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Sensitivity to hydrocortisone is a relevant factor in the immunoendocrine relationship. I. The cell-mediated immune response in relation to blood levels and in vitro immunosuppressive effects of hydrocortisone in patients with asthma and healthy control subjects.

The role of endogenous hydrocortisone in the regulation of lymphocyte activity was assayed in patients with asthma (patients with chronic nonspecific lung disease, characterized by attacks of dyspnea, alternating with symptom-free periods) and healthy control subjects. After priming, delayed-type hypersensitivity skin reactions were induced with Helix pomatia hemocyanin (HPH). Hydrocortisone blood levels were measured. The effect of hydrocortisone on HPH-induced lymphocyte proliferation was determined in vitro. The results demonstrate that hydrocortisone in low concentrations (100 ng/ml) inhibited in vitro lymphocyte proliferation equally in patients and control subjects. However, both groups demonstrated a large interindividual variation in hydrocortisone sensitivity. Therefore, in order to determine the immunologic effect of hydrocortisone blood levels in vivo, a hydrocortisone suppression index (HSI) was calculated by use of the information on hydrocortisone concentrations in vivo and the biologic effect of hydrocortisone in vitro. This HSI appeared to be inversely related with the in vivo cell-mediated immune response to HPH. This was reflected in an inverse correlation between HSI and delayed-type hypersensitivity skin reactions to HPH, both in patients (R = -0.64), in control subjects (R = -0.69), and in the total group (R = -0.68; p less than 0.001). No differences were observed between patients and control subjects. It is concluded that endogenous hydrocortisone is likely to play an important role in the regulation of lymphocyte activity in patients with asthma and healthy control subjects. This may have important consequences for the clinical expression of asthmatic symptoms, since the role of lymphocyte activity in the pathogenesis of asthma is increasingly recognized.

Adult

Enzyme inhibition in human skin homogenates by hydrocortisone, hydrocortisone acetate and hydrotisone butyrate.

In fresh human skin homogenates, the activities of four enzymes, lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-PDH), "acid" phosphatase (AcP), and "leucine aminopeptidase" (LAP) were assayed following an incubation with hydrocortisone, hydrocotisone acetate, or hydrocortisone-17-butyrate, respectively. Concentration of the three compounds measured 2.75 mMol/l. Hydrocortison butyrate inhibited LDH-G-6-PDH-, and AcP-activities. Hydrocortisone and hydrocortisone acetate exerted a significant inhibitory action only in the case of G-6-PDH-activity.--On pure G-6-PDH from yeast, the inhibition exerted by hydrocortisone butyrate was significantly stronger than the inhibition exerted by the two other steroids. Time/action diagrams revealed the fact that hydrocortisone butyrate is superior to the other two compounds from the beginning of the incubation period.--The date sustain the assumption that hydrocortisone butyrate exerts biochemical-pharmacological actions of its own and that it may not be considered just as an esterified transport form of hydrocortisone.

Acetates

Screening for corticosteroid contact sensitivity. Comparison of tixocortol pivalate, hydrocortisone-17-butyrate and hydrocortisone.

3 corticosteroids have so far been tried as markers for corticosteroid contact sensitivity: hydrocortisone, tixocortol pivalate and hydrocortisone-17-butyrate. The present study compared these steroids for screening in addition to a standard patch test series. Of 727 patients, 28 (3.9%) reacted to tixocortol pivalate and 10 (1.4%) to hydrocortisone-17-butyrate; hydrocortisone gave an allergic reaction in 2 of 521 (0.4%) patients. Serial dilutions suggested that tixocortol pivalate, not marketed in Finland, caused allergic reactions which could possibly be cross-reactions to hydrocortisone. In contrast to previously published data, frequent cross-reactions occurred with hydrocortisone-17-butyrate and tixocortol pivalate. All allergic reactions to other corticosteroids found by testing with tixocortol pivalate concurred with reactions to hydrocortisone-17-butyrate. The study suggests that the most effective choice for routine testing for corticosteroid contact sensitivity would be both tixocortol pivalate and hydrocortisone-17-butyrate.

Administration, Topical

Inhibition by epidermal growth factor (EGF) of epidermal DNA synthesis in cultured chick embryonic skin pretreated with retinol and/or hydrocortisone: specific increment in EGF binding activity in both retinol- and hydrocortisone-pretreated epidermis without correlation to EGF-mediated inhibition of cell growth.

