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PubMed2000

Identification of a cysteine residue in the active site of nitroalkane oxidase by modification with N-ethylmaleimide.

The flavoprotein nitroalkane oxidase catalyzes the oxidative denitrification of primary or secondary nitroalkanes to the corresponding aldehydes or ketones with production of hydrogen peroxide and nitrite. The enzyme is irreversibly inactivated by treatment with N-ethylmaleimide at pH 7. The inactivation is time-dependent and shows first-order kinetics for three half-lives. The second-order rate constant for inactivation is 3.4 +/- 0.06 m(-)(1) min(-)(1). The competitive inhibitor valerate protects the enzyme from inactivation, indicating an active site-directed modification. Comparison of tryptic maps of enzyme treated with N-[ethyl-1-(14)C]maleimide in the absence and presence of valerate shows a single radioactive peptide differentially labeled in the unprotected enzyme. The sequence of this peptide was determined to be LLNEVMCYPLFDGGNIGLR using Edman degradation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The cysteine residue was identified as the site of alkylation by ion trap mass spectrometry.

Amino Acid Sequence↗

PubMed2002

Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design.

Ganciclovir (GCV), a promising antiviral compound, has poor ocular bioavailability as a result of its relatively low partition coefficient. In this study, lipophilic ester prodrugs of GCV were synthesized in an effort to improve its uptake into ocular tissues. In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic mono-acyl ester prodrugs of GCV to determine the effect of lipophilicity and corneal hydrolysis rate on transcorneal diffusion. The GCV prodrugs showed a progressive decrease in solubility and a corresponding increase in Log P values as the chain length was ascended. Permeation studies using freshly isolated rabbit corneas showed that all prodrugs permeated as intact prodrug as well as hydrolyzed GCV. Corneal permeability coefficients increased with increasing lipophilicity for mono-ester prodrugs having more than three carbon atoms in the side chain. The permeability of GCV increased about 6-fold in ascending from the parent drug-ganciclovir (3.82 +/- 0.19 x 10(-6) cm sec(-1)) to its valerate ester prodrug (23.70 +/- 1.36 x 10(-6) cm sec(-1)). Among the prodrugs studied, the valerate ester showed the highest permeability and holds the most potential for development. Overall prodrug permeability correlated linearly with increased susceptibility of the GCV esters to undergo hydrolysis in the cornea. The present work indicates that the ideal prodrug is one that not only possesses enhanced partitioning characteristics, but also high enzyme susceptibility. Concentration of active GCV penetrating the corneal epithelium was substantially increased through the bio-reversible ester prodrug strategy.

Animals↗

PubMed2005

Highly potent and moderately potent topical steroids are effective in treating phimosis: a prospective randomized study.

PURPOSE: We report a prospective randomized study comparing the effects of highly potent and moderately potent topical steroids in treating pediatric phimosis. MATERIALS AND METHODS: A total of 70 boys 1 to 12 years old with phimosis were randomly assigned to receive topical application of either betamethasone valerate 0.06% (a highly potent steroid) or clobetasone butyrate 0.05% (a moderately potent steroid). Parents of the boys were instructed to retract the foreskin gently without causing pain, and to apply the topical steroids over the stenotic opening of the prepuce twice daily for 4 weeks, then for another 4 weeks if no improvement was achieved. Retractibility of the prepuce was graded from 0 to 5. Response to treatment was arbitrarily defined as improvement in the retractibility score of more than 2 points. RESULTS: Mean treatment and followup periods were 4.3 and 19.1 weeks, respectively. The response rates in boys treated with betamethasone valerate and clobetasone butyrate were 81.3% and 77.4%, respectively (p = 0.63). Mean retractibility score decreased from 3.9 +/- 1.0 to 1.7 +/- 1.1, and 4.2 +/- 1.0 to 1.9 +/- 1.0 in the betamethasone and clobetasone groups, respectively. Both steroids were effective in all age groups. Pretreatment retractibility score did not affect treatment outcomes. No adverse effect was encountered. CONCLUSIONS: Highly potent and moderately potent topical steroids are of comparable effectiveness in treating phimosis. A less potent steroid may be considered first to decrease the risk of the potential adverse effects.

Administration, Cutaneous↗

PubMed1991

Efficacy of bimolane in the Malassezia ovalis model of psoriasis.

