Influence of hydrophiling agents on gel formation rate on Carbopol base

The aim of the study was to assess the impact of substrate composition on the physicochemical and pharmaceutical availability of hydrocortisone. Gels prepared on the basis of contained varying amounts of Carbopol propylene glycol-1,2, and polyethylene glycol 200. Applied hydrophilic substances affect the diversity of hydrocortisone half release times from hydrogels.     

Effect of some ethoxylated sorbitan alkanoate on hydrocortisone release from methylcellulose gels

The process of hydrocortisone release from the nonionic polymer--methylcellulose hydrogels with the addition of 1% and 3% ethoxylated sorbitan alkanoate: polysorbate 20 or polysorbate 80, in the presence of 1,2-propylene glycol or PEG 200 has two stages. In the first stage the release rates are higher in comparison with the second stage. Concerning the hydrogel as a two-compartment system with micellas of polysorbates, the release rates of the first stage are in the range 4.27 x 10(-4)-6.23 x 10(-4) h-1 and in the second stage are in the range 8.29 x 10(-6)-1.16 x 10(-5) h-1 what can be affected by HLB of mentioned polysorbates.     

The effect of sofalcone on the kinetics of the generative cells and superficial epithelial cells in mouse gastric mucosa

Effects of an anti-ulcer drug, 2'-carboxymethoxy-4,4'-bis(3-methyl-2-butenyloxy) chalcone (sofalcone), on the generative cells and kinetics of superficial epithelial cells in mouse gastric mucosa, including the effect of hydrocortisone on them, were investigated by the use of 3H-thymidine autoradiography. The labeling indices and the width of the generative cell zone in the fundic mucosa were significantly decreased by administration of hydrocortisone. The decrease in the labeling indices and the width of the generative cell zone induced by administration of hydrocortisone were not inhibited by sofalcone. Hydrocortisone had no significant influence on the labeling indices of the generative cell zone in the pyloric mucosa, but decreased the width of it. The decrease in the width of the generative cell zone induced by hydrocortisone was inhibited by sofalcone. Concerning the influence on the kinetics of superficial epithelial cells, hydrocortisone inhibited the increase in the labeling indices of the superficial epithelial cells after continuous administration of 3H-thymidine in both the fundic mucosa and pyloric mucosa. In the fundic mucosa, sofalcone showed no influence on the inhibition by hydrocortisone, but in the pyloric mucosa, the effect of hydrocortisone was abolished by sofalcone. These results suggest that sofalcone inhibits the reduction of the cell production and the prolongation of the life span of superficial epithelial cells caused by hydrocortisone in the pyloric mucosa.     

Metabolism of phenazone in man after hydrocortisone administration

Summary The influence of a high plasma concentration of hydrocortisone on the metabolism of phenazone in humans has been studied. Two series of experiments were carried out, Group A to demonstrate any enzyme-inducing effect of hydrocortisone, and Group B to study the immediate effect of hydrocortisone on the metabolism of phenazone. 9 subjects (Group A) received a total 250–400 mg hydrocortisone i.m. twice daily for three days and the 24-hour elimination of phenazone was studied before and afterwards. In a further 5 subjects (Group B) the elimination of phenazone was examined during administration of hydrocortisone or placebo. The elimination rate and the apparent volume of distribution of phenazone remained unchanged under both experimental conditions.     

Effect of hydrocortisone on the pituitary response to growth hormone releasing hormone

