The Administration of Flumethasone, by Three Different Routes, its Measurement in the Plasma and Some Effects on Wool Growth in Merino Wethers

Self Cite

Aust. J. Bioi. Sci., 1978, 31, 373-83 The metabolism of [1,2(n)-3Hldexamethasone intravenously infused for periods of 4 and S days was examined in four Merino wethers.On average 85·6±2·8 (s.e.m.) % of the total dose was recovered, 56·2±5·1 and 29·4±3·3% being excreted in urine and faeces respectively. In total 12·4 % of the dose was associated with the unconjugated steroid fraction which represented 22% of the total urinary radioactivity.Thin layer chromatography of the urinary unconjugated fractlon revealed, apart from dexamethasone, five major and three minor radioactive components designated as I, III, IV, V, VIII and II, VII, IX respectively. Approximately 83 % of the radioactivity associated with the unconjugated fractions was found in constituents more polar than dexamethasone with the radioactivity mainly confined to the principal metabolite IV, Rc = 0·24 (dexamethasone, Rc = 0·45;'cbloroform: formarnide 50:1). The urinary constituent VI, Rc = 0·37, was detected only -during-the second half of the 8-day infusion with the peak of excretion on day 6.During the first 30 h of [3Hldexamethasone administration the plasma radioactivity reached the level which remained relatively constant throughout the infusions. The initial high level of radioactivity detected in the plasma unconjugated fraction as well as dexamethasone during the first 24 h infusion declined over the next 2 days; this was followed by a small increase during the final period of infusions.The radioactivity of the plasma unconjugated fraction was distributed, apart from dexamethasone, into six constituents (I, III, IV, V, VIII and IX) which when analysed by thin layer chromatography appeared to be qualitatively similar to those found in urine.These results led to the conclusion that one or more products of dexamethasone metabolism might be biologically active and thus potentially important in inhibiting wool fibre growth in sheep.

Section: Effects Of Dexamethasone On Fibre Sheddingmentioning

confidence: 99%

“…Subsequently it has been found that the slow intravenous infusion of glucocorticoid analogues over an 8-day period caused wool shedding in a greater proportion of the total fibres than when the same dose was infused over a shorter period (Panaretto and Wallace 1978b).…”

Section: Introductionmentioning

confidence: 99%

Studies on Intravenously Infused Dexamethasone in Sheep

Leish¹,

Panaretto²

1978

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“…The inhibition of wool growth after treatment is also variable and occasionally persists for long periods. An earlier study dealt with wool growth and plasma steroid concentrations following the injection of synthetic glucocorticoids by different routes (Panaretto and Wallace 1978b). However, no comparisons have been made when animals are treated by the same route with different forms of a particular steroid.…”

Section: Introductionmentioning

confidence: 99%

Comparisons of the Plasma Steroid Concentration Profiles and Wool Growth Responses After Administration of Two Forms of Dexamethasone to Sheep

Panaretto¹

1979

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Sheep were treated with dexamethasone (1) as the water-soluble 21-phosphate intravenously or (2) subcutaneously, and (3) as the water-insoluble parent compound subcutaneously.In (1) the infusion was continued for 8 days and plasma· concentrations of dexamethasone exceeded 40 ng/ml. The analogue quickly disappeared from the circulation after the infusion was stopped. Compared with pretreatment values wool growth decreased by about 80 % 17 days after cessation of the infusion. By 31 days, wool growth was almost back to normal. At this stage most of the fibres that made up the fleece at the time when the sheep were infused had been shed, and it was possible to defleece three of the four treated animals by brushing the wool off manually.In (2) plasma concentrations of dexamethasone reached very high levels (maximum c. 8 jlg/mi) but only for a relatively short period ( < 48 h). Wool growth was depressed by about 30 % 17 days after treatment. No fibre shedding was evident, and the animals could not be defleeced. Recovery in wool growth was almost complete 1 month after treatment.In (3) plasma concentrations of dexamethasone were in the range of 3-10 ng/ml 15 days after dosage (three out of four animals); dexamethasone could not be detected in the plasma of the fourth animal 12 days after treatment. Wool growth was decreased by about 80% 77 days after steroid administration. Three out of four treated animals could be defleeced manually and in all of them wool growth was depressed 3 months after treatment.It was concluded from this work that high concentrations of dexamethasone had to be sustained for long periods (8 days) before the majority of sheep could be defleeced manually. A similar result was ultimately achieved following an undesirably prolonged period of wool growth depression, when relatively low concentrations of dexamethasone were sustained for> 15 days. Very high steroid concentration for about 2 days did not have sufficient effect to permit defleecing.

“…Administration of several glucocorticoids to sheep and the resultant inhibition of growth of wool fibres have been well documented (Panaretto and Wallace 1978a, 1978b, 1979Leish and Panaretto 1978). In ,order to induce shedding of the majority of wool fibres, it was found necessary to maintain elevated glucocorticoid concentrations in the plasma of sheep over 8 days or longer (Panaretto 1979).…”

Section: Introductionmentioning

confidence: 99%

Effect of Intravenously Infused Dexamethasone on Collagen Metabolism in Skin of Merino Sheep

Leish¹,

Panaretto²

1979

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The effects of an 8-day intravenous infusion of dexamethasone (7·6 mg kg-o . 75 body weight) on collagen biosynthes's and wool growth in skin were examined in four Merino wethers.Plasma dexamethasone concentrations reached their peaks during the first 24 h infusion, which were followed by relatively stable levels (c. 1 x 10-7 M) for the next 4-5 days. Minor increases in plasma dexamethasone levels were recorded during the final 2 days of treatment. Dexamethasone concentrations quickly fell below the level of detection once infusion ceased.Marked decreases in the wet weight, thickness and protein content of skin were observed at the end of infusion. DNA content was reduced to 42·4±4·9 % s.e.m. during the first 2 days of treatment, but in the next 4 days of infusion gradually increased to 85·0±12·5% of controls. The level of collagen (expressed as hydroxyproline content of its acid hydrolysate) was elevated throughout the infusion and then gradually declined in 3 weeks to about 60 % of controls.The biosynthesis of collagen measured by the rate of [14C]hydroxyproline formation and the activity of proline, 2-oxoglutarate dioxygenase (EC 1.14.11.2, formerly prolyl hydroxylase) was reduced during the first half of treatment to a greater extent than the rate of [14C]proline incorporation into proteins.Wool growth was reduced by 80·4 ± 11 ·6% in the post-infusion period which allowed three sheep out of four to be defleeced.Inhibition of collagen biosynthesis in sheep skin was due initially to a decrease in the activity of proline, 2-oxoglutarate dioxygenase and later to the reduced rate of proline incorporation into proteins. It ,was also evident that changes in biosynthetic rate of collagen were not reflected in the total level of skin collagen. The extent of wool growth depression in individual animals paralleled the changes in DNA content and the extent of collagen biosynthesis inhibition.