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Objective: Glucocorticoid-remediable aldosteronism (GRA) is caused by the presence of a chimeric gene originating from an unequal cross-over between the CYP11B1 and CYP11B2 genes. Aldosterone suppression by dexamethasone and high 18-hydroxycortisol (18-OHF) levels have been used to differentiate GRA from the other forms of primary aldosteronism., Methods: A dexamethasone suppression test including serum 18-OHF determination and the measurement of urinary excretion of aldosterone, its metabolites and 18-OHF were performed in 3 children of a family with primary aldosteronism. Polymerase chain reactions were performed to identify the chimeric gene., Results: The chimeric gene was identified in 2 children, their mother and grandmother. The affected children had an aldosterone-to-plasma renin activity ratio >30, elevated serum 18-OHF concentration and increased urinary excretion of aldosterone, its metabolites, and 18-OHF. Post-dexamethasone concentrations of serum aldosterone and 18-OHF concentrations were suppressed., Conclusion: Although very rare, the possible diagnosis of GRA should be considered in all children or young adults with low-renin hypertension. Since genetic testing is more specific than biochemical testing, a definitive diagnosis can only be obtained by identification of the CYP11B1/CYP11B2 chimeric gene., (Copyright © 2011 S. Karger AG, Basel.)

The evaluation of the benefit/risk ratio (BRR) for topical glucocorticoids (TGC) allows the comparison of active ingredients and thereby includes aspects of dosage (blanching response, BR) as well as adverse effects (skin atrophy). In the present study, the BRR of hydrocortisone aceponate, prednicarbate and betamethasone valerate was investigated according to an adapted procedure for investigating the BR. The main difference is the longer application period of the investigational substance without occlusion. Thus, the pharmacokinetic characteristics of all of the systems are considered more intensely and the penetration conditions are designed in a realistic way, namely oriented towards the preparation in order to improve the significance and relevance of the BRR for practical use. The results demonstrate that the investigated substances also show differences in the extent of the BR, but on the other hand they show that the improved penetration characteristics of the double-esterified compounds are clearly less effective. In comparison to the BRR, this results to a large extent in a balanced picture without relevant advantages for single preparations. Nevertheless, the already mentioned positive characteristics of the investigated TGC and the positive practical clinical experiences have been approved. Further investigations have to show whether the method presented here for investigating the BR offers advantages in the comparative assessment of TGC.

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., (Copyright (c) 2007 S. Karger AG, Basel.)

We measured the superoxide dismutase (SOD) activity in human skin from tissue homogenates after topical application of hydrocortisone-21-acetate and clobetasol proprionate, dissolved in propylene glycol. SOD was measured spectrophotometrically. SOD activity was higher in the treated skin than in the control untreated skin. We separated epidermis from the dermis by curettage and measured the level of SOD in each homogenized layer; SOD activity was higher in the epidermis compared to the dermis in untreated skin. After corticoid application, SOD activity was higher in the dermis compared to the epidermis to a degree dependent on corticoid potency. These experiments demonstrate that the epidermis may have a role in the barrier function of the skin by its antioxidant capacity and that the dermis is the major location of the metabolic activity in the skin. On the other hand, our results suggest that these corticosteroids may stimulate SOD production and may release antioxidants. This could be another anti-inflammatory property of corticosteroids.

Rabbit ears were single-pass perfused with a buffer solution containing either 6% hetastarch or 5% bovine serum albumin. Hydrocortisone 21-butyrate (5 mM), diflunisal (17 mM) or permethrin (33 mM) was added to isopropyl myristate with 5% polyethylene, and applied to about 40% of the epithelial surface area of the ear. Hydrocortisone 21-butyrate or permethrin were not found in the effluent with hetastarch or albumin. Following cutaneous ester hydrolysis, the appearance rate of hydrocortisone was about 4 pmol/min per cm2 in the hetastarch- or the albumin-containing buffer solution. No hydrolysis of permethrin was detected; the appearance rate of 3-phenoxybenzyl alcohol with 3-phenoxybenzoic acid corresponded to the absorption rate of the substrate impurities. During ex vivo perfusion of intact skin, serum albumin in the perfusion fluid may not enhance the appearance rate of xenobiotics in the effluent following dermal application when the distribution coefficient n-octanol/water is > 2,000 or when the xenobiotic is ionized at physiological pH. In general, for all substances investigated with our perfusion model thus far, the appearance rates decreased with rising distribution coefficient (n-octanol/buffer pH 7.4). High lipophilicity hinders the release from isopropyl myristate and the penetration through the skin.

