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At least 19 recordsLinked to original sources
PubMed1976

The corticosteroid dose graph. Use in determination of corticosteroid requirements, characterization of patients, and prevention of seasonal exacerbation in corticosteroid-dependent patients.

Sixty-three corticosteroid(CS)-dependent asthmatics were evaluated by a method which records asthmatic exacerbations as a function of change in CS dosage. This method, the Corticosteroid Dose Graph (CSDG), is a graphic representation of the patients' narrative charts. It is useful in assessing and directing the care of these patients and in evaluating the efficacy of altered therapeutic regimens in asthmatics. The CSDG categorizes cooperative patients (CP) and distinguishes these patients from those who are less cooperative (LCP). Evaluation of the progress of CP by the graphic analysis system showed that CP have fewer severe exacerbations of asthma than LCPs. Evaluation of the 63 patients by this graphic method shows a significantly increased incidence of asthmatic exacerbations in the Chicago area in October as compared to other months. The CSDG also demonstrates that some individuals experienced significantly increased numbers of asthma exacerbations at certain times of the year unique to themselves. Because the CSDG predicts exacerbations, it was shown to be applicable to prevent such exacerbations by prophylactic increase in CS dose during a high-risk season for selected CS-dependent asthmatics.

Adolescent↗
PubMed1975

Inhaled corticosteroids compared with oral prednisone in patients starting long-term corticosteroid therapy for asthma. A controlled trial by the British Thoracic and Tuberculosis Association.

Inhaled beclomethasone dipropionate and inhaled betamethasone valerate have been compared with oral prednisone in the treatment of 75 patients with asthma who were starting long-term corticosteroids for the first time. Both of the inhaled corticosteroids controlled asthma as well as did oral prednisone in those who had responded to therapy in the initial period of the trial. A daily dose of 400 mug of inhaled drug was approximately equivalent to 7-5 mg daily of prednisone. Prednisone suppressed the adrenal response to tetracosactrin, whereas the mean responses in the groups receiving inhaled corticosteroids did not change significantly from pre-trial values. The 30% incidence of other systemic unwanted effects of prednisone contrasted sharply with the low incidence (5%) of symptomatic oropharyngeal candidiasis in the patients receiving inhaled corticosteroids. In a sample of 19 patients no change in exfoliative cytology was detected over the period of the trial nor was there any evidence of fungal colonisation of the bronchial tree. There was no difference between the three treatment groups in the number of antibiotic courses prescribed. The persistent production of sputum made no difference to the response to inhaled corticosteroids. Patients not on sodium cromoglycate did as well in the trial as those receiving sodium cromoglycate. Both inhaled beclomethasone dipropionate and inhaled betamethasone valerate have advantages over oral prednisone in the maintenance treatment of patients with asthma, but in the management of exacerbations systemic corticosteroids will usually be needed as a supplement to inhaled therapy.

Administration, Intranasal↗
PubMed1977

Extremely high levels of corticosteroids and low levels of corticosteroid binding macromolecule in plasma of marmoset monkeys.

Marmoset monkeys were shown to have extremely high resting plasma corticosteroid levels compared to those of macaque monkeys and humans. A major component of corticosteroids seems to be cortisol. Levels of total 11-deoxy-17-KS in plasma of marmoset monkeys were very low (less than 0.01-0.04 microng/ml). Following the injection of ACTH, plasma corticosteroid levels of marmoset monkeys increased by 18-62% (at 1 h), and by 62-160% (at 2 h). Concentrations of plasma corticosteroid binding macromolecule in marmoset monkeys were extremely low (less than 10 nM). It was suggested that in these monkeys, the majority of plasma corticosteroids exists in non-protein bound forms.

Adrenal Cortex Hormones↗
PubMed1977

[Treatment of acute asthma. Comparison of the effectiveness of corticosteroids and of a combination of corticosteroids and an adrenergic beta-stimulant (author's transl)].

