.59 +/- 6.87 nmol/l) 2-3 days after treatment. Concentrations of these steroids were raised as long as the synthetic glucocorticoid was present in the circulation (as judged by depression of cortisol concentrations). After clearance of the drug, concentrations of these steroids declined to values present in the control group. Concentrations of unconjugated oestrogens were only slightly raised after flumethasone. In contrast to the effect observed after administration on day 260, treatment on day 270 induced parturition in four of six treated animals. In these cows, mean circulating concentrations of epitestosterone, unconjugated and conjugated oestrogens increased to 9.50 +/- 2.96, 9.62 +/- 1.48 and 36.51 +/- 4.8 nmol/l respectively to reach concentrations observed in the control group at parturition. After parturition the concentrations of epitestosterone and oestrogens declined rapidly in all groups.

Animals

[The effectiveness of cholecalciferol and flumethasone for the prevention of hypocalcemic parturient paresis in dairy cows].

Investigations on the efficacy of high doses of cholecalciferol and flumethasone for prophylaxis of hypocalcemic milk fever were performed in dairy cows. Only one cow in the group of 25 treated animals diseased by milk fever, but 5 of 25 control animals showed signs of hypocalcemia. A placenta retention was observed in three treated animals and in four control animals. The results show that the additional application of flumethasone for birth induction after the injection of vitamin D3 was unchanged.

Animals

[Clinical comparative study of between difluocortolone and flumethasone].

We report the results of a controlled double blind assay of treatment in 51 dermatologic cases, with a new steroid cream (diflucortolone) and an already known one (flumetasone). The diflucortolone valerate was significantly better than the flumetasone pivalate in the treatment of 16 cases of psoriasis, 33 eczemas and two cases of lichên planus.

Clinical Trials as Topic

[Contralateral comparison between diflucortolone valeriante and flumethasone pivalate in ointments. Double-blind study].

Double blind study with contralateral comparison, between diflucortolon valerianat, 0.1% and the flumetason pivalat, 0.02% in pomades (ointments). Selection of 52 patients both sexes and variable ages with bilateral dermatological inflamatory lesions and with simetric preference: Psoriasis, "eczema vario" and neurodermatitis. In psoriasis, diflucortolon offered better results: the same occurred in the cases of eczema, and in neurodermatitis. The efficacy was similar. There were no appearances of negative secondary effects because of the used doses and time.

Adolescent

Lactational response of dairy cows to oral administration of a synthetic glucocorticoid.

Effects of oral administration of 0, 5, 10, or 20 mug of 6 alpha, 9 alpha-difluoro-16alpha-methyl-prednisolone (Flumethasone) daily on milk and milk component yields, udder health reproductive performance, and body weight change were measured. With 24 Holstein cows in a randomized block design, daily Flumethasone administration was initiated 4 days postpartum and continued until milk secretion ceased or the completion of 305 days on treatment. Mature equivalent yields (adjusted for days open) of milk, solids-not-fat, and milk fat were higher for cows receiving 5 or 10 mug Flumethasone than for cows receiving 0 or 20 mug Flumethasone daily. Lactations for cows receiving 20 mug Flumethasone were 37 to 48 days shorter than lactations for cows in other treatment groups. There were no differences between treatment groups for measures of udder health, reproductive efficiency, and body weight changes. A second experiment of 45 Holstein cows in their second or third lactations included treatments 0, 5, or 10 mug Flumethasone daily for 25 days followed by a 5 day withdrawal. Treatments were begun between day 210 and day 270 of lactation. During the 30 days, Flumethasone failed to alter milk production. These experiments indicate that Flumethasone given continuously increased milk components and milk yield but had no significant effect on milk yield when given only during the latter stage of lactation.

Animals

Comparative evaluation of skin atrophy in man induced by topical corticoids.

