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Biomedical subjects

H Schaefer

Publications and source records attributed to H Schaefer.

At least 19 recordsLinked to original sources
PubMed1994

Serum amyloid A protein (SAA): a marker for liver allograft rejection in humans.

Serum amyloid A protein (SAA) concentrations were monitored in 12 consecutive liver transplant recipients until the 70th postoperative day. Fourteen rejection episodes were identified histologically in 42 liver biopsies of the grafts. Of 12 rejections 8 (66.7%) were characterized by pronounced simultaneous increases in SAA concentrations in plasma, the mean peak value being 16.94 +/- 8.82 mg/dl (range 4.58-28.55 mg/dl) compared with a mean normal value of 0.98 +/- 0.42 mg/dl in healthy controls. Of 42 biopsies 28 did not show histological evidence of graft rejection. Of 25 negative biopsies 24 (96.0%) were not accompanied by a parallel SAA increase in plasma. These findings demonstrate that measurements of SAA concentrations may provide a valuable noninvasive aid in identifying acute liver allograft rejection in humans.

Adolescent↗
PubMed1994

Repeated topical administration of all-trans-retinoic acid and plasma levels of retinoic acids in humans.

BACKGROUND: Vitamin A ingestion raises plasma levels of several potentially teratogenic retinoic acids (RAs) with all-trans and 13-cis configuration, but definitive data concerning the consequences of topical administration of all-trans-RA are lacking. OBJECTIVE: The study objective was to investigate the potential for inducing systemic activity after topical administration of 0.025% all-trans-RA by measuring plasma retinoid levels. METHODS: Plasma levels of all-trans-RA, 13-cis-RA, and 4-oxo-13-cis-RA were measured in four healthy subjects before, during, and after 14 daily topical applications of all-trans-RA. RESULTS: Topical administration of all-trans-RA did not significantly increase plasma levels of all-trans-RA, 13-cis-RA, and 4-oxo-13-cis-RA. Significant decreases in levels of these RAs observed during the night may reflect diurnal variations of retinoid metabolism or lowered absorption of dietary vitamin A. CONCLUSION: Diurnal and nutritional factors influence plasma levels of endogenous retinoids to a greater extent than topical administration of all-trans-RA at doses used for acne therapy, which on the basis of these results appears unlikely to induce systemic effects.

Administration, Topical↗
PubMed1994

Ki-S1 and proliferating cell nuclear antigen expression of bone marrow macrophages. Immunohistochemical and morphometric study including reactive (inflammatory) myelitis, secondary aplastic anemia, AIDS, myelodysplastic syndromes and primary (idiopathic) osteomyelofibrosis.

There is general agreement on the fact that bone marrow macrophages present a non-proliferating cell population. Using a sequential double-immunostaining technique, a morphometric analysis was performed on routinely processed bone marrow biopsies derived from 70 patients. The purpose of this study was, firstly, to determine the frequency of bone marrow macrophages in a variety of lesions and, secondly, to elucidate whether there is any proliferative activity detectable by immunohistochemical markers. Bone marrow pathology included reactive myelitis (RM), secondary aplastic anaemia (AP), AIDS-related myelopathy, primary (idiopathic) osteomyelofibrosis (OMF) and myelodysplastic syndromes (MDS). The monoclonal antibody PG-M1 which recognizes a formalin-resistant epitope on macrophages and PC10 raised against proliferating cell nuclear antigen (PCNA) were employed. For comparison with the PCNA-labelling index, the newly developed monoclonal antibody Ki-S1, which is associated with cell proliferation, was applied. In comparison with normal bone marrow, morphometric evaluation revealed a significant increase in macrophages in MDS, OMF, RM and especially in HIV-infected patients. Moreover, a positive immunostaining of single macrophages with PC10 was noted very infrequently. This rather inconspicuous PCNA labelling increased in AIDS. By contrast, Ki-S1 expression was found in none of the other pathologies studied. The prevalence of the macrophage population in certain disorders may have a multifactorial origin, such as inflammatory changes like intercurrent infections in AIDS and enhanced cell turnover in MDS as well as involvement of the complex pathomechanisms generating bone marrow fibrosis. In keeping with previous studies, the insignificant PCNA expression of macrophages should not be related to cell proliferation, but to unscheduled DNA strand repair which may be generated in the course of viral infection in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Lipid composition and barrier function of human skin after grafting onto athymic nude mice.