When 0.25 mumol of hydrocortisone succinate sodium (HC) was administered to 15-day-old hen's fertile eggs, almost all lenses of the embryos became cataractous with stages IV-V (> 90%) 48 h after the treatment. However, a triple application of propylene glycol (1.5 mmol/egg) at 3, 10 and 20 h after HC treatment effectively prevented the HC-induced cataract formation (I: 84%, II: 12%, III: 4%, IV-V: 0%) and repressed the decline of glutathione and the elevation of lipid peroxide in the lens caused by HC. Propylene glycol is metabolized to lactate and pyruvate producing NADH and is known to possess protective activities against X-ray irradiation. These properties have modified the HC-induced effects and decreased the production of oxidative stress in ovo, protecting the lens from losing its transparency after HC administration. Furthermore, a marked elevation of glucose in cataractous lenses noted after HC administration was not directly involved in opacification of the lenses.

Allergic contact dermatitis to corticosteroids is not uncommon and is increasingly reported. Contact allergy to nasal corticosteroids is rare and may present with atypical symptoms, which may be confused with infectious complications. We report on a patient in whom the misinterpretation of her allergic nasal symptoms to the corticosteroid tixocortol pivalate resulted in hospitalization and considerable medical expenses.

Recently several attempts have been made to develop glucocorticoids which show less pronounced side effects. We intended, therefore, to use experimental systems to examine the influence of newly developed nonhalogenated glucocorticoids and conventional fluorinated congeners, demonstrating similar anti-inflammatory activity in vivo, on biosynthetic capacities of human fibroblasts. Fibroblasts were kept in monolayer cultures and exposed to different concentrations of the active compounds for 6 days to analyze the influence on proliferation. Chemotaxis of fibroblasts was studied in blind well Boyden chambers. Fibroblast-conditioned medium was used as chemoattractant. All glucocorticoids tested influenced fibroblast proliferation at high (10(-5) M) and low (10(-9) M) concentration. Yet the effect was clearly more marked with fluorinated compounds. Basically, the same applied for chemotaxis. At the low concentration, however, nonfluorinated glucocorticoids exerted almost no influence. These results suggest that modifications of steroidal structure can specifically influence their effects on biosynthetic capacities of fibroblasts.

Aim of our study was to investigate the acute effects of intravenous infusion of hydrocortisone on circulating growth hormone (GH) levels in acromegaly. We studied 5 adult patients with active acromegaly, 3 males and 2 females; age 52 +/- 3.6 years, body mass index 27 +/- 1 kg/m2. The patients underwent in randomized order from 0 to 120 min: (1) intravenous infusion of saline, 250 ml; (2) bolus intravenous injection of hydrocortisone succinate, 100 mg at time 0 followed by intravenous infusion of hydrocortisone succinate, 250 mg in 250 ml of saline for 120 min. Blood samples for GH, cortisol and glucose assay were taken at -15, 0 (time of beginning of saline or hydrocortisone infusion), 15, 30, 45, 60, 90, 120, 150 and 180 min. In all the acromegalic patients, during hydrocortisone succinate infusion, GH values clearly fell with respect to saline (nadir range 18.4-50.5% with respect to baseline levels) with nadir between 60 and 180 min after the beginning of the infusion. Our data show that acute and sustained hypercortisolism, decreases circulating GH levels in acromegaly. It seems likely that also in acromegalic patients as well as in normal subjects short-term increases in serum cortisol levels may be able to cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid-mediated GH inhibition.

The present study examined whether hypolipidemic therapy with a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, influences corticosteroid metabolism in patients with heterozygous familial hypercholesterolemia (FH). Urinary excretion of tetrahydrocortisone, tetrahydrocortisol, 6 beta-hydroxycortisol and free cortisol were determined in 22 patients with heterozygous FH before and after pravastatin administration (10 mg/day for 2 months). Pravastatin induced a statistically significant decrease in serum total cholesterol in patients with heterozygous FH from 6.9 +/- 0.1 to 5.9 +/- 0.1 mmol/l (p less than 0.05). No significant changes were seen in the urinary tetrahydrocortisone, tetrahydrocortisol and free cortisol levels before and after pravastatin therapy. Urinary excretion of 6 beta-hydroxycortisol was significantly (p less than 0.05) increased after pravastatin administration. These results suggest that the hypolipidemic effect of pravastatin in patients with heterozygous FH does not influence the corticosteroid metabolism. The increase in urinary 6 beta-hydroxycortisol may be caused by pravastatin-induced hepatic microsomal 6 beta-hydroxylase induction.