Bimolane, an analog of razoxane has been used in China with comparable efficacy but less toxicity than razoxane in the treatment of psoriasis. In an attempt to characterize further its mode of action it was administered both systemically and topically in the Malassezia ovalis animal model of psoriasis. Intravenous methotrexate and topical 0.1% betamethasone valerate were also used as positive control treatments. The animal model of psoriasis was effectively treated by bimolane, both systemically and topically, and also by parenteral methotrexate and topical betamethasone valerate. The time course of bimolane's effect with this model was different from methotrexate's suggesting the possibility of a different mode of action. Because bimolane, like razoxane, is an ethylene diamino tetraacetate acid (EDTA) derivative, it is possible that its effects on this reaction relate to its chelating properties and that inhibition of complement activation is important to its mode of action.

Administration, Cutaneous↗

PubMed1980

Effects of corticosteroids on the proliferation of normal and abnormal human connective tissue cells.

Four corticosteroids were tested in vitro for effect on the proliferation of four strains of fibroblasts from scleroderma skin, four strains from normal adult skin and four strains of rheumatoid synovial cells. Significant effects on fibroblasts occurred only at the highest steroid concentration tested (10 microgram/ml) where the inhibitory ranking of the steriods was clobetasol propionate greater than clobetasone butyrate greater than betamethasone valerate greater than hydrocortisone. Hydrocortisone and betamethasone valerate stimulated proliferation of two normal strains, had no certain effect on the scleroderma group, and inhibited growth of synovial cells. Clobetasone butyrate and clobetasol propionate inhibited growth of all cells. All four steroids substantially reduced acid mucopolysaccharide secretion by scleroderma fibroblasts. These results suggest that fibroblasts from normal and abnormal skin show only small differences in their responses to corticosteroids in vitro, but contrast sharply with the mouse L-929 fibroblasts previously used in some assays of topical corticosteroid potency.

Adrenal Cortex Hormones↗

PubMed1980

Effect of five anti-inflammatory steroids on collagen and glycoaminoglycan synthessis in vitro.

The effect of five anti-inflammatory corticosteroids, i.e. hydrocortisone, hydrocortisone 17-butyrate, betamethasone 17-valerate, nicocortonide acetate and nicocortonide, on the synthesis of hyaluronic acid, sulphated glycosaminoglycans and collagen by cultured skin fibroblasts was studied. As inhibitors of all these parameters the steroids could be arranged in order hydrocortisone < hydrocortisone 17-butyrate < betamethasone 17-valerate, nicocortonide acetate and nicocortonide. The corticosteroid concentrations required for inhibition of hyaluronic acid were very low as compared to those required for inhibition of sulphated glycosaminoglycan and collagen synthesis.

Anti-Inflammatory Agents↗

PubMed1983

The effect on epidermal DNA synthesis of a combination of topical steroid with either dithranol or tar as used for psoriasis.

The hairless mouse was used to investigate the effects of a combination of glucocorticosteroid with either dithranol or tar on epidermal DNA synthesis, in order to determine whether such combinations reduce epidermal DNA synthesis more effectively than the single agents. Dithranol alone produced a significant local inhibition of DNA synthesis at concentrations of 0.1% and 0.05% but not at lower concentrations. Dose-response data for dilutions of clobetasol propionate and betamethasone 17-valerate showed progressive diminution of both local and systemic effects with decreasing concentrations. An additive effect was found from combining clobetasol propionate with dithranol and from combining betamethasone 17-valerate with liquor picis carbonis. These combined preparations were tested again after storage for 6 months and 2 months respectively and showed no loss of efficacy. These results lend justification to the use of these combined preparations in the treatment of psoriasis.

Animals↗

PubMed1984

Objective determination of the bioavailability of dermocorticoids--influence of the formulation.

In order to quantify the intensity of skin blanching and thus predict the bioavailability of topical corticoids, a physical device allowing the measurement of light reflected from skin without any contact between the probe and the skin was used (Leveque et al., 1984). Three series of experiments were carried out: firstly, to assess the vasoconstrictor potency of four corticoids; secondly, to show the influence of the vehicle on the bioavailability of the same drug under various galenic forms, such as fatty ointments or water in oil (W/O) and oil in water (O/W) creams; thirdly, to determine the reservoir effects, if any, of some of these formulations. The results confirm previous findings about the potency of hydrocortisone acetate, triamcinolone 17-acetonide, betamethasone 17-valerate, diflucortolone valerate and clobetasol 17-propionate.

Administration, Topical↗

PubMed1993

A corticosteroid, a non-steroidal anti-inflammatory drug and an antihistamine modulate in vivo vascular reactions before and during post-occlusive hyperaemia.

