Hydrocortisone 21-hemisuccinate Research Articles

Hydrocortisone metabolism by Staphylococcus: Effects on anti-inflammatory and antimicrobial action.

Hydrocortisone 21-hemisuccinate (HCHS) influenced the growth and metabolism of Staphylococcus aureus S. aureus metabolic activity was high and antibiotic susceptibility low at 1.4mg/mL HCHS S. aureus metabolized HCHS to cortisol and reduced poly(I:C)-induced IL-6 secretion.

DETERMINATION OF HYDRO-CORTISONE 21-HEMISUCCINATE, OXYTETRACYCLINE AND NYSTATIN IN PHARMACEUTICAL PREPARATIONS BY CAPILLARY ZONE ELECTROPHORESIS

ABSTRACT A capillary zone electrophoresis method is presented to separate hydrocortisone 21-hemisuccinate, oxytetracycline HCl and nystatin by using a fused-silica capillary (57 cm × 75 µm I.D.). The separation was carried out at 30 kV and 25°C in a 10 mM phosphate buffer adjusted to pH = 11 as electrolyte. Under these conditions, the run time was 4 min and the limits of quantification were about 2 mg/L for every component. The new method was applied to two pharmaceutical preparations and the results provided recoveries close to 100%. These results compared well with a reference HPLC method.

Inhibitory Effects of Anti-Inflammatory Drugs on Interleukin-6 Bioactivity.

Interleukin-6 (IL-6) is known as a proinflammatory cytokine involved in immune response, inflammation, and hematopoiesis. Inhibitory effects of anti-inflammatory drugs on IL-6 bioactivity using IL-6-dependent hybridoma have been evaluated. Three out of 16 nonsteroidal anti-inflammatory drugs (NSAIDs) showed IC50 values of less than 100 microM, which were in the order of oxyphenylbutazone hydrate (IC50=7.5 microM)>meclofenamic acid sodium salt (31.9 microM)>sulindac (74.9 microM). Steroidal anti-inflammatory drugs (SAIDs) exhibited significant inhibitory effects at 100 microM on the IL-6 bioactivity, and their inhibitory potencies were in the order of budesonide (IC50=2.2 microM)>hydrocortisone 21-hemisuccinate (6.7 microM), prednisolone (7.5 microM), betamethasone (10.9 microM)>dexamethasone (18.9 microM) and triamcinolone acetonide (24.1 microM). The results would provide an additional mechanism by which anti-inflammatory drugs display their anti-inflammatory and immunosuppressive effects at higher concentrations.

Nuclear localization of bovine immunoglobulin G (bIgG) in the liver of rats injected with hydrocortisone-bIgG conjugate intravenously.

Bovine serum albumin conjugated with steroid hormone injected intravenously into rats can enter the hormone-target cell nuclei with its antigenicity kept intact (Nishimura and Nakano, 2000). Antinuclear antibodies (ANA) such as immunoglobulin G (IgG) are found in some autoimmune diseases. To confirm immunocytochemically whether immunoglobulin G (IgG) conjugated with steroid hormone enters in the hormone-target cell nuclei, bovine IgG (bIgG) was conjugated with hydrocortisone 21-hemisuccinate. The hydrocortisone-bIgG conjugate was injected into the vascular system of adrenalectomized rats. Then the rats were killed 2 or 3 h after injection to detect bovine IgG in the hormone-target cell nuclei of the liver by fluorescein-isothiocyanate labeled-anti bovine IgG antibody under confocal laser scanning microscopy. In the liver of both rats injected with hydrocortisone-bIgG, the fluorescence was observed in not only the cytoplasm but also the nuclei of liver cells. In control rat injected with bIgG, few nuclei showed fluorescence. These results demonstrate that bovine IgG conjugated with steroid hormone can enter the hormone-target cell nuclei of rat with its antigenicity kept intact, and suggest that antinuclear antibody in some autoimmune diseases may be transported from blood plasma into the nucleus.

Coadsorption of the sodium salts of two steroid molecules at a silica/interface as induced by the adsorption of a cationic surfactant

The incorporation of two ionic steroids, namely the sodium salts of hydrocortisone 21-hemisuccinate (HNa) and prednisolone 21-succinate (PNa), at a silica/water interface in the presence of adsorbed cetyltrimethylammonium bromide has been investigated first at a constant pH value. It is shown that this coadsorption effect is qualitatively similar to the adsolubilization effect which is described for neutral molecules. The adsorption of the cationic surfactant induces the coadsorption of the anionic drug molecules although the silica surface is negatively charged. At surfactant equilibrium concentration above the critical micelle concentration the drug molecules are distributed between the adsorbed aggregates and the free micelles. At larger surfactant concentration, the drugs may be completely depleted from the silica/water interface. Based upon Langmuir-type isotherms, the equilibrium constants of the drug molecules with the adsorbed aggregates and the free micelles are calculated. The constants are about three times larger for the former than for the latter aggregates. The signification of such results is discussed. The coadsorption of HNa at low surfactant surface coverage was also investigated in the pH interval between 3 and 9. HNa is strongly coadsorbed at lower pH onto the silica surface. The coadsorption goes through a maximum at a pH value which may be considered as equal to the apparent pK of the drug and decreases to zero at higher pH values. A pK value equal to 4.2 is proposed for HNa. This behaviour is interpreted as the result of the interplay of the drug dissociation and that of the surface silanol groups upon the change of pH.