RATIONALE: In depression, the growth hormone (GH) response to clonidine and L-tryptophan (L-TRP) is reduced, suggesting reduced alpha2-adrenergic and serotonin (5-HT)1A receptor function. Pretreatment with hydrocortisone (100 mg, orally 11 h before) also blunts the GH response to L-TRP. This effect may be mediated at the hypothalamic level via reduced 5-HT1A receptor function or at the pituitary level, either by a direct effect on somatotrope cells or via enhanced insulin-like growth factor-1 (IGF-1) or somatostatin (SS) release. OBJECTIVES: To examine the effects of acute and chronic exposure to hydrocortisone on baseline and stimulated GH release from the pituitary. METHODS: Twelve healthy male volunteers received pretreatment with acute hydrocortisone (100 mg, 11 h before), chronic hydrocortisone (20 mg twice a day for 1 week) and placebo in a double blind, balanced order, crossover design. Serial measurements of plasma GH, IGF-1 and thyroid stimulating hormone (TSH) levels were made at baseline and following intravenous administration of 1 mcg/kg GHRH. RESULTS: The GH response to growth hormone releasing hormone (GHRH) was significantly blunted by pretreatment with both acute and chronic hydrocortisone. Baseline IGF-1 levels were significantly lower at baseline after chronic hydrocortisone compared with placebo. Baseline TSH levels were significantly lower after acute hydrocortisone compared with placebo, suggesting an increase in somatostatin levels. CONCLUSIONS: These data suggest that hydrocortisone acts at the pituitary level to reduce GH release. The TSH and IGF-1 data support the hypothesis that hydrocortisone reduces GH release by enhancing somatostatin and IGF-1 release.     

PEG Hydrogels for the Controlled Release of Biomolecules in Regenerative Medicine

Polyethylene glycol (PEG) hydrogels are widely used in a variety of biomedical applications, including matrices for controlled release of biomolecules and scaffolds for regenerative medicine. The design, fabrication, and characterization of PEG hydrogels rely on the understanding of fundamental gelation kinetics as well as the purpose of the application. This review article will focus on different polymerization mechanisms of PEG-based hydrogels and the importance of these biocompatible hydrogels in regenerative medicine applications. Furthermore, the design criteria that are important in maintaining the availability and stability of the biomolecules as well as the mechanisms for loading of biomolecules within PEG hydrogels will also be discussed. Finally, we overview and provide a perspective on some of the emerging novel design and applications of PEG hydrogel systems, including the spatiotemporal-controlled delivery of biomolecules, hybrid hydrogels, and PEG hydrogels designed for controlled stem cell differentiation.     

Replacement therapy of oral hydrocortisone in adrenal insufficiency: the influence of gastrointestinal factors

BACKGROUND: Replacing glucocorticoids in primary adrenal insufficiency (AI) or Addison's disease (AD) is today based on oral replacement therapy with hydrocortisone in a conventional immediate-release tablet. It is recognised that physiological gastrointestinal factors may have a strong influence on the plasma concentration-time profile of hydrocortisone. Hydrocortisone has a sufficiently high permeability in both the small and large intestine, but in vivo dissolution from the available oral product is limited at higher doses. The short elimination half-life of hydrocortisone (approximately 1.5 h) when given in traditional immediate-release dosage forms requires two or more dose administrations per day, with high peaks and low trough values in between. The endogenous secretion of cortisol from the adrenal cortex follows a distinct diurnal pattern, with increasing and high plasma levels of cortisol early in the morning (approximately 05.00-08.00 h), intermediate levels in the afternoon, low levels in the evening and a cortisol-free interval at night. There is, therefore, a clinical need for an improved drug delivery product that more closely follows the circadian pattern of cortisol in plasma. OBJECTIVE: The pharmaceutical and biopharmaceutical properties of the dosage form containing hydrocortisone will determine intestinal absorption rate and the plasma concentration-time profile of hydrocortisone (cortisol). Factors that cause or result in pharmacokinetic variability should be understood and avoided where possible. METHODS: A literature search was performed with the aim of covering the field of gastrointestinal drug absorption of hydrocortisone in AD. RESULTS/CONCLUSION: Novel oral drug delivery principles for facilitation of once-daily dosing and providing a safe and physiologically based plasma concentration-time profile of hydrocortisone in replacement therapy are discussed. Development of new drug formulations is ongoing and will certainly lead to an improved replacement therapy of AD with hydrocortisone. Of special interest is a therapy based on once-daily treatment and less fluctuating plasma concentrations of hydrocortisone (cortisol).     

Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers

This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC₅₀) was about 200 times lower for fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered.     

