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K M Tramposch

Publications and source records attributed to K M Tramposch.

At least 37 records · Page 2Linked to original sources
PubMed1993

Effects of all-trans retinoic acid on glycosaminoglycan synthesis in photodamaged hairless mouse skin.

All-trans retinoic acid (tRA) was previously shown to be active in wrinkle reduction in the hairless mouse photoaging model. To address the questions of whether tRA also alters glycosaminoglycan (GAG) synthesis and whether observed wrinkle effacement can be attributed to changes in total GAG production, the effects of tRA on de novo GAG synthesis were examined in this model. Sulfated glycosaminoglycans (S-GAG) and the non-sulfated hyaluronic acid (HA) labeled with [3H]-glucosamine or [35S]-sulfate were found to diffuse differentially into the medium during the labeling period in the control animals (9% and 35% of total incorporated label for HA and S-GAG, respectively). Furthermore, the diffusion of HA into media was significantly changed after tRA treatment (from 9% to 24%), but no alteration was observed in the diffusion of S-GAG. Separation of epidermis and dermis indicated that the additional HA in medium after retinoid treatment primarily originated from the dermis. When incorporated label from the medium and skin fractions was combined, both labeling protocols revealed that 10 weeks of tRA treatment did not increase the total (medium plus skin) de novo synthesis of either HA or S-GAG. Wrinkle effacement as induced by retinoids in the photodamaged mouse skin therefore can not be related to an increased total GAG synthesis.

Animals↗
PubMed1992

Novel inhibitor of phospholipase A2 with topical anti-inflammatory activity.

Activation of a phospholipase A2 (PLA2) is a key step in the production of precursors for the biosynthesis of lipid mediators of inflammation. Inhibition of this enzyme could result in the suppression of three important classes of inflammatory lipids, prostaglandins, leukotrienes and platelet activating factor (PAF), and offers an attractive therapeutic approach to design novel agents for the treatment of inflammation and tissue injury. In this report we describe a novel compound, BMS-181162 4(3'-carboxyphenyl)-3,7-dimethyl-9(2",6"6"-trimethyl-1"-cyclohexenyl),++ +2Z,4E,6E, 8E-nonatetraenoic acid which specifically inhibits a 14 kD human PLA2 and effectively blocks phorbol ester induced skin inflammation in mice. BMS-181162 is the first reported specific inhibitor of PLA2 and its specificity may make useful tool in the dissection of the role of PLA2 in the inflammatory process.

Animals↗
PubMed1992

PMN binding to P-selectin is inhibited by sulfatide.

The endothelial adhesion protein P-selectin binds to a ligand present on the surface of leukocytes. We have characterized the binding interaction between P-selectin and polymorphonuclear leukocytes (PMNs) in an in vitro assay. These studies have utilized a soluble chimeric protein termed receptor globulin (Rg), which consists of the lectin-EGF-CR-CR extracellular domains of P-selectin fused to a human immunoglobulin G Fc domain. The PMNs bound to immobilized Rg in a saturable and concentration-dependent manner. The binding was specific for the Rg, as preincubation of the cells with soluble Rg inhibited binding to immobilized Rg, and binding was dependent on the presence of free divalent cations. The PMNs expressed a ligand for both P-selectin and E-selectin but not for L-selectin. Previously it was shown that sulfatide is a ligand for P-selectin binding in transformed cells. We have demonstrated that the presence of sulfatide in the P-selectin-PMN adhesion assay inhibits binding in a dose-dependent manner.

Antigens, CD↗
PubMed1992

Temporal infiltration of leukocyte subsets into mouse skin inflamed with phorbol ester.