When tarsometatarsal skin of 13-day-old chick embryos that had been cultured in medium containing 5% delipidized FCS with or without retinol (20 microM) and/or hydrocortisone (20 nM) for 1 day was cultured in a chemically defined medium without either the hormone or retinol for 1 day, epidermal DNA synthesis of hydrocortisone- and/or retinol-pretreated skin was inhibited when compared to that of control skin. The addition of epidermal growth factor (EGF, 10 ng/ml) to retinol- or hydrocortisone-pretreated skin further inhibited the epidermal DNA synthesis. Epidermal DNA synthesis in retinol- and hydrocortisone-pretreated skin was more strongly inhibited than in retinol- or hydrocortisone-pretreated skin, but was not further inhibited by EGF. In epidermis which was induced to differentiation toward keratinization by hydrocortisone or mucous metaplasia by retinol, EGF inhibited DNA synthesis. The extent of [125I]-EGF binding to the epidermis of retinol- and hydrocortisone-pretreated skin was 160-180% that in control skin, with no change in affinity. Hence there is no correlation between EGF-binding and the mitogenic activity of EGF.

Animals

Seborrhoeic dermatitis and Pityrosporum orbiculare: treatment of seborrhoeic dermatitis of the scalp with miconazole-hydrocortisone (Daktacort), miconazole and hydrocortisone.

Seventy patients (36 males and 34 females) with seborrhoeic dermatitis of the scalp were treated in a double-blind controlled study, for a maximum of 6 weeks, with 2% miconazole base and 1% hydrocortisone (Daktacort), 2% miconazole base, or 1% hydrocortisone. Patients who were cured were treated with the same formulation prophylactically twice monthly for 3 months or until recurrence. Nineteen of 21 patients were cured in the Daktacort group, 15 of 22 in the miconazole group and 17 of 24 in the hydrocortisone group. The number of cultured Pityrosporum orbiculare was significantly lower in all groups after treatment, but in the hydrocortisone group was still significantly higher than in the two other groups. After 3 months of prophylactic treatment, both Daktacort (16 of 19 patients clear) and miconazole (10 of 15 patients clear) were significantly better than hydrocortisone (3 of 17 patients clear) (P less than 0.01). The numbers of P. orbiculare remained low in the Daktacort and miconazole groups and also significantly lower than in the hydrocortisone-treated group (P less than 0.01). In patients with recurrence, the numbers returned to pre-treatment levels. This study demonstrates the aetiological significance of the Pityrosporum yeasts in seborrhoeic dermatitis. Both Daktacort and miconazole were effective in treatment and as prophylactic agents.

Adult

Hydrocortisone succinate and hydrocortisone simultaneously determined in plasma by reversed-phase liquid chromatography, and their pharmacokinetics in asthmatic children.

Hydrocortisone succinate and hydrocortisone are chromatographed with a mobile phase consisting of sodium acetate/acetonitrile (77/23, by vol), the effluent being monitored at 254 nm. p-Hydroxybenzoate-N-propyl is used as the internal standard. Detection limits are 0.5 mg/L for hydrocortisone succinate, 0.2 mg/L for hydrocortisone. For five different concentrations the respective mean analytical recoveries were 88.2% and 100.5%, the mean intra-assay CVs for slope 3.9% and 2.1%, and the inter-assay CVs 3.3% and 1.6%. Simultaneous measurement of hydrocortisone and its succinate ester may be useful for pharmacokinetic study. Concentration-time profiles for plasma after administration of hydrocortisone sodium succinate are presented.

Adolescent

Solution kinetics of a water-soluble hydrocortisone prodrug: hydrocortisone-21-lysinate.

Hydrocortisone-21-lysinate was synthesized as an amino acid prodrug of hydrocortisone to serve as a substrate for brush border aminopeptidases. This strategy was developed to demonstrate that an improvement in oral absorption could be obtained through reconversion in vivo. The aqueous stability of hydrocortisone-21-lysinate was studied over the pH range 3-8 at 25 degrees C. Reversible acyl migration of the lysine group between the 21- and 17-position hydroxyl groups was observed as well as hydrolysis. The observed half-life for direct hydrolysis of hydrocortisone-21-lysinate is 40 d at pH 3 and 30 min at pH 7. The relative instability at pH 7 is probably due to electrostatic stabilization of the negatively charged tetrahedral intermediate by the protonated amino groups.