Skin permeation of liposomal incorporated hydrocortisone

With the liposomal incorporated hydrocortisone a very much improved concentration-time profile was obtained in the different layers of human skin after topical application when compared with conventional hydrocortisone in the ointment. The increased hydrocortisone penetration into human skin correspond with the degree of blanching results by vasoconstriction test. Under in vivo conditions the influence of liposomal hydrocortisone on percutaneous resorption was investigated. In guinea pigs a decreased serum concentration and urinary excretion of hydrocortisone could be demonstrated. Thus, hydrocortisone-loaded liposomes, when applied topically, act as a selective drug delivery system, it can be provide increased therapeutic efficacy and, simultaneously, decreased unwanted systemic effects. The significance of liposomal incorporated attenuative and higher potent glucocorticoids in external therapy is discussed.     

Inter-relationships between the absorptions of hydrocortisone,sodium, water and actively transported organic solutes in the human jejunum

Summary The effect of intraluminal hydrocortisone (100 mg/l) on sodium and water transport in the small intestine was investigated by jejunal perfusion (flow rate 15 ml/min) of healthy subjects with normal saline and saline containing 56 mmol/l galactose or alanine. Minimal absorption of sodium and water occurred with normal saline and did not change significantly in the presence of hydrocortisone. Galactose and alanine enhanced sodium and water absorption and further significant increases occurred in the presence of hydrocortisone. Glucocorticoidinduced increases in absorption were detected within 20–30 min, while plasma cortisol concentrations were in the normal range. 43% of the perfused dose of hydrocortisone was absorbed with normal saline (p<0.01). There was a significant positive correlation (p<0.0025) between hydrocortisone and water absorption. Thus, in the presence of actively absorbed organic solutes, hydrocortisone rapidly increased sodium absorption and the concurrent increase in water absorption appears to have facilitated passive absorption of hydrocortisone.     

Biomolecule-sensitive hydrogels.

Stimuli-sensitive hydrogels have attracted considerable attention as intelligent materials in the biochemical and biomedical fields, since they can sense environmental changes and induce structural changes by themselves. In particular, biomolecule-sensitive hydrogels that undergo swelling changes in response to specific biomolecules have become increasingly important because of their potential applications in the development of biomaterials and drug delivery systems. This article provides an overview of the important and historical research regarding the synthesis and applications of glucose-sensitive hydrogels which exhibit swelling changes in response to glucose concentration. Enzymatically degradable hydrogels and antigen-sensitive hydrogels are also described in detail as protein-sensitive hydrogels that can respond to larger biomolecules. The synthetic strategies of other biomolecule-sensitive hydrogels are summarized on the basis of molecular imprinting and specific interaction. The biomolecule-sensitive hydrogels reviewed in this paper are expected to contribute significantly to the exploration and development of newer generations of intelligent biomaterials and self-regulated drug delivery systems.     

Effect of thermal cycling on the properties of thermoresponsive poly(N-isopropylacrylamide) hydrogels

Crosslinked poly(N-isopropylacrylamide) hydrogels have been widely studied for a variety of thermoresponsive applications, including chromatography, affinity precipitation, controlled biocatalysis, viable cell immobilisation, biomimetic actuators and, in particular, modulated drug delivery. The exploitation of crosslinked poly(N-isopropylacrylamide) hydrogels in all these applications relies on the well-known temperature-sensitive swelling properties of these hydrogels. The purpose of the current study was to determine the effects of repeated thermal cycling on the thermoresponsive swelling behaviour of crosslinked poly(N-isopropylacrylamide) hydrogels. The results show that repeated thermal cycling leads to the formation of cracks on the surface of the hydrogels. Repeated thermal cycling also results in a decreased degree of swelling in the crosslinked poly(N-isopropylacrylamide) hydrogels at temperatures below the volume phase transition temperature (VPTT).     

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.     