The barrier properties of human epidermis grafted for 1-3 months onto nude mice are compared with normal human skin. Beside penetration studies with tritiated water and measurements of transepidermal water loss (TEWL), we analyzed the epidermal lipids by high-performance thin layer chromatography and evaluated the ultrastructure of the intercorneocyte lipid arrangement by freeze fracture electron microscopy (FFEM). The permeability of human skin for tritiated water and the TEWL exhibit no significant changes after grafting onto nude mice. FFEM analysis showed that grafted epidermis has the same morphological pattern as normal human epidermis. Regular desmosomes and lamellar lipid structures are present. Grafting did not qualitatively affect the lipid composition of human epidermis. Ceramides which contribute largely to the barrier function, have the same distribution profile.

Animals↗
PubMed1994

Role of transepidermal and transfollicular routes in percutaneous absorption of steroids: in vitro studies on human skin.

Percutaneous absorption theoretically comprises two components: the transepidermal and the transfollicular routes. The aim of the present work was to confirm this hypothesis in the human skin by comparing the in vitro percutaneous absorption of four steroids through scar skin without hair follicles and sebaceous glands and through normal adjacent skin from abdominal or mammary plasties. In all cases, the absorption of the four steroids was significantly higher in normal skin than in scar skin. The cumulative percentages of progesterone and testosterone after 8 h of application were, respectively, 3.1- and 2.4-fold higher in normal skin than in scar skin. After 24 h of application, the cumulative percentages of estradiol and hydrocortisone were 1.7- and 2.4-fold higher in normal skin than in scar skin. At the end of the experiments, the quantities of drugs remaining in the skin after 8 or 24 h of application were the same in normal skin and in scar skin except for progesterone for which they were 2-fold greater in normal than in scar skin. In each case, a histological characterization of the scar skin was made in comparison with the normal adjacent skin. The main modifications observed on scar skin were the following: absence of hair follicles and sebaceous glands, thinning of the collagenous fibers with parallel orientation to the dermoepidermal junction and decrease in the number or disappearance of the elastic fibers. These experiments confirmed that human skin appendages, hair follicles and sebaceous glands, constitute a route of penetration for steroids and thus probably for other chemicals of similar molecular weight and properties.

Adult↗
PubMed1994

Percutaneous absorption of estradiol and progesterone in normal and appendage-free skin of the hairless rat: lack of importance of nutritional blood flow.

Percutaneous absorption occurs after passive diffusion through the different layers of the skin and its appendages. Thereafter, a resorption process into the cutaneous microcirculation brings the compounds into the systemic circulation. The objective of this in vivo study in the hairless rat was to compare the percutaneous absorption of two steroids on normal and appendage-free (scar) skin and to show if differences in absorption result only from the lack of hair follicles and sebaceous glands and/or from a modification of local blood flow. Percutaneous absorption was evaluated with estradiol and progesterone after 30 min, 2 and 6 h. Except after 30 min, the reservoir function of the stratum corneum of scar skin was approximately twice as high as in normal skin. Eighty to ninety percent of the estradiol and progesterone found in the stratum corneum were located in its superficial layers. Inversely, whatever the application time was, the concentrations of both steroids in the epidermis and dermis were significantly higher in normal skin than in scar skin with maximal difference between about 40 and 400 microns, the area of sebaceous gland localization. Cutaneous blood flow in full-thickness skin, assessed by the thallium-201 method, was globally identical in normal and in scar skin. In scar skin, at the level of papillary dermis, a decrease in blood flow due to the thicker viable epidermis and the flat dermoepidermal junction has been shown without implying an accumulation of drug in the epidermis and superficial dermis. Under these conditions, our results clearly demonstrate that the nutritional blood flow does not interfere with the percutaneous absorption of estradiol and progesterone in normal and scar skin. Thus, they confirm the significant contribution of hair follicles and sebaceous glands to drug penetration into the skin and subsequently the systemic circulation.