The systemic effects of topically applied 0.1% hydrocortisone 17-butyrate during treatment with and without occlusion were measured in terms of the functions of the pituitary-adrenal axis. Corticosteroid levels in the blood were determined by the modified method of MURPHY, a competitive protein-binding radioassay. Circulating eosinophils were counted and the urinary 17-OHCS and 17-KS excretion were also determined. Percutaneous absorption following the topical application of 14C hydrocortisone 17-butyrate 1 (HC 17-B, Locoid) was measured by means of autoradiography. The application of the corticosteroid to the normal skin without occlusion did not induce systemic effects, whilst the application of the drug under occlusive dressing showed that systemic effects may possibly be induced. The number of circulating eosinophils, corticosteroid levels in the blood and urinary 17-OHCS excretion all decreased. However, these values returned to normal about 2 days after the withdrawal of the application, so we consider the systemic effect induced by the topical corticosteroid to be of a temporary nature. The percutaneous absorption of the corticosteroid was proved by an autoradiographic technique using 14C-labelled HC 17-B. At various intervals after the application, radioactive substances were observed as silver grains in the horny layer of the epidermis and skin appendages, and the density of the silver grains gradually increased with the course of time. It may be surmised that locally applied HC 17-B will be retained in the horny layer of the epidermis at a very early stage after the application and then absorbed in the blood via the epidermis and skin appendages. The reservoir of the corticosteroid in the skin was demonstrated 24 h after the withdrawal of the application.

In a series of hydrocortisone 17-esters, hydrocortisone 17-butyrate (HC-17B) has almost optimal lipophilicity resulting in a topical effect comparable to that of the fluorinated corticosteroids as measured in the McKenzie test on the human skin. In rats its systemic effects are weak, being in the order of those of hydrocortisone. In man systemic effects have been demonstrated, but no exact comparative. In man systemic effects have been demonstrated, but no exact comparative data are available. Important FACTORS controlling the intensity of systemic effects are: rate of liberation into plasma from the depot in the horny LAYER, RATE of metabolic degradation, and rate of plasma clearance. In rats the main factor seems to be rapid clearance from plasma (t 1/2 = 0.5h) by selective concentration in the liver and, to a lesser extent, in the kidneys. Rapid hydrolysis by esterases in plasma and liver plays an additional role. In man hydrolysis by esterases appears to be rather slow; the rate of clearance from plasma is still unknown, whereas the absorption from the intact skin into the blood seems to be very slow (t 1/2 = 25 h).

Maternal treatment with p-chlorophenylalanine strongly inhibits brain tryptophan hydroxylase (TPH) activity in the embryo, whereas administration of tryptophan significantly elevates the activity of this enzyme. Maternal stress, glucocorticoid injections, or a corn diet (low in tryptophan) do not change embryonic TPH activity, however. Since TPH is thought to be rate-limiting for serotonin (5-HT) synthesis in the developing animal as well as in the adult altered TPH activity as a result of maternal influences could change 5-HT synthesis in the embryo. If 5-HT is a developmental signal in the early differentiation of specific neurons during embryogenesis, as previously suggested, such maternal influences could affect this process, resulting in altered neuronal genesis in those brain regions receiving a serotonergic innervation.

The transmission of labelled IgG by the proximal small intestine was assessed in 16- and 18-day-old rats. Closure had commenced by 18 days and in some animals was well advanced by this age. The injection of large doses of cortisone acetate, hydrocortisone sodium succinate, deoxycorticosterone acetate and corticosterone induced precocious closure of the small intestine by 16 days; and all but the latter steroid also induced precocious cell replacement in the ileum. Maternal deprivation for about 18 h daily led to closure of the proximal small intestine but did not induce precocious replacement in the ileum. The injection of metopirone, aminoglutethimide and ACTH resulted in partial closure of the proximal small intestine but did not induce precocious cell replacement in the ileum. Maternal deprivation for about 8 h daily produced a similar result.