The effect of hydrocortisone on the activity of the alkaline proteinase systems in the rat thymus

The effect of single and chronic administration of hydrocortisone on the thymus proteinase activity in the alkaline pH range was studied on rats. The presence in the thymus of the glucocorticoid-sensitive alkaline proteinase system induced by hydrocortisone was shown. A decrease of the activity of the system in the adrenalectomized animals was found. The possible relationship between the thymolytic effects of hydrocortisone and the increased activity of the alkaline proteinase systems of the thymus is concluded.     

氢化可的松及其注射液有关物质检查

目的:对氢化可的松原料及其注射液中含有的有关物质进行测定。方法:采用高效液相色谱法进行分析,同时采用二极管阵列检测器进行杂质波谱扫描,液质联用法辅助确定主要杂质的结构。结果:氢化可的松和杂质峰分离良好,试验样品主要杂质确证为6,17,21β-三羟基孕甾-4-烯-3,20-二酮、表氢化可的松、17,21-二羟基孕甾-4-烯-3,20-二酮、可的松及泼尼松龙。结论:本法准确、灵敏,杂质检出性强,适用于氢化可的松及其注射液有关物质的测定。     

Effect of dose size on the pharmacokinetics of intravenous hydrocortisone during endogenous hydrocortisone suppression

The pharmacokinetics of hydrocortisone were examined following single intravenous doses of 5, 10, 20, and 40 mg hydrocortisone, as the sodium succinate salt, to healthy male volunteers. Endogenous hydrocortisone was suppressed by administration of 2 mg dexamethasone the night before hydrocortisone injection. Plasma samples obtained serially during 8 h after hydrocortisone injection were assayed by reversephase HPLC using a fixed wavelength (254 nm) ultraviolet detector. Initial concentrations of hydrocortisone in plasma were proportional to dose size. The subsequent decline in hydrocortisone concentrations was biphasic, and individual data sets were adequately described in terms of the pharmacokinetic two-compartment open model. Values of pharmacokinetic parameters were similar from the 5, 10, and 20 mg doses. Following the 40 mg dose, the overall elimination rate constant decreased, while the distribution volume, V_dss,and plasma clearance increased, in comparison with the values obtained from lower doses. Changes in the pharmacokinetics of hydrocortisone at high doses may be related to drug concentrationdependent changes in the binding of hydrocortisone to plasma proteins. Previously reported dosedependent changes in some pharmacokinetic parameters following oral hydrocortisone are attributed to absorption rather than distribution or elimination effects.     

Transdermal Iontophoretic Delivery of Hydrocortisone from Cyclodextrin Solutions

Enhanced skin penetration of hydrocortisone can be desirable for treatment of several diseases. Transdermal iontophoretic delivery of hydrocortisone solubilized in an aqueous solution of hydroxypropyl-β-cyclodextrin (HP-β-CyD) was investigated and compared with chemical enhancement of co-solvent formulations. The passive permeation of hydrocortisone through human cadaver skin was higher when delivered from propylene glycol than when delivered after solubilization in an aqueous solution of HP-β-CyD. However, the iontophoretic delivery of the 1% hydrocortisone-9% HP-β-CyD solution was higher than the amount delivered passively by the 1% hydrocortisone-propylene glycol formulation, even if oleic acid was used as a chemical enhancer. Iontophoretic delivery of 1% hydrocortisone with 3% or 15% HP-β-CyD was lower than that of the 9% HP-β-CyD solution. These data suggest that free hydrocortisone rather than complexes is predominantly delivered iontophoretically through the skin and the HP-β-CyD complex serves as a carrier to replenish depletion of hydrocortisone. HP-β-CyD prevents hydrocortisone from forming a skin reservoir. Iontophoresis provides better enhancement of transdermal delivery of hydrocortisone than the chemical approach when just sufficient HP-β-CyD is added to solubilize the hydrocortisone.     