Chromatography, High Pressure Liquid

Chlorocoulometric determination of hydrocortisone and hydrocortisone acetate.

A chlorocoulometric method for the determination of small amounts of hydrocortisone and hydrocortisone acetate is presented. The method is simple and rapid, the results obtained are accurate and reproducible. It can be successfully applied to the determination of hydrocortisone and hydrocortisone acetate in pharmaceutical formulations.

Electrochemistry

Regulation of hydrocortisone binding sites by hydrocortisone in human bone marrow fibroblasts.

The incubation of human bone marrow fibroblasts with hydrocortisone (10(-7) M) produces a time-dependent depletion of hydrocortisone-binding sites. This effect is glucocorticoid-specific, since glucocorticoid agonists cause depletion to the same extent as hydrocortisone. After withdrawal of the hormone from the incubation medium, cells are able to replenish their complement of receptor. The existence of this down-regulation process may represent a protective mechanism against the partial proliferative inhibitory action of glucocorticoids for bone marrow fibroblasts and also a stimulus for differentiation to adipocytes.

Binding Sites

A randomized phase II trial of aminoglutethimide and hydrocortisone versus combined aminoglutethimide, hydrocortisone and fluoxymesterone in advanced breast cancer.

Fifty postmenopausal women with advanced breast cancer were included in the following randomized phase II trial: 25 patients received aminoglutethimide 1000 mg and hydrocortisone 40 mg daily. Twenty-five patients received aminoglutethimide 1000 mg, hydrocortisone 40 mg and fluoxymesterone 20 mg daily. The two groups of patients were comparable in respect to the most important pretreatment characteristics. The majority of patients in both groups had bone lesions. There was a history of response to tamoxifen in all the cases and 17 patients had positive estrogen and progesterone receptors. The evaluation of response was based on the system adopted by the UICC. In the aminoglutethimide-hydrocortisone group, 16 (64%) patients obtained a partial remission, 3 (12%) remained stable and 6 (24%) had progressive disease. In the combination treatment group, 17 (68%) patients obtained a partial remission, 3 (12%) remained stable and 5 (20%) developed progressive disease. The median duration of partial remission and stabilization of the disease was 9 and 7 months respectively in both groups.

Adult

[Effectiveness of intra-articular dimexide in combination with hydrocortisone and hydrocortisone in patients with juvenile rheumatoid arthritis].

A course of 4-5 intra-articular injections was given to 25 children aged 4-15 years with juvenile rheumatoid arthritis: 20% dimexide++ solution in combination with hydrocortisone (2 ml) was administered into the right knee joint and hydrocortisone (12.5 mg) into the left knee joint once a week. Dimexide++ solution combination with hydrocortisone proved to be most effective: all signs of inflammation subsided, the joint function was restored and there were no untoward reactions.

Arthritis, Juvenile

Treatment of stage D2 prostatic cancer refractory to or relapsed following castration plus oestrogens. Comparison of aminoglutethimide plus hydrocortisone with medroxyprogesterone acetate plus hydrocortisone.

A total of 59 patients with advanced prostate cancer relapsed from or refractory to castration plus oestrogen were treated in a randomised trial comparing 1000 to 1250 mg aminoglutethimide + 40 mg hydrocortisone (AG + HC) with 500 mg medroxyprogesterone acetate + 40 mg hydrocortisone (MPA + HC). A significantly higher objective response rate and better symptomatic control was noted in patients treated with AG + HC (31%) compared with those treated with MPA + HC (3%). The median time to treatment failure was also significantly longer for patients treated with AG + HC. These findings suggest a role for AG in the treatment of advanced prostate cancer. While both second-line hormone treatment regimens resulted in significant suppression of adrenal androgen secretion, the differences in response rate could not be explained by alterations in peripheral blood hormone levels. AG in high doses may have cellular effects which require further study.

Aged

Problems with clinical trials in general practice--a double-blind comparison of cream containing miconazole and hydrocortisone with hydrocortisone alone in the treatment of intertrigo.

A double-blind comparative study between 1% hydrocortisone cream and a combination of 1% hydrocortisone cream and 2% miconazole cream has highlighted some of the problems with this type of research in general practice. The collection of adequate patient numbers within a predefined time scale proved a major problem. However, the study demonstrated the safety and efficacy of both these preparations in the treatment of intertrigo.

Double-Blind Method

Simultaneous analysis of hydrocortisone and hydrocortisone phosphate by high-pressure liquid chromatography: reversed-phase, ion-pairing approach.