In this in-patient study, mild skin atrophy was observed clinically in 6 out of a total of 22 patients after fluocinolone acetonide and in one patient after flumethasone pivalate ointment applications (P less than 0,05). Investigations were discontinued prematurely on days 14 and 17 in 2 patients because they developed early atrophy due to fluocinolone acetonide applications. Histological findings indicating either moderate or marked skin atrophy were evident in 15 patients after flucinolone acetonide as against one patient after flumethasone pivalate ointment applications (P less than 0.001). In comparison with the controls the mean decrease in epidermal thickness was more marked after fluocinolone acetonide applications, namely 30.5% vs 21.3% after flumethasone pivalate applications. The ultrastructural tissue changes were less marked at the sites to which flumethasone pivalate was applied. In comparison with controls, the percentages of mean decrease in diameters of collagen fibrils measured in six volunteer patients ranged from 5.1% to 27.6% after fluocinolone acetonide and from 0% to 12.3% following flumethasone pivalate ointment applications, This difference was statistically significant (range P less than 0,01 to less than 0.001). This experimental study has demonstrated that flumethasone pivalate displays only a mild atrophogenic effect and it is clinically and histologically significantly less atrophogenic than fluocinolone acetonide. Flumethasone pivalate can therefore be reckoned as a suitable topical corticosteroid especially for the long-term treatment of corticoid-responsive dermatoses.

Administration, Topical

Synchronised calvings after withdrawal of norgestomet implants from cows treated near term with prostaglandin.

To investigate whether calving could be controlled by the withdrawal of progestogen implants from cows treated near term with prostaglandin three cows (group 1) received an intramuscular injection of 5 mg flumethasone on day 270 of pregnancy, and four cows (group 2) and three cows (group 3) received implants containing 3 mg norgestomet in both ears on day 262 of gestation and were treated with a prostaglandin F2 alpha analogue on day 264. On day 270 the implants were removed and at the same time the cows of group 3 were treated with 5 mg flumethasone. Jugular blood samples were taken daily to estimate progesterone concentrations in the plasma. Luteolysis was achieved by the injection of prostaglandin, as judged by the decrease in plasma progesterone concentration in the cows of groups 2 and 3 on day 264. Pregnancy was maintained in these cows until after the removal of the norgestomet implants. The interval from the removal of the implants and, or, the injection of flumethasone on day 270 until the onset of second stage labour ranged from 36 to 47 hours and the mean intervals for the three groups were not significantly different. In all the cows except one from group 3 the dilatation of the cervix and vagina and the softening of the pelvic ligaments appeared normal at calving. It is concluded that calving near term can be synchronised by a progestogen in the absence of a corpus luteum.

Animals

Effect of clenbuterol administered during the expulsive stage of bovine parturition on uterine activity and the fetus.

The effect of an intravenous injection of 0.3 mg clenbuterol on myometrial activity, fetal heart rate and fetal outcome was studied in three groups of animals: six heifers in active labour at term, in which fetal oversize was diagnosed just before the drug was injected and whose calves were delivered by caesarean section within 50 minutes; four cows at the start of the expulsive stage of parturition which had been induced with flumethasone on day 270 of gestation; and in four parturient cows which had had electrodes implanted on the myometrium at least one week before calving was induced with flumethasone on day 270. Electrocardiograph electrodes were placed on the calf and an intrauterine pressure catheter was inserted between the calf and the uterine wall upon rupture of the amniotic membrane. Clenbuterol induced a significant decrease of myometrial activity for at least 20 minutes. Recovery was most rapid in the heifers in which an obstetrical examination had taken place during active labour. There was no significant effect on basal fetal heart rate but decreases in heart rate were absent as long as uterine contractions were inhibited. The fetal outcome, judged either before or at birth by blood pH, base-excess and PCO2 and by a clinical examination, was not adversely affected.

Animals

Adrenocortical suppression by topical application of glucocorticosteroids in infants with seborrheic dermatitis.

Fifteen infants with seborrheic dermatitis were treated with topical glucocorticosteroids (flumethasone pivalate 0.02%). Early morning plasma cortisol levels were determined prior to treatment, during the 10-day treatment period, and 2 days after its termination. The mean plasma cortisol level prior to treatment was 8.8 +/- 3.4 micrograms%; after 2 days of application there was a significant decrease of the mean to 2.5 +/- 1.3 micrograms% that persisted throughout the treatment period. Two days after termination of treatment, the mean plasma cortisol level rose to 7.1 +/- 3.7 micrograms% but in five infants was still less than 5 micrograms% and in two less than 2 micrograms%, the latter two having shown the greatest involvement of the skin. The possibility of pituitary/adrenocortical inhibition similar to that observed with the systemic administration of glucocorticosteroids and the potential associated risks should be considered when treating cases that would require extensive application of flumethasone pivalate in infants.

