Dose-dependent pharmacokinetics of dexamethasone

Loew, D.; Schuster, O.; Graul, E.H.

doi:10.1007/bf00614309

Cited by 102 publications

(49 citation statements)

References 14 publications

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“…chronic (more than I year in Cushing's syndrome), 48, 12 and 3 h. The pharmacokinetic profile of Dex [21). as well as the cortisol values at 0 min, veri fied the dose-related effectiveness of the models.…”

Section: Discussionmentioning

confidence: 77%

Dual and Selective Actions of Glucocorticoids upon Basal and Stimulated Growth Hormone Release in Man

Burguera¹,

Muruais²,

Peñalva³

et al. 1990

Neuroendocrinology

109

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In humans, corticoids suppress growth and growth hormone (GH) secretion elicited by a variety of stimuli, while in the rat they potentiate both in vivo and in vitro GH release. To further study this problem, growth-hormone-releasing hormone (GHRH) tests were performed in 6 nonobese Cushing’s syndrome patients and 6 controls. The normal GHRH-induced GH secretion was completely abolished in the Cushing’s syndrome group. To study the action of shorter corticoid exposures, 34 volunteers were subjected to four tests each: placebo treatment (control); dexamethasone (Dex) administration 4 mg i.v., 3 h before; Dex 8 mg p.o., 12 h before, and Dex 22 mg p.o. over the 2 days before the pituitary challenge that was always administered at 0 min (12.00 h). In the first test (n = 9), GHRH (1 µg/kg i.v.) induced a GH peak of 14.5 ± 3.8 ng/ml (control) that was potentiated by Dex 4 mg i.v. administered 3 h before (26.4 ± 6.8 ng/ml). On the contrary, longer Dex treatments suppress GHRH-induced GH values (6.0 ± 1.1 ng/ml after Dex 8 mg and 1.8 ± 0.3 ng/ml after Dex 22 mg). Clonidine administration 300 µg p.o. (n = 7) increased GH secretion with an area under the secretory curve (AUC) of 1,274 ± 236 that was potentiated by Dex 4 mg i.v. given 3 h before clonidine (2,380 ± 489) and reduced by Dex 8 mg, the reduction being significant only after 22 mg Dex(595 ± 47). When arginine 30 g was used as pituitary challenge (n = 6), the GH peak (19.1 ± 4.8 ng/ml) and the AUC (1,318 ± 322) were not significanty altered by Dex 4 mg nor by Dex 8 mg, but clearly reduced after pretreatment with Dex 22 mg (11.1 ± 4.6 ng/ml peak; 635 ± 189 AUC). The action of Dex was rather selective for GH secretion, because it did not alter (n = 6) prolactin, luteinizing hormone and follicle-stimulating hormone stimulated by a combined administration of luteinizing-hormone-releasing hormone and thyrotropin-releasing hormone. In this group, thyrotropin was only altered after the higher (22 mg) Dex treatment. These results showed a dual action of Dex on GH release in man. Short-term treatment potentiated basal and GHRH-stimulated GH secretion. The stimulatory action of corticoids becomes an inhibitory one when longer treatments are employed, suggesting, though not proving, to be mediated by somatostatin release from the hypothalamus.

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Section: Discussionmentioning

confidence: 77%

Dual and Selective Actions of Glucocorticoids upon Basal and Stimulated Growth Hormone Release in Man

Burguera¹,

Muruais²,

Peñalva³

et al. 1990

Neuroendocrinology

109

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“…A study on liver transplant recipients who had received 1 g of methylprednisolonehemisuccinate by a 1-h intravenous infusion for the treatment of acute rejection demonstrated that maximum serum concentrations of methylprednisolone were from 16 to 46 mol/L, which correspond to the equivalent dexamethasone concentrations from 3.2 to 9.2 M (46). A pharmacokinetic analysis using RIA showed that the peak plasma concentration of dexamethasone was 0.0882 Ϯ 0.0153 M after intramuscular injection of 3.0 mg of dexamethasone (47). On the basis of these data, we tested the effect of dexamethasone at the concentrations from Figure 7.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Prevents Podocyte Apoptosis Induced by Puromycin Aminonucleoside