We have previously shown that multiple topical applications, over 11 days, of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a persistent inflammatory reaction characterized by edema, cell infiltration and epidermal hyperplasia. In order to characterize the cell infiltrate during the establishment of this inflammatory reaction, immunohistochemistry was performed using two monoclonal antibodies: MOMA-2, a macrophage antibody and Thy-1, a pan T-cell antibody. The level of polymorphonuclear leukocytes (PMNs) peaked by day 3 at 160-fold over nontreated controls and then subsided to a 30-fold elevation on days 7-10. By day 4, the number of macrophages increased 2.9-fold over the nontreated control and by day 10 were elevated 6.0-fold over the nontreated control. In comparison, the number of T-cells present by day 7 was significantly elevated 9.5-fold over the nontreated group and peaked at day 8 with a 19-fold elevation relative to nontreated controls. Topical treatment of animals with hydrocortisone valerate resulted in a dramatic (> 60%) reduction in the number of T-cells present in the tissue. In contrast, there was no effect of the steroid on the number of macrophages present in the tissue. The identification of specific cell types and their time course of infiltration is consistent with the development of a chronic inflammatory lesion.

Animals↗
PubMed1992

Effects of all-trans retinoic acid on UVB-irradiated and non-irradiated hairless mouse skin.

The effects of all-trans retinoic acid (t-RA) on photodamaged and normal non-irradiated skin were examined in hairless mice (Skh:HR-1). After being exposed to increasing doses of UVB for 10 weeks (total dose = 1.4 J/cm2), the animals were then treated with 0.1% t-RA in ethanol (50 microliters, five times per week) for another 10 weeks. Several animals (the follow-up group) were further observed after the termination of the t-RA treatment to investigate if the t-RA effect was reversible. Wrinkle effacement induced by t-RA was compared with three other parameters: a) de novo collagen synthesis, b) width of the dermal repair zone, and c) epidermal thickening. Interestingly, t-RA did not stimulate collagen synthesis in animals not exposed to UVB. In the irradiated animals, the time course of wrinkle reduction correlated with the stimulation of collagen synthesis. After a synchronous initial lag phase of 4-6 weeks, the wrinkling decreased from the maximum grade of 4 to a mean grade of 1.3, whereas collagen synthesis was enhanced to 245% of the control at week 10 of t-RA treatment. In contrast, a similar lag phase was not observed for either the appearance of the dermal repair zone or epidermal thickening. In the follow-up group, upon termination of t-RA treatment, collagen synthesis returned to the control level. Wrinkle effacement and thickening of the dermal repair zone, however, did not regress, suggesting the anti-photoaging effect of t-RA was not reversible over this time frame. The correlation between the length of the lag phases for collagen synthesis and wrinkle reduction points to the possibility that collagen plays an important role in tRA-induced wrinkle effacement. Both parameters are thus important endpoints for investigating the mechanism of RA-induced repair of photodamaged skin.

Animals↗
PubMed1992

The pharmacology of a novel topical retinoid, BMY 30123: comparison with tretinoin.

Preclinical studies pertaining to the pharmacology and toxicology of BMY 30123 (4-acetamidophenyl retinoate) are reported. BMY 30123 is a novel compound which has topical retinoid activity. This compound exhibits lower toxicity, both local and systemic, than other clinically used topical retinoids such as tretinoin (all-trans retinoic acid) in animal models. BMY 30123 is effective in a number of retinoid sensitive skin models including the rhino mouse utriculi reduction assay, the mouse epidermal hyperplasia model and in the suppression of DNA synthesis in mouse skin stimulated with phorbol ester. BMY 30123 was equipotent with tretinoin in these topical models. In the rhino mouse model the ED30 values for BMY 30123 and tretinoin were 0.037 and 0.015 mM, respectively. In addition, BMY 30123 was active in the UVB-induced photodamaged mouse model, another retinoid sensitive model. One of the problems associated with topically applied tretinoin is local irritation. Therefore, for topical therapy to be optimal, it is important to reduce or minimize local irritation. Repeated applications of BMY 30123 to rabbit skin resulted in low skin irritation. The first perceptible signs of skin irritation produced by BMY 30123 occurred at a dose 10 times higher than that observed for tretinoin. BMY 30123 also exhibits low retinoid activity after oral or i.p. administration in mice and produced no signs of hypervitaminosis A-related toxicity at twenty times the no effect dose of tretinoin. Because retinoids are effective modulators of epidermal growth and differentiation, this compound should be useful for the treatment of cutaneous disorders that exhibit altered epidermal differentiation such as acne, psoriasis, ichthyosis and epithelial tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1992

The priming effect of ultraviolet B radiation on retinoic acid-stimulated collagen synthesis in the mouse photodamage model.