Two comparable groups of patients hospitalised for acute asthma received an intravenous infusion for two hours, containing corticosteroids in the first group and corticosteroids combined with an adrenergic beta-stimulant in the second. Course was assessed by the hourly measurement of forced expiratory volumen in one second (FEV1), heart rate and blood pressure. It was found that corticosteroids alone had a modest action (5,1% improvement in FEV1). By contrast, the combination of corticosteroids with an adrenergic beta-stimulant resulted in a rapid and pronounced improvement in FEV1 (19,9%), without producing any undisrable side-effects. No changes in arterial blood gases were noted under the influence of treatment. Injectable adrenergic beta-stimulants are therefore worthy of use in the treatment of an asthma attack, in the absencd of any contraindication.

Adrenal Cortex Hormones↗
PubMed1977

20beta-Hydroxysteroid oxidoreductase. Kinetics and binding of corticosteroids and corticosteroid-21-aldehydes.

Corticosteroid-21-aldehydes were reduced only at C-20 by 20 beta-hydroxysteroid dehydrogenase (EC 1.1.1.53) of Streptomyces hydrogenans, and the reduction occurred by transfer of hydrogen from the B-side of NADH. A kinetic investigation of cortisol, cortisone, cortexolone, and the 21-aldehydes of each indicated: (a) the magnitude of the Michaelis constant for any substrate was independent of the second substrate concentration; (b) the 21-aldehydes had larger Michaelis constants (5- to 8-fold) and larger maximum velocities (16- to 40-fold) than the steroids from which they were synthesized; (c) the Michaelis constant for NADH, 29 muM, was independent of the steroid substrate. With cortisol and cortisol-21-aldehyde, product inhibition patterns showed only slope effects with steroid product and NAD+, suggesting a "random" mechanism. Inhibition studies with the "poor" substrate cortisol indicated that cortisol and cortisol-21-aldehyde were reduced at the same site. The inhibition constant (180 muM) agreed with the Michaelis constant of cortisol (140 muM). The steroid product, 20beta-hydroxyprogesterone, gives noncompetitive inhibition patterns with respect to NADH and cortisol-21-aldehyde, indicating a separate binding site exists on the enzyme for this inhibitor. The intrinsic protein fluorescence of 20beta-hydroxysteroid dehydrogenase was quenched by NADH (56%) with a dissociation constant of 16 muM. NAD" quenched the protein fluorescence somewhat less (31%) with a dissociation constant of 104 muM. The fluorescence of 2-p-toluidine-6-naphthalene sulfonate is enhanced in the presence of enzyme, and there is a blue shift in the emission wavelength maximum. The enzyme-enhanced 2-p-toluidine-6-naphthalene sulfonate fluorescence is quenched by NAD+ (32%) with a dissociation constant of 128 muM. Corticosteroids and their corresponding 21-aldehydes completely quench the enhanced 2-p-toluidine-6-naphthalene sulfonate fluorescence and this feature can be used to determine enzyme-steroid dissociation constants. Corticosteroid-21-aldehydes and NAD+ dissociation constants determined in this manner agree with values obtained in kinetic measurements. The dissociation constants determined for cortisol, cortisone, cortexolone, progesterone, and 20beta-hydroxyprogesterone were at least 1 order of magnitude greater than the corresponding kinetic constants, and these findings suggest the presence of a kinetically insignificant binding site.

Adrenal Cortex Hormones↗
PubMed1977

Studies of the diurnal pattern of plasma corticosteroids and gonadotropins in two cases of feminizing adrenal carcinoma: measurements of estrogen and corticosteroid production.

Two adult men with feminizing adrenal cortical carcinoma had measurements of their 24-h plasma corticosteroid and gonadotropin patterns as well as 24-h mean hormone levels of estradiol, estetrol, 11-desoxycortisol, DHEA-S, DHEA and testosterone. Cortisol, 11-desoxycortisol and estrogen production rates were also measured. The 24-h corticosteroid patterns showed preservation of the normal 24-h episodic and circadian patterns, albeit at higher levels. The cortisol production rates were markedly elevated despite only moderate elevation of the 24-h mean cortisol level. There were elevated plasma 11-desoxycortisol levels and a markedly elevated 11-desoxycortisol production rate in one patient and THS excretion in the other. The plasma estradiol levels, urinary excretion and production rates were markedly elevated. In addition, there was a decrease in the specific activity of estriol compared with estrone and estradiol as well as measurable levels of estetrol in both patients. These latter observations coupled with the urinary immunoassayable hCG in one patient suggest that these tumors may be functioning like trophoblastic tissue. The possibility that estetrol may serve as an additional marker for tumors of trophoblastic origin is of additional interest.

