Tolerance of fondaparinux in a patient allergic to heparins and other glycosaminoglycans.
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Anticoagulants↗
Biomedical subjects
Roland Kaufmann
Publications and source records attributed to Roland Kaufmann.
Occlusive treatment of chronic hand dermatitis with pimecrolimus cream 1% results in low systemic exposure, is well tolerated, safe, and effective. An open study.
BACKGROUND: Pimecrolimus cream 1% (Elidel, SDZ ASM 981) is a novel, non-steroid inflammatory cytokine inhibitor, effective in the treatment of atopic dermatitis. Here, we evaluate the treatment of chronic hand dermatitis with pimecrolimus cream 1%. OBJECTIVES: To determine pimecrolimus blood concentrations, and evaluate the safety, tolerability and efficacy following application of pimecrolimus cream 1% to subjects with chronic hand dermatitis. METHOD: In this open-label, multiple-topical-dose, non-controlled, pharmacokinetic study, pimecrolimus cream 1% was applied twice daily to dorsal and palmar areas (affected and unaffected) of both hands. Evening applications (except day 8) were immediately followed by overnight occlusion (> or =6 h). Full pharmacokinetic profile (days 1, 8 and 22), trough concentrations (days 3 and 15), physical examinations, laboratory measurements and adverse events were recorded. Efficacy was assessed via Investigators' Global Assessment (IGA), total key signs and symptoms and the subject's overall self-assessment. RESULTS: Twelve patients completed the study. The majority of pimecrolimus blood concentrations (73.6%) remained below the limit of quantitation (0.1 ng/ml). The maximum concentration observed was 0.91 ng/ml and the maximum area under the concentration-time curve from 0-12 h post dose was 7.6 ng.h/ml. Treatment was well tolerated locally and systemically. No serious adverse events occurred; 4/13 subjects showed a total of 6 adverse events at the application site: burning (n=4), and pruritus (n=2). No clinically relevant or drug-related changes were observed. Clear efficacy of the treatment was shown by all 3 assessment methods. Disease state at day 22 had improved in 11 (85%) subjects compared with baseline (IGA). CONCLUSION: Twice daily topical treatment of moderate to severe chronic hand dermatitis with pimecrolimus cream 1% results in low pimecrolimus blood levels, is well tolerated, safe, and effective.
Administration, Topical↗
Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host disease.
Graft versus host disease (GVHD) is an important problem following allogenic bone marrow transplantation (BMT). The beneficial effects of photochemotherapy with psoralens plus UVA irradiation (PUVA) have been described repeatedly; however, PUVA is limited by a wide range of unwanted effects. A novel improved form of UV-B phototherapy, narrowband UV-B, has been proven to be very effective in T-cell mediated dermatoses. Therefore, we investigated the effect of narrowband UV-B phototherapy (5 times per week) in 10 patients with cutaneous GVHD (grade 2-3) resistant to standard immunosuppressive drugs. It was tolerated well by all patients, and no side effects were observed. Skin lesions showed complete clearance in 7 out of 10 patients within 3 to 5 weeks. 3 patients showed significant improvement of GVHD. We suggest that narrowband UV-B phototherapy is a nonaggressive treatment that may benefit patients with cutaneous GVHD who already take high doses of immunosuppressive drugs.
Adult↗
The responsiveness of human V delta 1 gamma delta T cells to Borrelia burgdorferi is largely restricted to synovial-fluid cells from patients with Lyme arthritis.
It has been shown that human gamma delta T cells expressing the V delta 1 T cell receptor (TCR) respond to the spirochete Borrelia burgdorferi. Lysates of 3 Borrelia genospecies triggered the proliferation of peripheral-blood mononuclear cells not only from patients with skin manifestations of Borrelia infection and from patients with Lyme arthritis but also from healthy donors. However, with the exception of 1 patient with Lyme arthritis, no selective expansion of V delta 1-expressing gamma delta T cells was induced. In contrast, synovial-fluid mononuclear cells (SFMC) from 3 of 5 patients with Lyme arthritis responded with a selective outgrowth of V delta 1 gamma delta T cells. V delta 1 gamma delta T cell lines established from SFMC coexpressed various TCR V gamma chains, although V gamma 8 was preferentially used. Thus, the responsiveness to Borrelia antigens is not a general property of V delta 1-expressing gamma delta T cells but is largely restricted to V delta 1 gamma delta T cells recruited into the inflamed tissue.
Adolescent↗
Challenging cases and diagnostic dilemmas: case 3. Positron emission tomography scan mimicking lymph node metastases in a high-risk melanoma patient.
