High-Output, Low-Resistance Gram-Negative Septic Shock in Man

Dietzman, Ronald H.; Ersek, Robert A.; Bloch, Jack M.; Lillehei, Richard C.

doi:10.1177/000331976902001108

Cited by 8 publications

(4 citation statements)

References 6 publications

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“…Three parenteral dosage forms of dexamethasone (DA) and its phosphate ester (DP) were administered as follows: (1) DA, 12 mg/ml in ethanol, diluted to 100 ml with saline and infused over 10 to 30 min; (2) DP, 4 mg/ml (injection Decadron phosphate); (3) DP, 24 mg/ml sterile parenteral solution. The last two were injected undiluted.…”

Section: Methodsmentioning

confidence: 99%

“…Especially in lifesaving situations, it may be desirable to achieve a rapid pharmacologic effect; for this reason a single bolus injection has been used. 1 A formulation that facilitates the delivery of the active form of a steroid should be characterized primarily by (1) a high degree of solubility and stability in an aqueous medium and (2) appropriate disposition and rapid conversion of the soluble "pro-drug" to its pharmacologically active form.…”

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confidence: 99%

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Bioavailability of dexamethasone; II. Dexamethasone phosphate

Hare

Yeh

Ditzler

et al. 1975

Clin Pharma and Therapeutics

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Plasma levels of dexamethasone phosphate (DP) and dexamethasone free alcohol (DA) were determined by a modification of existing radioimmunoassay methodology following intravenous administration of DP in man. Areas under DA plasma profiles were a linear function of DP dosage over the 40-fold range 0.05 to 2.0 mg/kg, and, by comparison with values obtained after DA was intravenously administered, indicated an overall conversion of DP to DA of 90%. The first-order rate constant for the conversion, 4.03 hr-1, was approximately 25 times that for hydrolysis in whole blood incubated in vitro. This relationship as well as disposition kinetics suggested that the major component of DP hydrolysis occurs within highly perfused organ(s) comprising the central kinetic compartment. Eighteen subjects were studied in a crossover experiment, and no significant differences were observed in best-fit parameters for the 4 mg/ml parenteral solution of DP in current use and an experimental high potency preparation of 24 mg/ml.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Bioavailability of dexamethasone; II. Dexamethasone phosphate

Hare

Yeh

Ditzler

et al. 1975

Clin Pharma and Therapeutics

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“…Therefore, an initial high dosage is occasionally recommended in the clinical setting; however, the consecutive use of Dex at high dosage is not recommended. Although the most effective dose of Dex (80 mg/kg) was studied, is higher compared with therapeutic doses, which may be as high as ~6 mg/kg in emergency treatment, according to the US Food and Drug Administration approved drug dosage information for Dex (34), used in patients, a trend of inhibition was additionally observed at the lower, therapeutic, doses. Therefore, the underlying risks require consideration.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Fgf15 expression in the intestine by glucocorticoid receptor

2019

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Fibroblast growth factor 15 (FGF15) was previously identified to be highly expressed in the ileum and functions as an endocrine factor to regulate bile acid synthesis in the liver. FGF15 targets its receptor fibroblast growth factor receptor 4 in the liver and serves important roles in energy metabolism, including bile acid homeostasis, glucose metabolism and protein synthesis. The expression of FGF15 is known to be regulated by the transcription factor farnesoid X receptor (FXR). In the present study, reverse transcription-quantitative polymerase chain reaction was used for measuring Fgf15 expression from the animal and tissue culture experiments, and it was identified that dexamethasone, a drug widely used in anti-inflammation therapy, and a classical inducer of glucocorticoid receptor (GR)- and pregnane X receptor (PXR)-target genes, may downregulate Fgf15 expression in the ileum. GR was identified to be highly expressed in the ileum by western blot analysis. Furthermore, it was demonstrated that the downregulation of Fgf15 by dexamethasone is due to the repression of ileal FXR activity via GR; however, not PXR, in the ileum. The present results provide insight for a better understanding of the adverse effects associated with dexamethasone therapy.

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“…Moreover, it is known that tolerance is relative rath er than absolute [27], In any event, the protective mechanism could be thwarted if a brisk endotoxinaemia causes impairment of hepatic blood flow [68], Thirdly, one has to reconcile the recorded facts regarding the haemo dynamic changes in endotoxinaemia with the acute renal failure theory. Measurements of peripheral resistance give variable results [12] but the cal culated value may be low because of the opening of arteriovenous shunts, whereas in fact there is intense vasoconstriction [12]. Thus only total resistance is measured and intense vasoconstriction in some vascular beds can be over looked.…”

Section: Discussion O F Discrepanciesmentioning

confidence: 99%