Wada

Pippin

Marshall

et al. 2005

Journal of the American Society of Nephrology

169

150

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Nephrotic-range proteinuria is due to glomerular diseases characterized by podocyte injury. Glucocorticoids are the standard of care for most forms of nephrotic syndrome. However, the precise mechanisms underlying the beneficial effects of glucocorticoids on podocytes, beyond its general immunosuppressive and anti-inflammatory effects, are still unknown. This study tested the hypothesis that the synthetic glucocorticoid dexamethasone directly reduces podocyte apoptosis. Growthrestricted immortalized mouse podocytes in culture were exposed to puromycin aminonucleoside (PA) to induce apoptosis. Our results showed that dexamethasone significantly reduced PA-induced apoptosis by 2.81-fold. Dexamethasone also rescued podocyte viability when exposed to PA. PA-induced apoptosis was associated with increased p53 expression, which was completely blocked by dexamethasone. Furthermore, the inhibition of p53 by the p53 inhibitor pifithrin-␣ protected against PA-induced apoptosis. Dexamethasone also lowered the increase in the proapoptotic Bax, which was increased by PA, and increased expression of the antiapoptotic Bcl-xL protein. Moreover, the decrease in p53 by dexamethasone was associated with increased Bcl-xL levels. Podocyte apoptosis induced by PA was caspase-3 independent but was associated with the translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. AIF translocation was inhibited by dexamethasone. These results show that PA-induced podocyte apoptosis is p53 dependent and associated with changes in Bcl-2-related proteins and AIF translocation. The protective effects of dexamethasone on PA-induced apoptosis were associated with decreasing p53, increasing Bcl-xL, and inhibition of AIF translocation. These novel findings provide new insights into the beneficial effects of corticosteroids on podocytes directly, independent of its immunosuppressive effects.

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“…Our intention was to have two models of corti coid administration whose main difference would be the time of hypothalamo-pituitary exposure to dexamethasone. In fact, pharmacokinetic studies on dexamethasone [9], as well as our own results (cortisol values a 0 time), show that both doses are biologically effective although the 8-mg dose was more powerful.…”

Section: Discussionmentioning

confidence: 99%

Depending on the Time of Administration, Dexamethasone Potentiates or Blocks Growth Hormone-Releasing Hormone-Induced Growth Hormone Release in Man

Casanueva¹,

Burguera²,

Tomé³

et al. 1988

Neuroendocrinology

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In humans, corticoids suppress growth hormone (GH) secretion elicited by a variety of stimuli, while in vitro they potentiate GH release. To further study this problem, the effect of two doses of dexamethasone on GH secretion elicited by GH-releasing hormone (GHRH) in 6 normal volunteers was studied. Each subject underwent three tests, on 3 separate days with GHRH 1–29 (1 µg/kg i.v. at 12.00 h). On the control day, only GHRH was given, on the second day dexamethasone 4 mg i.v. was administered at 09.00 h (3 h before GHRH) and on the third day dexamethasone 8 mg p.o. was given 12 h before GHRH (at 00.00 h). The GHRH-induced GH peak was 9.9 ± 2.0 ng/ml, while 4 mg dexamethasone significantly (p < 0.05) potentiated GH secretion elicited by GHRH (29.2 + 5.7 ng/ml). When dexamethasone 8 mg was given 12 h before, GHRH-induced GH secretion was completely blocked (3.0 + 1.1 ng/ml) (p < 0.05). These results indicate that corticoids have two different actions: an acute potentiating activity on GHRH, and a delayed blocking action on GHRH-induced GH secretion.

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Dose-dependent pharmacokinetics of dexamethasone

Cited by 102 publications

References 14 publications

Dual and Selective Actions of Glucocorticoids upon Basal and Stimulated Growth Hormone Release in Man

Dual and Selective Actions of Glucocorticoids upon Basal and Stimulated Growth Hormone Release in Man

Dexamethasone Prevents Podocyte Apoptosis Induced by Puromycin Aminonucleoside

Depending on the Time of Administration, Dexamethasone Potentiates or Blocks Growth Hormone-Releasing Hormone-Induced Growth Hormone Release in Man

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