Animals↗
PubMed1993

Barrier function of human skin and human reconstructed epidermis.

The present study compares the stratum corneum of human skin and human reconstructed epidermis by histological examination as well as by estimation of water permeability. Measurement of the percutaneous absorption of benzoic acid, testosterone, and hydrocortisone revealed that under the same experimental conditions the reconstructed epidermis on de-epidermized dermis exhibits a barrier function with qualitative properties similar to that of normal skin: water and benzoic acid penetrate more rapidly than testosterone and hydrocortisone. Quantitatively, however, reconstructed epidermis is more permeable than normal human skin. This points to an impaired barrier function of the epidermis reconstructed in vitro.

Adult↗
PubMed1993

Site-specific drug delivery to pilosebaceous structures using polymeric microspheres.

In order to improve the therapeutic index of adapalene, a new drug under development for the treatment of acne, site-specific delivery to the hair follicles using 50:50 poly(DL-lactic-co-glycolic acid) microspheres as particulate carriers was investigated in vitro and in vivo. The percutaneous penetration pathway of the microspheres was shown to be dependent on their mean diameter. Thus, after topical application onto hairless rat or human skin, adapalene-loaded microspheres (5-microns diameter) were specifically targeted to the follicular ducts and did not penetrate via the stratum corneum. The in vitro release of adapalene from the microspheres into artificial sebum at 37 degrees C was controlled and faster than the in vivo sebum excretion in humans. Aiming to reduce either the applied dose of drug or the frequency of administration, different formulations of adapalene-loaded microspheres were evaluated in vivo in the rhino mouse model. A dose-related comedolytic activity of topical formulations of adapalene-loaded microspheres was observed in this model. Furthermore, by applying a site-specific drug delivery system (0.1% adapalene) every other day or by administering a 10-fold less concentrated targeted formulation (0.01%) every day, a pharmacological activity equivalent to a daily application of an aqueous gel containing drug crystals (0.1% adapalene) was observed. Since an aqueous gel containing 10% adapalene-loaded microspheres was not irritating in a rabbit skin irritancy test, this formulation was applied onto forearms of human volunteers. Site-specific drug delivery was further evidenced by follicular biopsy. Since an aqueous gel containing 10% adapalene-loaded microspheres was not irritating in a rabbit skin irritancy test, this formulation was applied onto forearms of human volunteers. Site-specific drug delivery was further evidenced by follicular biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adapalene↗
PubMed1993

The vellus hair follicle in acne: hair growth and sebum excretion.

In this study we investigated the activity of the vellus hair follicle in acne. Hair growth and sebum excretion in vellus hair follicles were measured on the forehead and back of men, and on the forehead, cheek, and back of women with acne. Hair growth was assessed by computerized image analysis (phototrichogram), and sebum excretion by computer analysis using Sebutape. In patients with acne, marked differences were revealed when results were compared with recent data from healthy persons. In particular, the mean growth rate of vellus hairs was higher, whereas the percentage of anagen hairs was lower, and the duration of the anagen phase shorter in patients with acne than in healthy individuals. Hair growth and sebum excretion depended significantly (P < 0.01) on the anatomical site (forehead 414 hairs/cm2, 0.053 mm/day, 34%; back 93 hairs/cm2, 0.16 mm/day, 21%). In addition, analysis of hair growth revealed significantly higher values in females than in males for (i) percentage of anagen hairs (P > 0.01), (ii) for vellus hair length (P < 0.05), and (iii) for the duration of the anagen phase (P < 0.01). The present study demonstrates that the activity of the vellus hair follicle is influenced by acne, and vice versa, and therefore its role in the aetiopathogenesis of acne should be reconsidered.

Acne Vulgaris↗
PubMed1993

Penetration and percutaneous absorption of topical retinoids. A review.