Post-occlusive reactive hyperaemia is the temporary increase of blood flow in a tissue following transient vascular obstruction, and has recently been proposed as an in vivo method for ranking topical corticosteroid potency. We investigated in vivo vascular reactions before and during post-occlusive hyperaemia using laser-Doppler flowmetry and reflectance spectroscopy (RS). RS enables resolution of in vivo erythema into deoxygenated (venous) [DOH] and oxygenated (arterial) haemoglobin (OH) components (expressed in arbitrary units, AU). Using a randomized 24-h occlusive exposure in 10 healthy volunteers the effects of a corticosteroid (betamethasone-17-valerate), a non-steroidal anti-inflammatory drug (NSAID) [indomethacin], an antihistamine (diphenhydramine), or vehicle, were studied before and during post-occlusive hyperaemia. The 24-h vehicle exposure decreased total haemoglobin (composed of a small increase in OH [P < 0.001] and a greater decrease in DOH [P < 0.005], [OH, 0.23 +/- 0.18 AU; DOH, 0.28 +/- 0.12 AU]). The blood flow increased 7.1% to 28 +/- 8 AU (P > 0.05). Betamethasone-17-valerate exposure decreased total haemoglobin further (OH, 0.10 +/- 0.09 AU [P < 0.005]; DOH, 0.18 +/- 0.08 AU [P < 0.05]), which corresponded to a 15% blood flow decrease (P < 0.05). Indomethacin reduced OH to 0.18 +/- 0.12 AU (P < 0.02) and increased DOH slightly, with a trend towards decreased blood flow (P > 0.05). Diphenhydramine caused no significant changes in RS or laser-Doppler flowmetry readings before post-occlusive hyperaemia. Post-occlusive hyperaemia increased total haemoglobin maximally at the first observation time (OH, 0.63 +/- 0.13 AU; DOH, 0.31 +/- 0.11 AU [P < 0.001]).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1976

Intranasal steroid aerosol in perennial rhinitis: comparison with an antihistamine compound.

Intranasal betamethasone valerate aerosol, given for 28 days, was compared with an oral antihistamine compound in a couble-blind, double-dummy, cross-over trial involving thirty patients with perennial rhinitis. The steroid aerosol was more effective in reducing symptoms and was preferred by the patients (P less than 0-01). Nasal blockage index, calculated from oral and nasal peak expiratory flow measurements, did not provide useful or additional information. There were no side effects from the steroid and Candida albicans was not cultured from nasal swabs. It is concluded that beta-methasone valerate aerosol is a suitable short-term alternative for patients whose perennial rhinitis fails to respond to conventional therapy.

Administration, Intranasal↗

PubMed1976

Desoxymethasone: a new topical corticosteroid.

In a double-blind controlled trial, desoxymethasone was compared with betamethasone valerate in 50 patients with bilateral acute dermatitis using a "within patient" type of comparison. The topical efficacy of desoxymethasone was somewhat greater than that of betamethasone valerate. It was well tolerated and produced no local side effects.

Administration, Topical↗

PubMed1991

Cleavage kinetics and anchor linked intermediates in solid phase peptide amide synthesis.

Kinetics and cleavage conditions of peptide amide synthesis were studied using the anchor molecules 5-(4'-aminomethyl-3',5'-dimethoxyphenoxy)valeric acid (4-ADPV-OH) and 5-(2'-aminomethyl-3'-5'-dimethoxyphenoxy) valeric acid (2-ADPV-OH). Unexpectedly the anchor amide alanyl-4-ADPV-NH2 was isolated and characterized as an intermediate during the cleavage with trifluoroacetic acid (TFA) of alanyl-4-ADPV-alanyl-aminomethyl-polystyrene to yield the alanine amide. As a matter of fact the NH--CH alpha bond of the alanyl spacer has to be cleaved to form this intermediate. Using TFA-dichloromethane (1:9) alanyl-4-ADPV-NH2 was obtained as a cleavage product in 50% yield within 60 min, whereas the isomeric alanyl-2-ADPV-NH2 was formed more slowly under these mild conditions. At high TFA concentration no difference between the 2- and 4-ADPV anchor was observed in the rate of formation of the free alanine amide. The presence of tryptophan amide in the cleavage mixture resulted in an anchor alkylated tryptophan amide, which remains stable in acidic solution but disappears rapidly in the presence of the resin. A low TFA/high TFA cleavage procedure is recommended for peptide amid synthesis applying the ADPV anchor.

Alkylation↗

PubMed1976

Halcinonide, a new topical anti-inflammatory steroid.

Halcinomide, a new topical fluorinated steroid was compared in a double-blind, simultaneous comparison with betamethasone valerate. Halcinoide was found to be superior in the treatment of psoriasis and equally effective as betamethasone valerate in the treatment of atopic dermatitis.

Administration, Topical↗

PubMed1975

double-blind"double-bind.