The clinical efficacy and the rebound phenomenon were studied in a left-right double-blind trial comparing triamcinolone acetonide (TA) and hydrocortisone 17-butyrate (HC 17-B, Locoid). The trial comprised 19 patients with rosacea-like dermatitis of whom 7 did not receive treatment and 12 were pretreated with betamethasone valerate (BMV). Tetracyclince was given all the time as additional treatment. Clinically there was no significant difference between TA and HC 17-B. No rebound phenomenon was observed. If corticosteroids are to be used at all in rosacea or resoacea-like dermatitis, preference is given to HC 17-B.

Five corticosteroid ointments and placebo were compared in 17 volunteers with regard to their influence on normal skin under occlusive conditions. Each volunteer had six simultaneous applications on the forearms and six on the back. The trial was double-blind and lasted 4 weeks. The ointments were placed in randomized order. The treatments were 0.1 and 0.03% domoprednate, 0.1% hydrocortisone butyrate, 0.1% betamethasone valerate, 0.05% clobetasole propionate and placebo. Skin thickness was measured on days 0, 7, 14, 21 and 28, transepidermal water loss on days 0, 14 and 28, while blood flow and telangiectasias were evaluated only on day 28 at termination of the trial. The skin thickness became significantly reduced on all corticosteroids, but not on placebo; 0.03% domoprednate, however, tended to have an intermediate position between placebo and the other ointments. The transepidermal water loss did not change. Rating of telangiectasia under stereomicroscope showed a significantly lower score after 0.03% domoprednate and placebo as compared to the other ointments. Assessment of telangiectasia by laser-Doppler flowmetry showed a similar tendency. It is concluded that 0.1% domoprednate is comparable to other topical corticosteroids with respect to atrophogeneity and formation of telangiectasia, but the 0.03% concentration seems to result in fewer side effects.

The ratio of 6beta-hydroxycortisol to 17-hydroxycorticosteroids in the urine of 73 patients with liver disease, and 53 controls has been measured. The mean ratio was significantly greater in the liver disease group (p less than 0.001), this elevation being most marked among patients with liver metastases and patients with acute hepatitis. We feel that the use of the ratio as a test of early liver cell dysfunction requires further evaluation, in particular in the early recognition of metastatic liver disease.

Description of adverse effects of strong corticosteroids in rosacea. Perioral dermatitis also seems to be caused by treatment with strong corticosteroids. The rebound effect after weaning the patient from strong corticosteroids might be obviated by hydrocortisone 17-butyrate or hydrocortisone 21-acetate. Continued oral tetracycline treatment is recommended.

It has previously been shown that jejunal sucrase activity becomes increasingly responsive to glucocorticoids between the postnatal ages of 4 and 15 days. This study examines the possibility that cyclic AMP is the mediator of the increasing responsiveness. When dibutyryl cyclic AMP was administered concomitantly with glucocorticoid to rat pups aged 6 days, there was no enhancement of sucrase activity in pups sacrificed either 30 or 54 h later. To check for short-lived effects of cyclic AMP, pups aged 5 days were pretreated with glucocorticoid for 2 days to elicit sucrase activity, then received dibutyryl cyclic AMP by injection and were sacrificed 1, 3 and 6 h later. Once again there was no effect of cyclic AMP on sucrase activity. The final approach was to use cholera enterotoxin to stimulate epithelial adenylyl cyclase in jejunal segments in vivo. Under these conditions the stimulation of fluid secretion served as positive evidence that intracellular concentrations of cyclic AMP were elevated. However, once again there was no stimulation of sucrase activity. It is concluded that cyclic AMP does not mediate the increasing responsiveness of the developing intestine to glucocorticoids.

The urinary excretion of 6 beta-hydroxycortisol (6 beta-OHF), free cortisol, and estriol was studied at 4-hourly intervals in 9 subjects between the 36th and 38th week of pregnancy. The ratio of 6 beta-OHF to creatinine showed a significant diurnal rhythm with a 40% fall from a peak at 06.00-10.00 h to a trough at 22.00-02.00 h. There was a significant positive correlation between the excretion of 6 beta-OHF and free cortisol. Estrogen excretion showed no diurnal variation. No increase was observed in the 6 beta-OHF:creatinine ratio in early morning urine samples from 5 subjects followed daily prior to the onset of spontaneous labour at term. Normal nonpregnant females were also found to excrete significant quantities of 6 beta-OHF. These findings suggest that the clinical significance of 6 beta-OHF levels measured in a single void sample of urine has to be reassessed in the face of such a marked diurnal variation.

A randomized, double-blind, left-right comparative study was carried out to compare the value of hydrocortisone 17-butyrate with that of betamethasone 17-valerate in the treatment of eczematous skin disorders. In a series of 23 patients with such disorders, no differences between the two preparations was demonstrated with regard to effectiveness.