Topical retinoids are therapeutically active at low pharmaceutical concentrations, i.e. in essence lack of penetration is not a problem. Thus studies on the cutaneous pharmacokinetics focus on the distribution pattern in the skin, the penetration pathways, the cutaneous metabolism, the systemic body load and the mode of excretion. Two basically different pathways have to be taken into account: the transepidermal pathway, which gives rise to a typical epidermal/dermal concentration gradient and which is certainly part of the mode of action in disorders of keratinization, and the transfollicular pathway, which sheds some light on the activity in follicular disorders like acne. The cutaneous part of the pharmacokinetics of retinoids depends largely on their chemical structure and thus differs. However, common features are relatively high cutaneous concentrations, whereas the spillover to the systemic compartment appears to be slow and small, giving rise to low or hardly detectable bodyloads. Concerning pharmacokinetics topical application of retinoids presents major advantages over systemic medication. They can be targeted to the intended site of action, furthermore systemic toxicity is of much lesser concern.

Administration, Topical↗
PubMed1992

(H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate.

[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1992

Reconstructed human epidermis: a model to study in vitro the barrier function of the skin.

In previous studies, we have shown that architecture and differentiation of human epidermis reconstructed by culturing dissociated keratinocytes on deepidermized dermis at the air-liquid interface resembles very much those of epidermis in vivo. The various types of epidermal layers are present with the appropriate differentiation markers, such as the bullous pemphigoid antigen, suprabasal keratins, involucrin, membrane-bound transglutaminase and filaggrin, positioned almost like in normal epidermis. At the ultrastructural level, heterogeneous keratohyalin granules and intra- and extracellular membrane-coating granules are observed. After 7 days of culture, a compact stratum corneum covers the reconstructed epidermis. In the present work, the barrier function of the reconstructed epidermis was evaluated by measuring fluxes of 3H-water. Our results show that under the various culture conditions tested, the presence of the reconstructed epidermis reduces dramatically the permeability of the deepidermized dermis although the skin equivalent exhibits a higher permeability than normal skin. Conditions that favor terminal differentiation of the keratinocytes such as maintaining the cultures in delipidized serum improve the barrier function. Reduction of the relative humidity has a similar effect, whereas the age of the culture is of no influence. Experiments are in progress to reconstruct human epidermis with a barrier function as efficient as in normal skin.

Culture Techniques↗
PubMed1992

Role of transepidermal and transfollicular routes in percutaneous absorption of hydrocortisone and testosterone: in vivo study in the hairless rat.

The importance of the transappendageal route on percutaneous absorption was assessed in the hairless rat. Skin permeation of two steroids, hydrocortisone and testosterone, was evaluated in vivo on normal and artificially damaged skin in which follicles and sebaceous glands disappeared during healing. The test compounds were applied for periods of 0.5, 2 and 6 h. Thereafter, the stratum corneum reservoir function, the epidermal and dermal distribution profiles, and systemic absorption were determined for both molecules. The results presented here show that the reservoir function of the stratum corneum of appendage-free (scar) skin is more pronounced than that of normal skin, whereas the concentration appearing in the epidermis and dermis was greater in normal skin. Moreover, sebaceous glands probably contribute to the penetration of hydrocortisone and testosterone. We show that the relative importance of the skin appendages depends on the intrinsic physical properties of the molecules tested, and the time of application.

Administration, Topical↗
PubMed1992

[Skin metabolism].

The skin, one of the organs which accounts for the largest proportion of total body weight, was long viewed only as a passive physical barrier between the body from the environment. Over the last ten years, many studies have demonstrated significant metabolic processes in the skin, due in particular to the effects of enzymes which are located mainly in the epidermis. This skin metabolism has a marked effect on percutaneous penetration of xenobiotics. In this review, enzyme activities detected in the skin and their location in the various skin layers are discussed, as well as the different in vitro and in vivo models for studying skin metabolism. Pharmacologic or toxic effects of active ingredients or their metabolites may be associated with the nature and magnitude of transformations of xenobiotics in the skin (first pass effect). The impact of skin metabolism on the effects of topically applied drugs and the factors capable of modulating skin biotransformations are discussed. The main difficulties faced by skin metabolism studies stem from the relatively complex structure of skin and in the low levels of enzymatic activities.

Cytochrome P-450 Enzyme System↗