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Adult↗
Expression of the thrombin receptor PAR-1 correlates with tumour cell differentiation of pancreatic adenocarcinoma in vitro.
Patients with pancreatic cancer frequently suffer from thrombosis due to excess thrombin generation. Yet, the effects of thrombin on pancreatic cancer are still poorly understood. The thrombin receptor PAR-1 is responsible for cellular effects of thrombin. PAR-1 plays an important role in the progression of different solid tumours in vitro. In breast cancer the level of PAR-1 expression correlates with invasiveness. Our aim was to correlate PAR-1 mRNA and protein expression level with the grade of differentiation of pancreatic tissue and cancer cell lines. PAR-1 protein was not detectable in the epithelium of healthy pancreas. Analysis of PAR-1 protein expression by immunofluorescence staining of pancreatic cancer cell lines revealed a correlation to the grade of differentiation. Quantitative analysis of PAR-1 protein expression by Western Blot analysis confirmed these observations. Analysis of PAR-1 mRNA expression showed low levels in healthy pancreas compared to pancreatic cancer tissue and the pancreatic cancer cell line MIA PaCa-2. The level of PAR-1 mRNA differed up to 25 fold between the respective pancreatic cancer cell lines. The eminent differences in PAR-1 expression, both protein and mRNA, between healthy pancreatic tissue and pancreatic cancer in vivo and in vitro emphasise the putative role of PAR-1 in pancreatic cancer progression.
Adenocarcinoma↗
Allergic contact dermatitis from black cumin (Nigella sativa) oil-containing ointment.
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Adult↗
Reproducible identification of the causative drug of a fixed drug eruption by oral provocation and lesional patch testing.
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Anti-Inflammatory Agents, Non-Steroidal↗
Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease.
BACKGROUND: The maximum thickness of a primary malignant melanoma as measured by Breslow's method is currently the most important prognostic factor. However, some thin melanomas (< or= 0.75 mm), which should have an excellent prognosis according to Breslow, can be lethal due to their ability to metastasize. METHODS: In our study, thin malignant melanomas (< or= 0.75 mm) from 36 patients were analyzed with immunohistochemical techniques using monoclonal antibodies directed against PLK1 and Ki-67. The immunoreactivity of 22 melanomas which developed metastases within 5 years of follow-up was compared with a group of 14 non-metastasized melanomas. Two independent investigators evaluated stained sections. Differences of PLK1 and Ki-67 indices between melanomas with and without metastases were tested statistically using the Mann-Whitney U-test. RESULTS: Malignant melanomas with metastases expressed PLK1 at markedly elevated levels compared to melanomas without metastases (median, 60.00% vs. 37.98%; p = 0.000053). The difference of the Ki-67 index between both groups was not significant (median, 6.35% vs. 4.53%; p = 0.150473). CONCLUSIONS: Our results suggest that PLK1 expression in thin melanomas is a reliable marker to identify patients at high risk for metastases.
Cell Cycle Proteins↗
Distinct TCR delta repertoires are present in the cutaneous lesions and inflamed duodenum of patients with dermatitis herpetiformis.
Intraepithelial gammadelta T cells are increased in the inflamed small bowel and are also found in increased numbers in cutaneous lesions from patients with dermatitis herpetiformis (DH). Thus, these cells might play an important role in the pathogenesis of the disease. We investigated the T-cell receptor (TCR) delta repertoire in involved and non-involved skin and compared it with the TCR delta repertoire of the inflamed duodenum and peripheral blood of the same patients. An identical TCR delta repertoire in the small bowel and in the cutaneous lesions would suggest a migration of antigen-specific gammadelta T cells from the intestine to the skin which cross-react with cutaneous antigens. T-cell receptor DV1-DV3 transcripts were amplified by reverse transcriptase (RT)-PCR and analyzed by complementarity determining region 3 (CDR3) size spectratyping and nucleotide sequencing. Our results indicate that the cutaneous TCR delta repertoires were oligoclonal and identical dominant gammadelta T-cell clones were present in the involved and non-involved skin. Furthermore, the TCR delta repertoire of the skin was distinct from that in the small bowel. The peripheral blood exhibited a restricted TCR delta repertoire, which differed from that in the intestine and skin. Thus, cutaneous gammadelta T cells are not specifically expanded within the involved skin and are unlikely to be derived from the inflamed duodenum.
Amino Acid Sequence↗
Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation.
Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.
Animals↗
Spatial distribution of 8-methoxypsoralen penetration into human skin after systemic or topical administration.