We have previously shown a marked diurnal variation in the excretion of cortisol and 6 beta-hydroxycortisol at 36-38 weeks pregnancy with no variation in estrogen excretion. Since others have shown a reciprocal relationship between plasma levels of estriol and cortisol at 30-35 weeks of pregnancy, we decided to determine whether a similar relationship was present in urinary concentrations of cortisol, 6 beta-hydroxycortisol and estriol at this gestational age. A significant variation in excretion of both cortisol and 6 beta-hydroxycortisol was found. The variation in urinary levels of estriol was less than that of the corticosteroids but followed the same pattern.

60 patients, aged 15-51 years, with chronic allergic or bacterial maxillary sinusitis, were entered in a controlled, double-blind study comparing the efficacy of endonasal irrigations of tixocortol pivalate (Pivalone)-neomycin and neomycin. The treatment lasted 11 days and was administered once daily. A ventilometric measurement of sinus pressure was performed every two endonasal irrigations to assess treatment efficacy. The percentage of nasal deobstruction was significantly higher with tixocortol pivalate-neomycin than with neomycin alone by the fifth examination (9th day) regardless of the etiology of the sinusitis (allergic or bacterial). After 11 days of treatment, significantly better results were obtained in cases of bacterial sinusitis (94% deobstruction with tixocortol pivalate-neomycin versus 74% with neomycin) than in cases of allergic sinusitis (69% deobstruction with tixocortol pivalate-neomycin versus 36% with neomycin).

Results of in vitro studies on the penetration of a corticosteroid hydrocortisone 17-butyrate (HCN) in relation to the vehicle are reported. When HCB is dissolved completely in the vehicle, penetration is enhanced, and only under this condition an increase in HCB concentration (in the range 0.05-0.2%) leads to an increase in the penetration. Evaluation of the efficiency of various vehicles (an oil/water cream, Plastibase or gels) in which HCB was dissolved in propylene glycol or ethanol, showed that Plastibase with propylene glycol was the most effective for both 0.1 and 0.2% HCB. The results of experiments in which HCB was applied in ethanolic solutions suggests that at least initially HCB and ethanol together penetrate through the epidermis.

Thirty-nine patients with mainly psoriasis vulgaris and atopic dermatitis were treated for 4 weeks with 0.1% domoprednate and hydrocortisone butyrate ointment according to a right-left, randomized design. Various assessments of efficacy only revealed marginal, but statistically insignificant differences. Patients' preferences for one of the two treatment favored domoprednate in 20 cases and hydrocortisone butyrate in 12 cases; 6 cases were ties (p greater than 0.2). The efficacy of domoprednate, a new, nonhalogenated topical steroid, is evidently at least of the same order as that of the hydrocortisone butyrate, and the tolerance of the two ointments is equally good.

Exogenous corticosteroids (dexamethasone, cortisol) inhibit the adrenal secretion of corticosterone in the rabbit and decrease the concentration of corticosterone in aqueous humour, increase glycaemia and cause a rise in glucose concentration in the aqueous. Except for a slight rise 16 h after the corticosteroid administration no effect on plasma or aqueous content of total protein was observed. This is in striking contrast with the increase of proteins in aqueous humour after ACTH injection. Thus it seems likely that corticosteroids do not mediate the effect of ACTH on the disruption of the blood-aqueous barrier.

The vasoconstriction caused by four topical corticosteroid preparations was compared according to subjective ranking and according to measurement by a tristimulus colourimeter (Momcolor). The measured results agreed well with visual evaluation. The colourimeter was proved to be measuring the degree of vasoconstriction. Among the preparations examined, the vasoconstriction effected by hydrocortisone 17-butyrate cream (Locoid) and by betamethasone dipropionate ointment (Diprosone) was stronger than that exerted by triamcinolone acetonide (Ftorocort) and fluocinolone acetonide (Flucinar). With the aid of colourimetric measurement of the vasoconstriction, differences could be demonstrated between clinically effective topical corticosteroid preparations. An open question remains, what the predictive significance is of the objectively measured vasoconstriction test, for clinical practice.