Ascorbic acid prevents cimetidine-induced decrease of serum hydrocortisone concentrations

A blind, parallel, prospective, clinical study was conducted to investigate the effect of ascorbic acid on human serum hydrocortisone concentrations which were decreased by the administration of cimetidine. The study population included 16 male adults scheduled for major abdominal vascular surgery. The study was conducted in surgical patients under anaesthesia, in which steroidogenesis was inhibited by cimetidine. The results showed a reduction in serum hydrocortisone concentrations in patients receiving a placebo. In patients receiving ascorbic acid, there was a significant increase in serum hydrocortisone concentration. This reflects the normal serum hydrocortisone profile for this operation and anaesthetic technique. Cimetidine can bind to cytochrome P-450 covering the active haem group, the cytochrome proves to be of vital importance for hydroxylation reactions, involved in human steroidogenesis. Serum hydrocortisone concentrations will decrease when cytochrome P-450 becomes blocked. Intravenous administration of ascorbic acid was supposed to cause relief for this decrease. The reasons are undetermined yet. This investigation proved that ascorbic acid can prevent cimetidine-induced decrease of human serum hydrocortisone concentrations.     

Assessment of topical corticosteroid activity using the vasoconstriction assay in healthy volunteers

OBJECTIVE AND DESIGN: The aim of the study was to evaluate the vasoconstrictive activity of four new galenic preparations of hydrocortisone and to compare it with concentration-equivalent reference preparations. The study comprised two study phases: the pilot study phase and the main study phase. During open, nonrandomized pilot study, the optimal administration period was tested. The main study was performed in a randomized, double-blind intraindividual comparative design. SUBJECTS: Twenty male and female volunteers with healthy skin who responded to topically applied clobetasol-17-propionate before entering the trial participated in this study. TREATMENT: All subjects received the same treatments. The test preparations new galenic formulation (NGF) hydrocortisone 0.25% cream, NGF hydrocortisone acetate 0.25% cream, NGF hydrocortisone 0.5% cream, and NGF hydrocortisone 1.0% cream were compared with the respective reference preparations Soventol hydrocortisone (hydrocortisone acetate 0.25%), Hydroderm HC 0.5% cream (hydrocortisone 0.5%), Hydrogalen cream (hydrocortisone 1.0%) and placebo (vehicle of test preparations). METHOD: The topical preparations were applied occlusively for 2 h (pilot study) or 24 h (main study) on outlined areas (5 x 5 cm with a distance of 3 cm) of both forearms (4 areas for each). Assessment of vasoconstriction was performed before treatment, and 0.5, 4, 6 and 24 h after treatment (observation period) using a subjective rating scale (OLSEN vasoconstriction score) and measuring the colorimetric parameter a* (redness) by use of the Chroma-Meter (Minolta company, Ahrensburg, Germany). RESULTS: A significant vasoconstriction (positive blanching effect) was measured by use of chromametry for test preparations hydrocortisone 0.25% cream, hydrocortisone 0.5% cream, hydrocortisone 1.0% cream and for the reference preparation Hydrogalen cream compared to placebo 30 min after the end of treatment. In contrast, the reference preparations Soventol hydrocortisone and Hydroderm HC 0.5% did not differ significantly from placebo 30 min after treatment. No statistically significant effect of all formulations was observed 4-24 h after treatment in comparison with placebo. CONCLUSIONS: The vasoconstrictive efficacy of test preparations was mostly stronger than the concentration-equivalent reference preparations. This effect was achieved by use of new galenics of test preparations resulting in enhanced skin penetration and improved efficiency. No unwanted side effects were observed during the course of the study despite increased efficacy of the topically applied test preparations.     

Inhibitory effect of hydrocortisone on cerebral salt wasting after subarachnoid hemorrhage in rats

Cerebral salt wasting (CSW) frequently occurs concomitantly with subarachnoid hemorrhage (SAH). CSW induces excessive natriuresis and osmotic diuresis, reduces total blood volume, aggravates cerebral vasospasm and causes cerebral ischemia after SAH. This study examined the inhibitory effect of hydrocortisone on CSW in rat SAH models. Hydrocortisone had an inhibitory effect on CSW because hydrocortisone functioned in a dose-dependent manner to inhibit the increase in sodium excretion and sodium/potassium ratio after SAH onset. We conclude that hydrocortisone is a useful drug for the treatment of CSW after SAH.