Adrenal Cortex Hormones↗
PubMed1977

Effect of corticosteroids on sciatic nerve-tibialis anterior muscle of rats treated with hemicholinium-3. An experimental approach to a possible mechanism of action of corticosteroids in myasthenia gravis.

We studied the effect of intraperitoneally administered corticosteroids on the neuromuscular transmission in the sciatic nerve-tibialis anterior muscle preparation of the anesthetized rat stimulated at a rate of 10 Hz. Administered simultaneously with hemicholinium-3 (HC-3), 80 mug per kilogram (that is, half the lethal dose for 50 percent survival), prednisolone and dexamethasone cause a marked reversal of the block of the neuromuscular transmission caused by HC-3. The effect of aldosterone is very small. The blocking action of d-tubocurarine is not antagonized by either prednisolone or dexamethasone. Choline provides total protection against the HC-3 blockade, whereas physostigmine, in a just sublethal dose, is ineffective. We tentatively conclude that in myasthenia gravis the carrier-mediated transport of choline into the nerve endings may be deficient and that the beneficial effect of corticosteroids in this condition is based on their ability to ameliorate the deficient choline transport.

Animals↗
PubMed1979

Synthesis and secretion of corticosteroid-binding globulin by rat liver. A source of heterogeneity of hepatic corticosteroid-binders.

Classical glucocorticoid receptors (type II) have a high affinity for synthetic and natural glucocorticoids. We have previously demonstrated an additional binding site in kidney cytosol (type III) which has a high affinity for corticosterone but a low affinity for dexamethasone. In many ways, this binder resembles plasma corticosteroid-binding globulin (CBG). The first goal of this study was to determine the organ distribution of the type III binding sites. Cytosol was prepared from isolated cells to avoid plasma contamination. Of the tissues examined, type III sites were found only in liver and kidney; sites were absent from thymocytes, IM-9 lymphocytes, adipocytes, and bone cells. The second goal of this study was to ascertain whether CBG is synthesized in liver and kidney. Liver and kidney slices were incubated in vitro and the concentration of type III sites was seen to rise in hepatic cytosol and incubating medium but not kidney. To verify the impression that liver was synthesizing and secreting CBG, the following experiments were performed: (a) To demonstrate that type III sites were CBG, steroid-binding profiles and migration on polyacrylamide gel electrophoresis were shown to be identical for hepatic type III sites and serum. (b) To indicate that the rise in type III sites was dependent on protein synthesis, it was shown that cycloheximide blocked the appearance of new type III sites. (c) To establish that the type III sites were being secreted, in situ liver perfusion experiments showed time-dependent release of new sites into the perfusate. In conclusion, liver synthesizes and secretes type III sites, a finding previously suspected but never proved. The presence of type III sites in kidney remains to be explained.

Animals↗
PubMed1978

Polar corticosteroids in human neonatal urine; synthesis and gas chromatography-mass spectrometry of ring A reduced 6-hydroxylated corticosteroids.

This report describes the synthesis of 3alpha,6beta,11beta,17alpha,21-pentahydroxy-5beta-pregnane-20-one, 3alpha,6beta,11beta,17alpha,21-pentahydroxy-5beta-pregnane-20-one, 3alpha,6alpha,11beta,17alpha,21-pentahydroxy-5alpha-pregnane-20-one, 3alpha,6beta,17alpha,21-tetrahydroxy-5beta-pregnane-11,20-dione, 3alpha,6beta,17alpha,21-tetrahydroxy-5alpha-pregnane-11,20-dione, 3alpha,6alpha,17alpha,21-tetrahydroxy-5beta-pregnane-11,20-dione and 3alpha,6alpha,17alpha,21-tetrahydroxy-5alpha-pregnane-11,20-dione. The gas chromatographic-mass spectrometric properties of these compounds are given. Proof of structure was accomplished using gas chromatography-mass spectrometry, microchemical reactions, optical rotatory dispersion and nuclear magnetic resonance spectroscopy.