Nine cases of perioral dermatitis and 16 cases of rosacea-like dermatitis have been treated for the last 3 years at our clinic. These cases were all females whose ages ranged from 18 to 61 years with a mean of 45 years. All had been under treatment with fluorinated steroids for a period of from 3 months to 10 years, about 3 years on the average. Tetracyclines were beneficial as remedies for these conditions, bringing about healing or remission in approximately 3 months. About 1 year was required for the recovery from atrophy of the skin and telangiectasia. Hydrocortisone 17-butyrate was more useful as a topical medication than hydrocortisone acetate but gave rise to withdrawal rebound eruptions in some cases.

In a double-blind comparative study, by 29 dermatological departments, the activity of hydrocortisone 17-butyrate (HC 17-B, Locoid), triamcinolone acetonide (TA) 0.1% and hydrocortisone 21-acetate (HA) 1%, were compared in patients suffering from acute eczematous dermatitis, atopic dematitis and psoriasis. After a 7-day period of observation, the results were evaluated by means of a chi2 test, and an Armitage tests. The following results were obtained: in acute eczematous dermatitis HC 17-B was found to be superior to the placebo and equal to TA; in atopic dermatitis HC 17-B was found to be superior to the placebo and HA, equal to TA; in psoriasis vulgaris HC 17-B was found to be superior to the placebo, HA and TA.

By modifying the blood supply in the upper part of the dermis, the colour of the skin is changed by any material in contact with it. This is a great difficulty when we want to measure the colour intensity in erythema or blanching. To avoid this problem, we designed and built a device which measures the skin reflectance value without any contact with the skin. The use of this device on man to study the skin blanching after application of dermocorticoids allows us to determine the more potent drug among a series (clobetasol propionate) and, for a given drug (betamethasone), the more efficient preparation (oil-in-water emulsion). The study of the effect of increasing irradiation doses of ultraviolet light show that the sensitivity of the device is equivalent to that of the clinical assessment and that the relationship between the irradiation dose and the skin reflectance is sigmoidal.

The effects of corticosteroids and pancreatic hormones on two mitochondrial enzymes of ureagenesis, carbamyl phosphate synthetase-I (CPS-I) and ornithine transcarbamylase (OTC), were investigated and compared in fetal rat liver. Supplementing hydrocortisone acetate (50 micrograms) to 18.5-day-old fetuses significantly increased CPS-I activity (by 36%) and decreased OTC activity (by 23%). An actinomycin D supply (2 micrograms) to 18.5-day-old fetuses prematurely increased OTC activity and decreased fetal insulin level (by 42%). This treatment had no effect on CPS-I activity. Glucagon supply (25 micrograms) during the late fetal period increased both activities within 2 h, while dibutyryl-cAMP enhanced OTC activity 17 h later. These results suggested that the fetal development of CPS-I activity was under the control of corticosteroids and glucagon. In contrast, corticosteroid hormones produced an inhibitory effect on OTC activity. This might be explained by the permissive effect of corticosteroids on insulin action, since insulin might act as a repressor in utero of enzyme development. Thus, the paradoxical effect of actinomycin D on OTC activity was probably due to the decrease in fetal insulinemia.

A method used to assess the atrophogenic effect of steroids by electron microscopy after ruthenium red staining is described. In two patients more atrophy was observed after fluocinolone treatment than after hydrocortisone 17-butyrate treatment.

This histological changes induced by 1 month's applications of various corticorteroids to normal forearm skin were studied. Marked epidermal atrophy was present at 1 month with the more potent steroids, but the dermal changes were minimal or absent. The methods outlined in this study could serve as a useful model for assessing the unwanted atrophogenic action of potent corticosteroid preparations.

This paper review our modification of the vasoconstrictor (blanching) assay for topical corticosteroids using human volunteers, which we have improved and extended so that it may be used as a useful screening test for clinical efficacy besides being employed to determine the bioavailability of steroids from topical bases. Work is reported on the blanching activities of (1) 14 novel steroids in ethanol, (2)hydrocortisone 17-butyrate in eight topical vehicles, (3) betamethasone 17-benzoate in foam, ointment, cream and gel bases, and (4) 61 commercial formulations used in Great Britain. Pharmacokinetic/pharmacodynamic relationships are discussed as aids to optimizing topical steroid treatment.

Abrption of antibiotics from combined preparations containing oxytetracycline, chlortetracycline, doxycycline or gentamicin and hydrocortisone 17-butyrate into the skin of rats was examined. The penetration of antibiotics from the ointment into the skin was inhibited by 0.2% hydrocortisone 17-butyrate to a significant degree. It is suggested that this effect of hydrocortisone 17-butyrate is the consequence of its vasoconstrictor action.