The reversed-phase, ion-pairing approach to high-pressure liquid chromatography was applied to the simultaneous analysis of hydrocortisone and its phosphate ester in laboratory-prepared samples and injectable solutions. Results of this technique were evaluated and compared with results of the official procedure.

Chromatography, High Pressure Liquid

Endocrine effects of aminoglutethimide plus hydrocortisone versus effects of high dose of hydrocortisone alone in postmenopausal metastatic breast cancer.

Aminoglutethimide (Ag) has been used in different dosages with and without combined treatment with glucocorticoids for the suppression of peripheral plasma levels of steroidal hormones. In the present work we have estimated changes in peripheral steroid levels after 3 days of adrenal suppression with a 'physiological' daily dose of 40 mg hydrocortisone (H). Subsequently Ag (1000 mg daily) was added or the dose of H was doubled in order to study the efficacy of the suppression of oestradiol by these conditions during a 6-week period. Sixteen postmenopausal patients with evaluable and measurable progressive breast cancer were selected for the initial treatment, thereafter Ag was added in eight patients, while the other eight patients continued on H with a double dose. Administration of 40 mg H daily during the first 3 days caused a significant decrease of plasma oestradiol (P less than 0.01), androstenedione (P less than 0.01) and DHEA-S (P less than 0.05). Basal plasma cortisol levels increased and the diurnal rhythm disappeared. These observations suggest suppression of adrenal function by the exogenous cortisol. Prolonged treatment with a higher dose of H (80 mg daily) caused further suppression of androstenedione (P less than 0.01) but not of oestradiol. The addition of 1000 mg of Ag to H had no further significant effect on plasma oestradiol levels either. The main difference between the effects of the two treatment modalities was in the levels of androgens. The group treated with H alone showed long-term significant suppression of both androstenedione and DHEA-S, while in the group treated with the combination of H + Ag a further pronounced suppression of DHEA-S and elevation of androstenedione was found. Finally, there was a significant difference between SHBG levels in the two groups at day 42. The increased levels of SHBG in the H + Ag-treated group might lower the 'free' oestradiol concentration. It is concluded that both drugs have different effects on the plasma levels of peripheral steroids. On theoretical grounds, the combination of H + Ag might be preferable, because 'free' oestradiol plasma levels may be lowest after this treatment. However, a direct correlation with clinical effects still remains to be proven.

Aged

Second line endocrine treatment of postmenopausal advanced breast cancer. Preliminary endocrine results of a 5-arm randomized phase II trial of medium vs low dose aminoglutethimide, with or without hydrocortisone vs hydrocortisone alone (EORTC 10861).

The supposed mechanism of action of aminoglutethimide (AG), medical adrenalectomy, has been challenged. AG is now considered to act as an inhibitor of the aromatization of mainly adrenal androgens to estrogens in peripheral tissues and/or breast cancer itself. To further establish the AG dose required to sufficiently reduce estrogen levels in plasma and the possible role of hydrocortisone (HC) in combination with AG or by itself, postmenopausal advanced breast cancer patients received AG low (125 mg bid) or medium (250 mg bid) dose alone or combined with HC (20 mg bid) or HC alone (20 mg bid). Preliminary hormonal data show a similar reduction of serum estrone and estrone sulphate by at least some 50% at 8 wk in all treatment groups. At 6 months these effects persist except for patients treated with HC alone. In the latter a normalization of estrone levels is observed with effective suppression of adrenal androgen precursors, suggesting increased aromatase activity with prolonged glucocorticoid treatment.

Aminoglutethimide

[Immunochemical characteristics of hydrocortisone induced and hydrocortisone non-induced rat liver tyrosine aminotransferase isoenzymes].

Two isoenzymes of tyrosine aminotransferase (induced and noninduced by hydrocortisone were isolated from rat liver tissue and subjected to chromatographic purification. Specific antibodies with high titer were obtained after immunization of rabbits by the inducible isoenzyme. The antigenic properties of the obtained tyrosine aminotransferase isoenzymes were compared after double immunodiffusion in agar and immunoelectrophoresis. The purified induced and non-induced isoenzymes were shown to possess both similar and different antigenic determinants. The data obtained suggest that differences in antigenic properties of the tyrosine aminotransferase isoenzymes reflect those variations in their structure, which are expressed as various thermostability, sensitivity to proteolytic enzymes and substrate specificity.

Animals