AIMS: Photochemotherapy employing psoralens combined with UVA irradiation (PUVA) is a standard therapy for a variety of dermatoses. Psoralens can be administered orally or topically in the form of bath or cream preparations. Recommendations for the time of UVA irradiation are mainly based on the time course of minimal phototoxic doses. However, the time course and depth of skin penetration of psoralens is not well characterized. METHODS: We assessed the time course of 8-MOP concentrations in horizontal epidermal and dermal skin sections in 10 patients undergoing oral (n = 3), cream (n = 4) and bath (n = 3) PUVA therapy. Punch biopsies (4 mm) were taken from "healthy" skin sites. A highly sensitive LC-MS-MS method was employed for 8-MOP analysis. RESULTS: Epidermal concentrations following cream or bath were highest at the end of the application period (time zero) when irradiation is performed. At this time, 8-MOP cream provided significantly higher epidermal concentrations (mean +/- s.e. mean 128.0 +/- 22.6 pg mm-3; 95% CI: 77.6, 178.4) than oral 8-MOP (27.0 +/- 25.3 pg mm-3; 95% CI: 29.3, 83.3 at 1 h; P = 0.025). Conversely, concentrations in the papillary dermis were significantly higher with oral 8-MOP (20.2 +/- 3.1 and 16.2 +/- 2.2 pg mm-3 at 1 and 2 h, respectively) than with 8-MOP cream (7.1 +/- 2.8 and 8.4 +/- 2.0 pg mm-3 time zero and 0.5 h, respectively; P = 0.020 and 0.045, respectively) or bath (8.8 +/- 3.1 and 7.7 +/- 2.2 pg mm-3; P = 0.050 and 0.039, respectively). The observed time courses of 8-MOP concentrations correspond to time courses of photosensitivity found previously with the different treatment modalities. CONCLUSIONS: The higher epidermal 8-MOP concentrations found after topical 8-MOP may explain the lower UVA doses needed with the topical route. These results suggest that topical 8-MOP may be superior in patients where the pathology is localized in the epidermis. In sclerosing diseases, which mainly affect the dermis oral PUVA might be advantageous because dermal concentrations are highest with this route of administration.
Administration, Cutaneous↗
Time course of 8-methoxypsoralen concentrations in skin and plasma after topical (bath and cream) and oral administration of 8-methoxypsoralen.
BACKGROUND: The combination of 8-methoxypsoralen with ultraviolet A exposure (PUVA therapy) is a standard treatment for a variety of dermatoses. The following three variants have been described: oral, bath, or cream PUVA. To achieve optimal therapeutic effects, ultraviolet A irradiation should be performed at the time of maximum photosensitivity, that is, at the time of maximum 8-methoxypsoralen tissue concentrations. METHODS: To further specify this point of time, we assessed the concentration-time courses of 8-methoxypsoralen in the skin after oral, bath, and cream administration of 8-methoxypsoralen in a 3-way crossover microdialysis study of 8 healthy subjects. RESULTS: Tissue concentrations after oral administration of 0.6 or 1 mg/kg 8-methoxypsoralen were low (peak plasma concentration range, 1.7-6.6 ng/ml) compared with topical administration for which maximum concentrations of 200 to 520 ng/ml and 720 to 970 ng/ml were achieved with 0.1% 8-methoxypsoralen cream and 3 mg/L 8-methoxypsoralen bath, respectively. Plasma concentrations after oral 8-methoxypsoralen, however, were up to 1000-fold higher than those found after topical application. With both topical applications, the tissue peak concentration uniformly occurred in the first 20 minutes after the end of the application time. In contrast, the time to reach the tissue peak concentration after oral administration ranged from 1 to 4 hours. CONCLUSIONS: The time course of tissue concentrations corresponds closely with the time course of minimal phototoxic doses found in previous studies. Because tissue concentrations after topical administration of 8-methoxypsoralen (bath and cream) were high compared with plasma concentrations and because they were less variable and occurred at better predictable time points than those after oral administration, we suggest that topical PUVA is superior to systemic PUVA, at least from a pharmacokinetic point of view.
Administration, Oral↗
Sweet's syndrome as initial presentation of diffuse large B-cell lymphoma.
We here report an uncommon association of Sweet's syndrome with non-Hodgkin lymphoma, in which the skin symptoms led to a diagnosis of the underlying disease. Association with the disease was implied by resolution of skin lesions during chemotherapy and reappearance of skin symptoms after renewed progression of the non-Hodgkin lymphoma.
Fatal Outcome↗
Mycosis-fungoides-type cutaneous T cell lymphoma of the hands and soles: a variant causing delay in diagnosis and adequate treatment of patients with palmoplantar eczema.