We have demonstrated previously that all-trans retinoic acid (tRA) stimulates collagen synthesis in ultraviolet B (UVB)-exposed but not in nonirradiated hairless mouse skin, suggesting that UVB exposure is required to prime certain tRA-induced events. The current study investigated further whether this tRA stimulatory effect on collagen synthesis could be regulated quantitatively by the accumulative dose of UVB. Mice were irradiated with the total amount of 0.25 (low), 0.77 (medium) or 1.43 J/cm2 (high) UVB radiation over 2, 5 and 10 weeks, respectively. Post-irradiation, 50 microliters of 0.1% tRA was applied topically 5 times a week. An initial delay was observed before tRA-induced collagen stimulation was detected in all 3 treatment groups. The first statistically significant increase in collagen synthesis was observed at the 6th week of tRA treatment in the high-UVB group. In the groups receiving medium and low UVB doses, onset occurred at the 8th week. Furthermore, at the end of tRA treatment, the degree of collagen stimulation correlated positively with the total UVB dose applied (increasing 183%, 224% and 250% over the vehicle control in the low-, medium- and high-UVB groups). By contrast, no collagen stimulation was detectable in the non-irradiated animals treated with tRA for 10 weeks, as previously reported. Although the mechanism by which UVB exposure primes skin to respond to tRA for collagen synthesis still remains unknown, the data indicate that the accumulative UVB dose positively affects the length of the initial delay and the magnitude of the stimulatory effect of tRA on collagen synthesis in photodamaged skin.

Animals↗
PubMed1991

The Yucatan miniature swine as an in vivo model for screening skin depigmentation.

The usefulness of the Yucatan miniature pig as a screen for skin dipigmenting activity by topical application was evaluated with standard compounds. This is a naturally occurring breed of swine with light brown to dark brown skin that is relatively hairless. The skin morphology, including the pattern of pigment distribution, in this breed of swine closely resembles the human skin. Test compounds examined in this study included the three standard compounds with known clinical depigmenting activity, hydroquinone (HQ), 4-hydroxyanisole (4HA) and tert-butyl catechol (TBC), each at a 5% concentration. Test materials in 25 microliters of propylene glycol/ethanol (50:50) were applied topically twice daily, 7 days a week for 90 days to test sites on each side of the dorsal mid-line. Test sites were graded weekly for variation in pigmentation and local irritation. After 90 days of test material application, skin biopsies of the test sites were taken for histological evaluation. Topical application of HQ, 4HA and TBC promoted marked skin depigmentation which was substantiated by reductions of pigment and melanocytes observed on microscopic examination. While both HQ and TBC produced marked local irritation, 4HA was only mildly irritating. These results suggest that the Yucatan pig, could be a potentially useful model for screening compounds with skin depigmenting activity.

Animals↗
PubMed1991

The effect of high and low ultraviolet-B dose exposure on the degree of hairless mouse skin wrinkling.

