Hydrocortisone 17-butyrate 21-propionate Research Articles

Allergic contact dermatitis induced by topical hydrocortisone butyrate propionate mimicking acute generalized exanthematous pustulosis

Auteur(s) : Natsuko Tohgi, Hiromitsu Eto, Hideki Maejima, Norimitsu Saito, Mika Nakamura, Kensei Katsuoka Department of Dermatology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 228-8555, Japan Herein, we report a rare case of allergic contact dermatitis induced by topical hydrocortisone 17-butyrate 21-propionate (HBP), which resembled acute generalized exanthematous pustulosis (AGEP). A 31-year-old Japanese woman with atopic dermatitis was treated by [...]

合成副腎皮質ステロイドＭｅｔｈｙｌｐｒｅｄｎｉｓｏｌｏｎｅ ａｃｅｐｏｎａｔｅの抗炎症作用

In the case of dermal application of the drugs to croton oil-induced ear edema in rats and picryl chloride-induced delayed type hypersensitivity in mice, the anti-inflammatory effect of methylprednisolone aceponate (MPA) was slightly weaker than those of clobetasol 17-propionate and diflucortolone 21-valerate, but stronger than those of hydrocortisone 17-butyrate and hydrocortisone 17-butyrate 21-propionate. Betamethasone 17-valerate applied dermally was less and more effective than MPA to ear edema in rats and delayed type hypersensitivity in mice, respectively. The anti-inflammatory effect of MPA was weaker in subcutaneous administration than in topical application to the two inflammatory models. It was suggested that MPA has strong anti-inflammatory effects and weak systemic effects by topical application. Methylprednisolone 17-propionate (MP-17P) and methylprednisolone (MP), unesterified in only the C-21 position and in both the C-17 and 21 positions of MPA, respectively, showed weaker anti-inflammatory activities than MPA by topical application to croton oil-induced ear edema. The ratio of the anti-inflammatory effects by topical application to subcutaneous administration of MPA was higher than those of MP-17P and MP. The excellent characteristics of MPA as a dermal anti-inflammatory drug are suggested to be derived from di-esterification of MP, which has a weak activity intrinsically.

Application of a drug delivery system to a steroidal ophthalmic preparation with lipid microspheres.

The applicability of a drug delivery system to an ophthalmic preparation was examined using lipid microspheres containing hydrocortisone 17-butyrate 21-propionate (HBP). A 3H-labelled HBP ophthalmic suspension and 3H-labelled HBP lipid microspheres were applied to rabbit eyes, which were then enucleated at fixed intervals to determine the level of 3H-labelled HBP in ocular tissues. The lipid microspheres were shown to deliver the drug to the anterior ocular tissues more effectively than the ophthalmic suspension. It is suggested that a lipid microsphere ophthalmic preparation of various lipophilic drugs including steroids may be useful as a drug delivery system for ophthalmic therapy.

Increase in incorporation into lymphocytesin vitro of esterified anti-inflammatory corticosteroids

Corticosteroids esterified at C-17 and C-21 such as hydrocortisone 17-butyrate 21-propionate (HBP) and prednisolone 17-valerate 21-acetate (PVA) inhibited PHA-induced blastogenesis of human blood lymphocytes more intensively than hydrocortisone (HC) and prednisolone (PSL), the parent corticosteroids. When lymphocytes were incubated with HBP or HC, the total amount of HBP incorporated into lymphocytes was much larger than that of HC. The amount of HBP bound specifically to the receptors was also increased, which may be due to the increased concentration of corticosteroid in lymphocytes. These results suggest that the increased incorporation of the esterified corticosteroids into cells would be most important to produce an intensive biological activity.

Enhancement of affinity to receptors in the esterified glucocorticoid, hydrocortisone 17-butyrate 21-propionate (HBP), in the rat liver

To investigate the affinity of glucocorticoid (GC) to its receptor, the binding of [ 3H]hydrocortisone 17-butyrate 21-propionate ([ 3H]HBP) and [ 3H]dexamethasone ([ 3H]DEX) in rat liver was analyzed kinetically. Scatchard analysis of [ 3H]hydrocortisone ([ 3H]HC) binding yielded a curvilinear plot with upward concavity with high and low affinities. The dissociation constant ( K d ) value of high affinity was 1.9 nM and of low affinity 68.7 nM. A Scatchard plot of [ 3H]HBP binding showed a straight line with high affinity. The K d value was 9.8 nM. The K d values for the low affinity site of HC were in good agreement with the K i values obtained from displacement experiments of [ 3H]DEX and [ 3H]HBP binding. The K i values of HC for [ 3H]DEX and [ 3H]HBP were 51.9 and 42.3 nM respectively. The association rate constant for HBP to the GC receptor was 2.9 times lower than that for HC. The dissociation rate constant for HBP was 6.1 to 8.3 times lower than that for HC. The K d values for [ 3H]HBP (9.5 nM) and [ 3H]HC (30.0 nM) obtained from the above two rate constants were approximately the same as the K i and K d values (in the case of HC, the value of the low affinity site). These results suggest that esterification of the hydroxyl group(s) in the side chain of GC by butyrate and propionate increased the affinity to the GC receptor, and that a decrease in the dissociation rate from the receptor caused the increase in the affinity to the GC receptor.