Synthesis and characterisation of polyethylene glycol conjugates of hydrocortisone as potential prodrugs for ocular steroid delivery

A method for the synthesis of polyethyleneglycol esters of hydrocortisone 21-hemisuccinate (H-PEGs) as potential ocular prodrugs, was developed using dicylohexylcarbodiimide to promote esterification. The products were purified by semipreparative high performance liquid chromatography (HPLC). The steroid derivatives were, mainly, highly water soluble. The products were characterised by NMR, fast atom bombardment mass spectrometry and elemental analysis. The polyethylene glycol esters were studied with respect to their stability in aqueous solution and their partition coefficients.

Induction of rat hepatic glucocorticoid-inducible cytochrome P450 3A by metyrapone

The bipyridyl compound metyrapone is a potent inhibitor of cytochromes P450, a gene superfamily of haemoproteins involved in the metabolism of many xenobiotics as well as endogenous compounds such as steroid hormones. Administration of metyrapone to male rats induces the expression of the cytochrome P450 sub-family 3A (CYP3A). In order to determine whether metyrapone was causing the induction of CYP3A by blocking endogenous glucocorticoid metabolism, CYP3A levels were examined in rat hepatocytes cultured in serum-free medium supplemented with hydrocortisone 21-hemisuccinate plus or minus metyrapone. Western blotting indicated that metyrapone alone induces CYP3A and that hydrocortisone 21-hemisuccinate is ineffective. However, hydrocortisone 21-hemisuccinate enhanced the levels of CYP3A induced by metyrapone. In contrast, glucocorticoid-inducible tyrosine aminotransferase (TAT) activity was unaffected by metyrapone but metyrapone enhanced the levels induced by hydrocortisone 21-hemisuccinate. An examination of the metabolism of hydrocortisone by rat hepatocytes in vitro indicated that metyrapone perturbed the catabolism of hydrocortisone under conditions which give rise to an enhancement of hydrocortisone 21-hemisuccinate and hydrocortisone-dependent TAT induction. However, evidence is presented to suggest that such a perturbation of hydrocortisone metabolism could not account for the glucocorticoid potency amplifying property of metyrapone. Thus the induction of CYP3A and the enhancement of glucocorticoid-mediated TAT induction appears not to be associated with any perturbation in glucocorticoid metabolism but with some other as yet undefined mechanism(s).

Absorption and metabolism of hydrocortisone 21-butyrate, 21-hemisuccinate and hydrocortisone by skin of the rabbit ear during single-pass perfusion.

1. Rabbit ear was single-pass perfused with protein-free buffer solution at a rate of 0.02 ml/min per cm2 surface area for up to 6 h. 2. Hydrocortisone or hydrocortisone 21-butyrate or hydrocortisone 21-hemisuccinate was applied dermally (0.01-1.0% w/w) in suspension with isopropyl myristate or dissolved in 1,2-propanediol. The ointments were stiffened with 5% polyethylene 1500 or 1.2% methylcellulose respectively. 3. Hydrocortisone was slowly absorbed and did not reach a steady-state absorption rate during the experimental period. 4. No metabolites of hydrocortisone were found during ear perfusion. In the supernatant of skin homogenate, however, cortisone, hydrocortisone-20 alpha-ol and another, as yet unidentified metabolite, were observed. 5. Hydrocortisone 21-butyrate was completely hydrolysed during dermal absorption, showing steady-state concentrations of hydrocortisone in the effluent. Hydrocortisone 21-hemisuccinate did not reach steady-state concentrations in the effluent. About two-thirds was hydrolysed during absorption. 6. During arterial perfusion approximately 30% of hydrocortisone 21-butyrate was hydrolysed whereas 97% of hydrocortisone 21-hemisuccinate remained intact. 7. First-pass ester hydrolysis in skin may be complete for the poorly absorbed glucocorticoids leading to metabolites of less lipophilicity.

Effect of Micellization on Rate of Cupric-Ion-Promoted Hydrolysis of Dicarboxylic Acid Hemiesters

The effect of micellar sodium lauryl sulfate on the rate of cupric-ion-promoted hydrolysis of some dicarboxylic acid hemiesters was investigated at pH 5, ionic strength 0.1 M, and 40, 45, and 50°. The rate of cupric-ion-promoted hydrolysis of sodium n-decyl oxalate in the micellar phase is about 50 times as fast as that in the bulk solution. The formation constant of the intermediate chelate complex, cupric decyl oxalate, was decreased in the micellar phase, while the rate of attack of hydroxide ion upon the chelate complex was increased. The overall rate increase is attributed to the increase in the entropy of activation for the reaction in the micellar phase. The rates of hydrolysis of sodium hydrocortisone 21-hemisuccinate and sodium hydrocortisone 21-hemi-(3,3-dimethylglutarate) were unaffected by copper ion.

Prediction of Stability in Pharmaceutical Preparations X: Alkaline hydrolysis of hydrocortisone hemisuccinate

The hydrolysis of hydrocortisone 21-hemisuccinate above pH 8 has been studied by constant pH derations in aqueous solution and appears to involve specific hydroxyl ion catalyzed hydrolysis as the only significant reaction pathway. The apparent heat of activation for specific hydroxyl ion catalyzed hydrolysis when corrected for the heat of ionization of water is unusually low for hemisuccinate esters, 7.0 Kcal./mole. This implicates the configuration and structure of the steroid side chain in the facile hydrolysis of 21-steroid esters. The stability of hydrocortisone 21-hemisuccinate at storage and physiological conditions is predicted.