Chronic exposure of hairless mice to ultraviolet light (UVB 290-320 nm) causes degradative changes in the dermal matrix and wrinkle production. We compared the effects of two different UVB dosing regimens on wrinkle production and dermal damage in female Skh:HR-1 hairless mice using a bank of unfiltered FS-40 lamps. One group of mice, the low dose group, was exposed to a sub-erythemal UVB dose of 12 mJ/cm2 (1 MED = 14 mJ/cm2), 3 times per week for 20 weeks (total dose = 0.72 J/cm2). A second group, the high dose group, was exposed also 3 times per week for 15 weeks to a UVB dose which started with the sub-erythemal dose of 12 mJ/cm2 at Week 1, and 1 MED at week 2. The dose was then increased weekly by 1 MED until reaching 4 MED at week 5. The animals were then dosed at 4 MED for 10 additional weeks (total dose = 2.1 J/cm2). Visual results indicate that, as expected, within the same group, the degree of wrinkling was generally dependent on the total UVB dose administered. However, comparison between the low dose and high dose groups shows that equal cumulative UVB doses did not always result in identical wrinkle grades. For example, at a cumulative dose of 0.5 J/cm2, the mean wrinkle grade for the low dose group was 1.75 compared to that of 1.2 for the high dose group (age-matched = 0). This observation may suggest that there are other factors in addition to total cumulative dose which are important for the appearance of wrinkling in this model.

Animals↗
PubMed1991

Mouse skin inflammation induced by multiple topical applications of 12-O-tetradecanoylphorbol-13-acetate.

It is well known that applications of a single dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ears induces an acute inflammatory reaction consisting of erythema, edema and polymorphonuclear leukocyte (PMN) infiltration. We report here that multiple topical applications of TPA to mouse ears produce a prolonged inflammatory reaction characterized by increases in ear weight, inflammatory cell infiltration and epidermal hyperplasia. TPA was applied 5 times over 10 days to mouse ears. Epidermal thickness and PMN infiltration (myeloperoxidase content) increased 3- and 160-fold, respectively, by day 3 and remained elevated over control values throughout the test period. Ear weight was elevated from day 1 and remained high. Hydrocortisone 17-valerate and betamethasone dipropionate significantly reduced all three parameters of inflammation. Indomethacin and two other cyclo-oxygenase inhibitors, and an antihistamine had little or no effect on any of the parameters. This chronic skin inflammation model may be more relevant for evaluating anti-inflammatory compounds than the acute TPA model because the test compounds are applied after the inflammatory lesion is established, which mirrors the use of clinical anti-inflammatory drugs. Also this model may be more selective than the acute TPA model for compounds which affect leukotriene production since other pharmacological agents which are active in the acute model are not active in the multiple-application model.

Administration, Topical↗
PubMed1991

BMY 30047: a novel topically active retinoid with low local and systemic toxicity.

In the treatment of various dermatological disorders, topically applied retinoids have potential therapeutic use with the advantage of improved localized activity and lower toxicity over systemically administered retinoids. However, most retinoids cause a significant degree of local irritation. In the present study, the ability to produce local activity with low local irritation potential was evaluated with a novel retinoic acid derivative. BMY 30047 (11-cis, 13-cis-12-hydroxymethylretinoic acid delta-lactone) is one of a series of retinoic acid derivatives in which the carboxyl function of the polar end was modified with the aim of achieving reduced local irritation and systemic toxicity while retaining the local therapeutic effect. BMY 30047 was evaluated and compared with all-trans retinoic acid for topical retinoid activity in several preclinical assay systems, including the utricle reduction assay in rhino mice, 12-o-tetradecanoylphorbol 13-acetate ester-stimulated ornithine decarboxylase induction in hairless mice and the UV light-induced photodamaged skin model in hairless mice. BMY 30047 was assessed for retinoid-type side effects by evaluating the skin irritation potential in rabbits after repeated topical application, and hypervitaminosis A-inducing potential in mice after i.p. injection. BMY 30047 demonstrated significant topical retinoid activity in several in vivo models with less skin irritation potential relative to the most used clinical concentrations of all-trans retinoic acid. BMY 30047 also showed very little systemic activity and did not produce any evidence of hypervitaminosis A syndrome at systemic doses 20 times greater than the no-effect dose of all-trans retinoic acid.

Administration, Topical↗
PubMed1990

Biochemical and pharmacological properties of a new topical anti-inflammatory compound, 9-phenylnonanohydroxamic acid (BMY 30094).