Hydrolysis of hydrocortisone 17-butyrate 21-propionate by cultured human keratinocytes

Hydrolysis of 17-butyrate 21-propionate (HBP) by human keratinocytes was studied using an in vitro system. In the culture of human keratinocytes 1.308 nmole/ml of hydrocortisone 17-butyrate (de-esterified HBP at the position of 21) was found at 1 h after the addition of 10 nmole/ml HBP. At 6 h most of HBP was de-esterified to become HB17 and a small amount of hydrocortisone 21-propionate (de-esterified HBP at the position of 17) was detected. Hydrocortisone (HC) was not detectable. These results indicate that when HBP is applied on the skin, it is hydrolyzed at the position of 21, and reaches the dermis where it finds the way to get into the systemic circulation. The intracellular concentration of HBP was estimated to be more than 5 times its extracellular concentration and its accumulation was higher than HC. These results were discussed in relation to the potentiation of local antiinflammatory action and the reduction of systemic effects of topical glucocorticoid.

P-184 - Possibility of contribution of the high affinity to polymorphonuclear leucocytes of hydrocortisone 17-butyrate 21-propionate(HBP) to increment of its efficacy

P-184 - Possibility of contribution of the high affinity to polymorphonuclear leucocytes of hydrocortisone 17-butyrate 21-propionate(HBP) to increment of its efficacy

Characteristics of Binding of a New Anti-Inflammatory Glucocorticoid, Hydrocortisone 17-Butyrate 21-Propionate (HBP), to Glucocorticoid Receptors of Rat liver

Characteristics of the specific binding of hydrocortisone 17-butyrate 21-propionate (HBP) to the cytoplasmic fraction from rat liver were investigated. The inhibition constant (Ki) of HBP for the site of 3H-dexamethasone (3H-DM) binding was approximately equal to the value of DM and significantly smaller than that of hydrocortisone (HC). The maximum number of binding sites (Bmax) and dissociation constant (Kd) for 3H-HBP were also approximately equal to those for 3H-DM. The Scatchard and Hofstee plots analyses of 3H-HC binding indicated that the HC binding sites consisted of three components with different affinity, while that of 3H-DM had only one site with an intermediate affinity, HBP and hydrocortisone 17-butyrate (HB) bound to other binding sites of HC in addition to the site for DM. The IC50 value for synthetic glucocorticoids determined from the inhibition curves of 3H-HC binding in the first phase agreed with the values determined by the displacement study of 3H-DM binding. Furthermore, the first phase of HBP in the inhibition curve of 3H-HC binding disappeared from the curve, and only the second phase remained following the addition of DM. These results indicate that the esterification of C-17 and C-21 OH increases the affinity of the binding site for synthetic glucocorticoid and attenuates the affinity for the other binding sites of HC.

Skin Safety and Clinical Evaluation of 0.1% Hydrocortisone 17-butyrate 21-propionate (HBP)

Skin Safety and Clinical Evaluation of 0.1% Hydrocortisone 17-butyrate 21-propionate (HBP)

ヒドロコルチゾン17,21-ジエステル類の合成と抗炎症作用

A new series of hydrocortisone 17, 21-diesters was prepared and their antiinflammatory activity was evaluated by the croton oil ear edema inhibition test in rats. The most potent compound was hydrocortisone 17-butyrate 21-propionate which was more active than betamethasone 17-valerate.