In a double-blind trial over a 2-week period in 34 patients with psoriases vulgaris, clobetasol propionate cream was shown to be more effective than betamethasone valerate cream. In a further 16 patients whose psoriasis had not responded to betamethasone valerate ointment, treatment with clobetasol propionate ointment was substituted. Fourteen of the 16 patients experienced a rapid improvement of their lesions.

Adolescent↗

PubMed1983

Systemic side-effects of three topical steroids in diseased skin.

Two clinical trials were carried out in order to study adrenal suppression in 6 patients with psoriatic erythroderma and in 28 patients with psoriasis treated with topical glucocorticosteroids. Betamethasone-17-valerate (0.1%), betamethasone-17,21-dipropionate (0.05%) and budesonide (0.025%) ointments were studied in erythroderma; betamethasone-17,21-dipropionate and budesonide in psoriasis. The erythroderma study was an open, crossover experiment; the psoriasis study was a double-blind, group-comparative study. Adrenal suppression was measured as plasma cortisol concentrations with and without ACTH stimulation. The depressive activity on the HPA-axis in increasing order was budesonide, betamethasone-17-valerate and betamethasone-17,21-dipropionate. The differences, however, did not reach statistically significant levels.

Administration, Topical↗

PubMed1998

Local anti-inflammatory activity and systemic side effects of NM-135, a new prodrug glucocorticoid, in an experimental inflammatory rat model.

The local anti-inflammatory activity and systemic side effects of NM-135 (6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21[[2 ,3,4,6-tetrakis-O-(4-methylbenzoyl)-beta-D-glucopyranosyl]oxy]-pregna-1, 4-diene-3,20-dione) in croton oil-induced granuloma pouches and ear edema in rats were studied. The local anti-inflammatory activity of NM-135 was stronger than that of betamethasone 17-valerate (BV). As to systemic side effects, BV and diflucortolon valerate (DFV) caused thymolysis at the doses required for the anti-inflammatory activity. In contrast, no clear systemic side effect was observed in rats administered NM-135 at the dose producing the anti-inflammatory activity. These results suggest that NM-135 is a drug exhibiting a high degree of dissociation between the local anti-inflammatory activity and systemic side effects.

Animals↗

PubMed1993

Intensity and area increase of UVB-induced erythema: two variables used for studies of the influence of topically applied drugs.

The area of UV erythema produced by a small beam head was found to increase with increasing doses. The aim was to investigate whether measurement of the area could be a more useful indicator of UV-induced damage than classic visual grading. Topical pretreatment with all-trans retinoic acid (tretinoin) and betamethasone valerate was used to test the applicability of the method in pharmacological studies. We used a round outlet head (5 mm2) connected by optical fibre to a monochromatic irradiator, and doses ranging from 0.05 to 0.2 Joule of 300 mm UV light were applied to the skin of 6 healthy subjects. Erythemal area was calculated by the measurement of two diameters, and intensity was graded visually (0-6 scale). The area of the erythema correlated with the increase in intensity up to score 6. Area measurement was less subject to intra-investigators' variability than the intensity score. By multiplying intensity by area, a good indicator of UV-induced reactivity was obtained. Pretreatment with betamethasone valerate decreased the area of erythema, as did tretinoin 12 h after irradiation. Thus, area measurement of erythema is a useful adjunct to visual grading of UV-induced skin reactions.

Administration, Cutaneous↗

PubMed1980

Effect of feeding isoacids with urea on growth and nutrient utilization by lactating cows.

In the growth study 10 g each of isobutyrate, isovalerate, 2-methylbutyrate, n-valerate, and phenylacetate were mixed with 80 g of urea, 50 g of molasses, and 270 g of ground hay and fed to nine dairy heifers for 90 days. The control group was fed the same diet minus isoacids and phenylacetate. All animals were fed ad libitum timothy hay as the sole roughage. In the digestion trial, two mixtures of isoacids and a control ration were fed to nine lactating cows in a 3 X 3 Latin square design with 28-day feeding periods. Corn silage was the sole roughage, and concentrate was fed in proportion to milk production. Collection of feces and urine was for the last 5 days of each period. Mixture 1 of isoacids contained on a molar basis 28, 24, 24, and 24% of isobutyrate, isovalerate, 2-methylbutyrate, and n-valerate, respectively. Corresponding for mixture 2 were 36, 17, 17, and 30%. Addition of isoacids increased growth rate of younger animals but not older ones. The isoacid mixtures improved utilization of nitrogen by lactating cows. Urinary nitrogen decreased, and retention of absorbed nitrogen increased. Digestibility of dry matter and nitrogen were not affected by isoacid additions.

Animals↗