Drugs which block the biosynthesis of leukotrienes and prostaglandins may have potential in the treatment of psoriasis and other skin diseases. The biochemical and anti-inflammatory activity of 9-phenylnonanohydroxamic acid (BMY 30094) is described. BMY 30094 inhibited human neutrophil 5-lipoxygenase with an IC50 of 5.7 microM. BMY 30094 also blocked human platelet cyclooxygenase and lipoxygenase with IC50 values of 15.2 and 15.0 microM, respectively. Topical application of this compound blocked arachidonic acid and 12-O-tetradecanoylphorbol ester-induced mouse skin inflammation with activity comparable to that observed for lonapalene. The topical ED50 for BMY 30094 in the arachidonic acid-induced inflammation model is 2.2 mumoles/ear. In the sub-cutaneous carrageenan sponge assay in rats, BMY 30094 blocked LTB4 and PGE2 production and inhibited neutrophil migration. This compound would be a useful tool to determine the role of arachidonic acid metabolites in the etiology of inflammatory dermatoses.

Administration, Cutaneous↗
PubMed1989

UVB-induced pigmentation in hairless mice as an in vivo assay for topical skin-depigmenting activity.

Several reports have demonstrated that exposure to ultraviolet light elicits increased pigmentation in the skin of the Skh:HR2 mouse. We have reexamined this model to assess its potential as a screen for compounds with skin-depigmenting activity. The application of the previously reported ultraviolet light-B (UVB) doses led to marked necrotic damage to the skin which greatly diminished the usefulness of the model for drug testing. We have modified this model by exposing the mice to a progressively increasing dose of UVB that promotes pigmentation with a marked reduction of skin irritation. Furthermore, for compound evaluation, we preselected only those mice which developed signs of increased pigmentation after the first week of UVB exposure. This was critical for any meaningful compound evaluation, since only about 50% of the mice eventually showed signs of increased pigmentation with UVB. Our modifications make it possible to use this model for evaluating new compounds with skin-depigmenting activity. The validity of this method has been examined with a number of compounds including hydroquinone, 4-hydroxyanisole, kojic acid and all-trans retinoic acid, all with known depigmenting activity.

Animals↗
PubMed1989

Effects of retinoids on phorbol ester-stimulated epidermal DNA synthesis and hyperplasia in hairless mice.

We investigated the effects of the retinoids, all-trans retinoic acid (t-RA), 13-cis retinoic acid, etretinate, and arotinoid ethyl ester, on 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced DNA synthesis, and epidermal hyperplasia in hairless mouse skin. Topical application of these retinoids produced dose-dependent inhibition of the TPA-induced epidermal DNA synthesis as measured by [3H]thymidine incorporation at 15 h after TPA application. However, this inhibition was only transient and did not affect the corresponding increase in epidermal cell layers measured at 40 or 70 h after TPA application. Fluocinonide also inhibited the epidermal DNA synthesis and failed to block TPA-induced epidermal hyperplasia. However, fluocinonide did effectively suppress the inflammation caused by TPA. In this paper we have shown that the suppression of TPA-stimulated DNA synthesis is a general property of topically applied retinoids. The biologic significance of a temporary suppression of TPA-stimulated epidermal DNA synthesis by the retinoids and fluocinonide is not understood at this time.

Animals↗
PubMed1988

Diphenylamine-colorimetric method for DNA assay: a shortened procedure by incubating samples at 50 degrees C.

We describe a modified procedure of the diphenylamine-colorimetric method for assay of DNA that is shorter than the procedure described by Burton. This improvement is achieved by raising the sample incubation temperature to 50 degrees C. The higher temperature hastens and stabilizes the diphenylamine reaction with DNA so that absorbances of samples can be measured as early as 3 h after the reaction is started. This shortened assay is able to detect as little as 3 micrograms of calf thymus DNA. This method is suitable for measuring DNA content of epidermal tissue.

Animals↗