Influence of hydrocortisone 17-butyrate 21-propionate on the visual and the auditory organs (author's transl)

The visual toxicity and the ototoxicity of hydrocortisone 17-butyrate 21-propionate (HBP), a newly synthesized anti-inflammatory steroid, was investigated using rats and dogs. (1) Electroretinogram (ERG) and visually evoked potential (VEP) in rats were not changed when HBP was administered intravenously and intraperitoneally, even at the semilethal doses. Consequently, it was suggested that HBP had no effect on the visual nervous system. (2) Similar to other corticosteroids, the intra ocular pressure rose in the dogs received HBP. Nevertheless, these dogs showed neither the remarkable changes in ERG, in the fundus of the eye, in the histological examination, nor the turbidity of the cornea and the lens. Based on these facts, it was reasonable to think that the the rise in the intra ocular pressure caused by HBP was not so severe that induce the secondary influence to other visual functions. (3) The rats received HBP did not show any changes in the auditory function by the audiometry. As the result, HBP was thought to be one of the rather safety corticosteroids concerning the visual toxicity and the ototoxicity.

Studies on toxicity of hydrocortisone 17-butyrate 21-propionate -4. Chronic toxicity in rats by subcutaneous administration (author's transl)

Chronic toxicity of hydrocortisone 17-butyrate 21-propionate (HBP), a new synthetic corticosteroid, was studied in rats. HBP was subcutaneously injected to rats as the daily doses of 0.001, 0.01, 0.01, 1.0 and 3.0 mg/kg for 6 months, and the following recovery test was carried out for 4 weeks. Hydrocortisone 17-butyrate (HB) and betamethasone 17-valerate (BV) were used as the reference drugs at the doses of 0.1, 1.0 and 3.0 mg/kg. The suppression of body weight gain by the administration of HBP was observed at the doses more than 1.0 mg/kg in male and more than 0.1 mg/kg in female, and the dead animals were sent at the highest dose of HB and BV. Mainly at the doses more than 0.1 mg/kg HBP induced the dose-dependent symptoms such as decrease in the number of white blood cells and total protein level in serum, and increase in total cholesterol, GOT and GPT level in serum, and atrophic changes of adrenals, lymphatic tissues, skin and subsexual organs. No usual abnormality was recognized at the doses less than 0.01 mg/kg of HBP. These symptoms were more toxic in male, and the strength of toxicity was in the order of BV greater than HB greater than HBP. Many of these findings have known as common effects of corticosteroids. The changes observed in this study were almost recovered after withdrawal of HBP at the doses less than 0.1 mg/kg. As the result, it was suggested that the maximum non-toxic dose of HBP was 0.001 mg/kg.

Studies on toxicity of hydrocortisone 17-butyrate 21-propionate -2. Subacute toxicity in rats by subcutaneous administration (author's transl)

Subacute toxicity of hydrocortisone 17-butyrate 21-propionate (HBP), a new synthetic corticosteroid, was studied in rats, using betamethasone 17-valerate (BV) and hydrocortisone 17-butyrate (HB) as the reference drugs. HBP was subcutaneously injected to rats at the daily doses of 0.08, 0.4, 2.0, 10 and 50 mg/kg for 30 days. BV and HB were also administered at the daily doses of 0.08, 0.4 and 2.0 mg/kg. The recovery test was performed for 4 weeks after administration of HBP, BV and HB. The suppression of body weight gain by HBP was observed at the doses more than 0.08 mg/kg in male and more than 2.0 mg/kg in female rats. In addition, at the doses more than 0.4 mg/kg of HBP induced the dose-dependent symptoms such as decrease in the number of circulating white blood cells, lymphocyte counts and S-ALP level, increase in total cholesterol, GOT and GPT level of serum, and regressive changes in adrenals, lymphatic and hematopoietic tissues. There were fatal cases in rats given 50 mg/kg of HBP. These changes are considered to be common phenomena to other corticosteroids, and less toxic in female than male rats. Changes of symptoms caused by the administration of HBP 2.0 mg/kg were almost recovered after withdrawal. The toxicities of three corticosteroids were in the order of BV greater than HB greater than or equal to HBP in strength. As the result, maximum non-toxic dose of HBP was estimated to be 0.08 mg/kg in female and lower than that in male rats.

Studies of toxicity of hydrocortisone 17-butyrate 21-propionate -5. Chronic toxicity in rats by percutaneous administration (author's transl)

Chronic toxicity of a new synthetic corticosteroid, hydrocortisone 17-butyrate 21-propionate (HBP), was investigated in rats of both sexes. HBP was percutaneously given to rats with 0.1%, 0.5% cream and ointment at the daily dose level of 150 mg per 100 g body weight for 6 months. For the comparison, the percutaneous toxicity with 0.12% betamethasone 17-valerate (BV) cream and ointment, and 0.1% hydrocortisone 17-butyrate (HB) cream and ointment at the daily dose level of 150 mg per 100 g body weight were studied. Rats receiving HBP showed the dose-dependent changes such as the suppression of body weight gain and food intake, emaciation, decrease in the number of white blood cells and lymphocytes, total protein, increase in the number of red cells, hematocrit, hemoglobin, blood sugar and total cholesterol, regressive changes in adrenal cortex, lymphatic and hematopoietic tissues and skin, and gastric erosion, which have been well known as toxic effects of synthetic corticosteroids. These findings were comparatively high toxic in male, and almost disappeared in rats elapsed recovery time of month after withdrawal of HBP. The toxicities of HBP, BV and HB were qualitatively same. However, the grade of effects of HBP toxicity was similar to that of HB, weaker than of BV.