BACKGROUND: The etiopathology of chronic eczematous lesions of the palms and/or soles remains elusive in a considerable proportion of patients. Accumulating evidence suggests that a rare variant of mycosis fungoides (MF)-type cutaneous T cell lymphoma (CTCL) restricted to the palms and/or soles may mimic common palmoplantar dermatoses. OBJECTIVE: In the present study, we analyzed the clinical and histological characteristics of 3 adult patients with preexisting nonclassified chronic palmoplantar eczema poorly responding to standard therapies. Palmar and/or plantar MF was eventually diagnosed. METHODS: The course of the disease, response to previous therapies and dermatological features are described, results of histochemical and immunohistochemical analyses are reported, including T cell receptor gamma gene rearrangement where obtainable. RESULTS: Onset of cutaneous lesions with broad clinical variation was experienced 2-10 years prior to diagnosis; conventional therapies led to short-time or partial remission only; except for 1 patient, the epidermotropic infiltrate was predominantly composed of CD4-positive cells; topical photochemotherapy seems to result in more durable responses. CONCLUSION: As therapeutic strategies for this disease variant differ from symptomatic standard treatment regimens, awareness of MF-type CTCL as a relevant differential diagnosis of palmoplantar eczema should be expanded to prevent delay in diagnosis and adequate therapy.
Aged↗
Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model.
There is increasing evidence that bacterial superantigens contribute to inflammation and T cell responses in psoriasis. Psoriatic inflammation entails a complex series of inductive and effector processes that require the regulated expression of various proinflammatory genes, many of which require NF-kappa B for maximal trans-activation. PS-519 is a potent and selective proteasome inhibitor based upon the naturally occurring compound lactacystin, which inhibits NF-kappa B activation by blocking the degradation of its inhibitory protein I kappa B. We report that proteasome inhibition by PS-519 reduces superantigen-mediated T cell-activation in vitro and in vivo. Proliferation was inhibited along with the expression of very early (CD69), early (CD25), and late T cell (HLA-DR) activation molecules. Moreover, expression of E-selectin ligands relevant to dermal T cell homing was reduced, as was E-selectin binding in vitro. Finally, PS-519 proved to be therapeutically effective in a SCID-hu xenogeneic psoriasis transplantation model. We conclude that inhibition of the proteasome, e.g., by PS-519, is a promising means to treat T cell-mediated disorders such as psoriasis.
Acetylcysteine↗
Characterization of pepsinogen C as a potential biomarker for gastric cancer using a histo-proteomic approach.
We analyzed 74 cryostat sections of central gastric tumor, tumor margin, and normal gastric epithelium using ProteinChip Arrays and SELDI-TOF MS. One peak was significantly down-regulated in tumor tissue (P = 1.43 x 10(-6)) and identified as pepsinogen C using MS/MS analysis and immunodepletion. This signal was further characterized by immunohistochemistry. This work demonstrates that differentially expressed signals can be identified and assessed using a proteomic approach comprising tissue-microdissection, protein profiling, and immunohistochemistry.
Biomarkers↗
Low systemic absorption and good tolerability of pimecrolimus, administered as 1% cream (Elidel) in infants with atopic dermatitis--a multicenter, 3-week, open-label study.
Pimecrolimus cream 1%, a nonsteroid inhibitor of inflammatory cytokines, offers an alternative to corticosteroids in the treatment of atopic dermatitis. Here we evaluate pimecrolimus blood concentrations and tolerability to pimecrolimus cream 1% in 22 infants below 2 years of age with atopic dermatitis (10-92% body surface area affected at baseline). Efficacy was assessed as a secondary objective. Pimecrolimus cream 1% was applied twice daily for 3 weeks. Blood concentrations were low, typically (96% of total 100 concentrations measured) below 2 ng/mL, the majority (71%) remaining below 0.5 ng/mL. The highest concentration observed was 2.26 ng/mL. At steady state, there was no indication of accumulation. Pimecrolimus was well tolerated locally and systemically, with no serious adverse events recorded. Most adverse events recorded (35 in 17/22 patients) were typical of the young pediatric population studied, of mild to moderate severity, and not considered to be study-medication related, with the exception of four local adverse effects limited to the site of cream application. No clinically relevant change was observed in physical examination, vital signs, or laboratory safety parameters. A rapid onset of therapeutic effect was observed within the first four days of treatment. Pimecrolimus cream 1% is well tolerated in infants 3 to 23 months of age treated for 3 weeks, and results in minimal systemic exposure.
Administration, Topical↗