Chromatography, Gas↗
PubMed1975

Corticosteroids in brain tissue.

Total corticosteroid concentrations were determined in the plasma and brains of five species: mouse, rat, cat, monkey and man. Corticosteroid concentrations were measured also in the livers of mice, rats and monkeys. Competitive protein binding techniques were validated and used for the tissue corticosteroid assays. In each species the brain corticosteroid value was less than the total plasma corticosteroid level but greater than the presumed unbound fraction of plasma corticosteroids. A clear circadian variation of brain corticosteroid values was found in mice, together with a rapid elevation of the tissue levels in response to stress. Reduction of both plasma and tissue corticosteroid concentrations was observed after adrenalectomy and in response to dexamethasone treatment of mice. Between 24 and 48 h post morten, mouse brain corticosteroid values decreased greatly. In cat, monkey and human brains all regions examined contained approximately equal amounts of corticosteroids. In particular, brain areas which are not involved in pituitary-adrenocortical regulation contained large amounts of corticosteroids.

Adrenal Glands↗
PubMed1978

[Study on suppression of the pituitary-adrenocortical function by the therapeutic use of corticosteroids and its spontaneous recovery (author's transl)].

The present study was undertaken to investigate suppression of the pituitary-adrenocortical function by long-term corticosteroid therapy and spontaneous recovery from such a suppressant drug effect. Sixty patients who were on corticosteroids (hereinafter their dosage is expressed as the equivalent of prednisolone) given at 10 to 40 mg initially and then on a gradually decreasing basis down to below 10 mg currently or who had already been withdrawn from such a drug regimen were involved in the study and analysed for baseline values for plasma cortisol. These patients were evaluated for the functional status of the pituitary-adrenocortical system in relation to varying combinations of such factors as the total dose of corticosteroids, the duration in days of medication, the duration in days of mecication at reduced dosage levels, and time in days elapsed from cessation of medication. The results led to the following conclusions: (1) In patients receiving corticosteroids at such daily dosage levels as are reduced gradually to 7.5 mg or below within the duration in days as defined by the inequality Y greater than or equal to 8.4X + 222 (where Y stands for total dose given and X stands for the duration in days of administration), the pituitary-adrenocortical function is assumed to be in a state of being suppressed. When corticosteroids have been given at daily dosages reduced gradually to 7.5 mg or below within the duration in days as determined by the inequality Y less than or equal to 6.8X + 140 (where Y and X, respectively, stand as mentioned above), the pituitary-adrenocortical function of the recipient patient is considered to be in a state either of being not suppressed or of being recovered from suppressant drug effect. (2) In cases where corticosteroid therapy is started with a moderate dosage, then reduced to a low dosage level or stopped within relatively short period of time, the recipient patient can be safely withdrawn from the drug therapy without suppression of the pituitary-adrenocortical function if the dosage schedule is in line with the inequality Y less than or equal to 5.9X + 331 (where X denotes the duration in days of medication and Y, total dose). These results led the author to formulate a model of a corticosteroid dosage schedule which is reasonable free from the risk of causing pituitary-adrenocortical insufficiency. More particularly, the dosage of corticosteroids is reduced by a 5 mg decrement at regular intervals of 5, 8, 13, 27 and 103 days, respectively, when the initial daily dose is 30, 25, 20, 15 and 10 mg. By following this dosage regimen one might expect safe withdrawal from corticosteroid therapy without risking suppression of the pituitary-adrenocortical function. (3) Corticosteroid therapy, when given at a dosage of 7.5 mg or less daily, is considered to have little suppressant effect on the pituitary-adrenocortical function...

Adolescent↗
PubMed1978

Corticosteroid effect on immunoglobulins.