Absorption

Effect of a synthetic corticoid on milk yield and composition and on blood metabolites and hormones in dairy cows.

Twenty-five dairy cows were assigned randomly by breed to flumethasone treatment (10 mug/day, 13 cows) or placebo control (12 cows) from 4 to 44 wk of lactation. Lactation means and trends with stage of lactation were treatment responses. Mean milk yields of cows supplemented with flumethasone were not significantly different from controls. Mean metabolite (glucose, nonesterified fatty acids, and total esterified fatty acids) and hormone concentrations (corticoids, insulin, and prolactin) of blood plasma and their trends throughout lactation were unaffected by supplementation. Data were pooled to determine effects of stage of lactation, temperature, pregnancy, and month on these variables. Changes during lactation were systematic for feed intake, body weight, milk yield, milk components except somatic cells, blood metabolites, and prolactin. At environmental temperatures above 18 C, effects were consistently negative for milk yield and composition, but only above 26 C for feed intake. Prolactin of plasma increased with increasing temperature to 18.2 C and then decreased. No other plasma metabolite or hormone was affected by days pregnant, age, or temperature. Months affected feed intake, milk yield, milk fat percentages, all blood metabolites, and prolactin. Prolactin concentrations increased as daylight hours increased. Our inability to augment established lactation by feeding a supplement of synthetic glucocorticoid to lactating cows is consistent with the view that a lack of avialable corticoids does not limit persistency of lactation in the cow.

Animals

Effect of steroidal anti-inflammatory drugs on Escherichia coli endotoxin-induced mastitis in the cow.

Effects of intramammary infusion of prednisolone (40 mg) or intramuscular injection of dexamethasone (30 mg) or flumethasone (5 mg) on local and systemic signs in Escherichia coli endotoxin-induced mastitis were studied. The effect of varying intervals (0, 2, and 4 h) between intramammary infusion of endotoxin and prednisolone in the same quarter was determined. Intramammary infusion of endotoxin (.01 mg lipopolysaccharide of E. coli) produced inflammation of the infused quarter, fever, tachycardia, and leukopenia followed by a neutrophilic leukocytosis in the blood and a decrease in plasma zinc and iron concentrations. All corticosteroid treatments, except intramammary administration of prednisolone 4 h after endotoxin infusion, enhanced leukocytosis and diminished local signs of inflammation. Intramuscular injection of dexamethasone or flumethasone together with intramammary infusion of endotoxin and intramammary administration of prednisolone 2 h after lipopolysaccharide infusion completely abolished the febrile response. Abolishment of fever and attenuation of several hematologic and blood biochemical changes may be explained by diminished synthesis of endogenous mediators within the inflamed quarters due to glucocorticosteroid action.

Animals

Dehydroepiandrosterone and epitestosterone in the blood of cows at term.

From Day 268 of gestation till two days after parturition blood samples were collected from the jugular vein of 5 cows with normal and 4 cows with flumethasone induced parturition and centrifuged immediately after sampling. In another experiment blood samples were taken from the jugular and uterine vein of 3 cows during the last week before normal parturition. The dehydroepiandrosterone (DHA) and epitestosterone (ET) concentrations in plasma were measured using radioimmunoassay. In the control group the DHA concentration was in the range of 2 to 5 nmol/l, ET levels varied from 4 to 8 nmol/l before term. In both groups, there was an increase in DHA concentrations during the last periparturient period whereas ET levels increased only after flumethasone induced parturition. The concentrations of both androgens declined after the expulsion of the placenta and they were higher in the uterine vein than in the jugular vein. It is concluded, that both androgens are secreted by the bovine placenta and that the delta 5-pathway of steroidogenesis is active in vivo.

Animals