Studies on toxicity of hydrocortisone 17-butyrate 21-propionate -1. Acute toxicity of hydrocortisone 17-butyrate 21-propionate and its analogues in mice, rats and dogs (author's transl)

The acute toxicity of hydrocortisone 17-butyrate 21-propionate (HBP), hydrocortisone 17-butyrate (HB17) and hydrocortisone 21-butyrate (HB21) were investigated by three administration routes (s.c., i. p. and p. o.) in mice, rats and dogs. In the case of HBP, LD50 by oral administration was the highest, and followed by subcutaneous and intraperitoneal administration in mice and rats. And LD50 of HB17 and HB21 were not different from HBP in mice by subcutaneous administration. The depression of spontaneous movement and respiratory rate, ptosis, larcrymation and the collapse were commonly observed in all drugs, and it was independent of administration routes. The autopsy revealed the atrophy of thymus, spleen and adrenal glands, the supprative nodules of heart and liver and the ulcers of alimentary tract in mice and rats. But the changes observed in mice and rats were recognized when 1000 mg/kg of HBP was administered to dogs subcutaneously. Many of these changes were common to glucocorticoids, and the LD50 of HBP was rather high compared with other synthetic steroids; therefore, HBP was among less toxic steroid.

Pharmacological study on hydrocortisone 17-butyrate 21-propionate (author's transl)

The topical and systemic anti-inflammatory activities of hydrocortisone 17-butyrate 21-propionate (HBP) were studied. The systemic anti-inflammatory activities of HBP and reference steroids were examined for their effects on dinitrochlorobenzene dermatitis, carrageenin edema, cotton pellet granuloma and adjuvant arthritis in rats and by the delayed allergic edema test in mice. The topical anti-inflammatory activities of these steroids were examined for their effects on croton oil dermatitis, croton oil ear edema, carrageenin edema and cotton pellet granuloma in rats. Furthermore, effects of these steroids on liver glycogen deposition in mice, thymolysis, and decrease of serum corticosterone level in rats were examined. Systemically administered HBP was less potent than betamethasone 17-valerate (BV), but was almost equal to hydrocortisone 17-butyrate (HB) in anti-inflammatory activity, and its effects on liver glycogen deposition, thymolysis, and the decrease of serum corticosterone level. However, the topical anti-inflammatory activity of HBP was more potent than that of BV and HB, although in the same experiment, thymolytic activity of HBP was less potent than that of BV, but was almost equal to HB. The inhibitory effect of HBP on hypotonic induced hemolysis was weaker than that of BV, but was stronger than that of HB in vitro. The affinity of HBP was higher than that of BV and HB to polymorphonuclear leucocytes used as the inflammatory cells in vitro. On the other hand no marked difference was observed in the affinity to erythrocytes used as the non-inflammatory cells in vitro. These results suggest that HBP is a useful drug which has superior topical anti-inflammatory activity, but has a weak systemic effect.

Studies on toxicity of hydrocortisone 17-butyrate 21-propionate -3. Subacute toxicity in rats by percutaneous administration (author's transl)

Subacute toxicity of hydrocortisone 17-butyrate 21-propionate (HBP) was studied in rats. HBP was percutaneously given to rats with 0.1% and 0.5% creame (0.1% HBP-C, 0.5% HBP-C) and ointment (0.1% HBP-O, 0.5% HBP-O) at the daily dose level of 150 mg per 100 g body weight for 1 month. Rats receiving HBP-C and HBP-O showed some dose-dependent symptoms such as the suppression of body weight gain, emaciation, decrease in the number of white blood cells, hemoglobin, hematocrit, and serum total cholesterol level, regressive changes in adrenals, skin, lymphatic and hematopoietic tissues, which are known as toxic effects of synthetic corticosteroids. These symptoms were comparatively high toxic in male rats and in cream groups, and almost disappeared in rats elapsed recovery time of 1 month after withdrawal of HBP.