The corticosteroid (prednisone) effect on serum immunoglobulins in 9 atopic asthmatic patients who required corticosteroids for the control of asthma was evaluated. Serum immunoglobulins were determined before corticosteroids were administered, an average of 15 days while on corticosteroids, and again an average of 22 days after corticosteroids were discontinued. While on corticosteroids (averaging 16.8 mg prednisone daily) for 15 days, mean serum IgG was significantly decreased (-22%, p less than or equal to 0.01), mean serum IgA tended to be decreased (-10%), and mean serum IgM was essentially unchanged. Serum IgE was initially significantly increased (p less than 0.01) when compared to levels of other serum immunoglobulins (IgG,A,M). An average of 22 days after corticosteroids were discontinued, mean serum IgG was still significantly decreased (p less than 0.05), and mean serum IgA again tended to be decreased. Serum IgM remained unchanged and mean serum IgE now was significantly decreased (p less than 0.01). Corticosteroids appear to have a significant effect on levels of some serum immunoglobulins.

Adolescent↗
PubMed2026

Single-nucleus profiling reveals hepatocyte identity and immune features associated with corticosteroid response in severe alcohol-related hepatitis.

BACKGROUND & AIMS: Severe alcohol-related hepatitis (sAH) is associated with high short-term mortality. However, 30-40% of patients fail to respond to corticosteroids, the only proven pharmacological treatment. The pathophysiological mechanisms underlying sAH and the marked heterogeneity in treatment response remain incompletely understood. We aimed to define cellular changes associated with corticosteroid response in sAH and to identify baseline markers predictive of treatment outcome. METHODS: Single-nucleus RNA sequencing was performed on liver biopsies from patients with biopsy-proven sAH (n = 17), including paired baseline and day 8 biopsies in a subset of patients (n = 8). Patients were classified as corticosteroid responders (sAH-R; Lille score <0.45) or non-responders (sAH-NR; Lille score &#x2265;0.45). Liver biopsies from patients with acute decompensation of alcohol-related cirrhosis (AD; n = 5) and healthy controls (n = 4) were included for comparison. Findings were validated using immunohistochemistry and spatial proteomics in a large multicenter validation cohort (n = 172). RESULTS: At baseline, sAH-R exhibited a significantly higher proportion of liver-infiltrating S100A8+ monocytes compared to sAH-NR, a difference that persisted at day 8. sAH livers showed a marked reduction in mature hepatocytes and an expansion of stressed and intermediate hepatocyte populations, indicating progressive loss of mature hepatocyte identity. This loss was more pronounced in sAH-NR, who also exhibited fewer cycling hepatocytes at day 8, consistent with impaired regenerative capacity. Expression of SULT2A1, a marker of mature hepatocyte identity, was significantly reduced in sAH-NR at baseline. Finally, liver biopsies with &#x2265;50% SULT2A1-positive hepatocytes at baseline were strongly predictive of corticosteroid response. CONCLUSIONS: This study delineates distinct immune and hepatocyte changes associated with corticosteroid response in sAH. Baseline SULT2A1 expression may facilitate stratified treatment approaches in sAH. IMPACT AND IMPLICATIONS: Severe alcohol-related hepatitis (sAH) represents one of the most devastating manifestations of alcohol-related disorders. sAH is characterized by acute hepatic inflammation and high short-term mortality. Clinical management remains challenging, as corticosteroids - the only pharmacological therapy currently applied - are ineffective in a substantial proportion of patients and are associated with significant adverse effects. These limitations highlight the need for a more detailed understanding of sAH pathophysiology and for approaches that enable improved patient stratification and therapeutic decision-making. In this study, we identify distinct pre-treatment differences between corticosteroid responders and non-responders at the level of both hepatocytes and myeloid cells, providing new insight into the cellular mechanisms underlying treatment heterogeneity in sAH. Furthermore, leveraging these findings, we developed a histology-based SULT2A1 scoring system using a commercially available antibody, which predicts corticosteroid response at baseline and may support stratified treatment approaches in clinical practice.

Humans↗