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Lutz Weber

Publications and source records attributed to Lutz Weber.

At least 19 recordsLinked to original sources
PubMed2006

A pseudo-ligand approach to virtual screening.

A virtual screening method is presented that is grounded on a receptor-derived pharmacophore model termed "virtual ligand" or "pseudo-ligand". The model represents an idealized constellation of potential ligand sites that interact with residues of the binding pocket. For rapid virtual screening of compound libraries the potential pharmacophore points of the virtual ligand are encoded as an alignment-free correlation vector, avoiding spatial alignment of pharmacophore features between the pharmacophore query (i.e., the virtual ligand) and the candidate molecule. The method was successfully applied to retrieving factor Xa inhibitors from a Ugi three-component combinatorial library, and yielded high enrichment of actives in a retrospective search for cyclooxygenase-2 (COX-2) inhibitors. The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets.

Antithrombin III↗
PubMed2005

Molecular staging in stage II and III melanoma patients and its effect on long-term survival.

PURPOSE: To assess the prognostic value of serial reverse transcriptase polymerase chain reaction (RT-PCR) -based measurements of tyrosinase mRNA in peripheral blood of stage II and III melanoma patients. PATIENTS AND METHODS: During routine follow-up of American Joint Committee on Cancer stage II and III melanoma patients, serial testing for tyrosinase transcripts in peripheral blood was performed by RT-PCR. The PCR results were compared with the clinical data collected during the follow-up. RESULTS: Over a period of 3 years, 111 patients (78 stage II and 33 stage III patients) were enrolled, and tyrosinase determinations were carried out. The 6-year disease-specific survival probability was 97% for patients always showing negative RT-PCR results and 67% for patients who tested positive at least once. In a Cox proportional hazards model, the prognostic value of sex, age, site of primary tumor, histologic subtype, stage, Breslow's tumor thickness, Clark level, and the time-dependent variable PCR result was assessed. Patients with a positive RT-PCR test had a distinctly higher risk of dying from melanoma, with a hazard ratio of 12.6 (95% CI, 3.4 to 46.3; P < .001). CONCLUSION: Our study shows a strong association between PCR and disease-specific survival time. Detection of tyrosinase mRNA in peripheral blood may be of similar importance for the clinical course of melanoma as the detection of micrometastatic disease in the sentinel lymph node. Whether a combination of these two factors leads to a better definition of the prognosis of melanoma patients is under investigation in current studies.

Adult↗
PubMed2005

Design of selective phenylglycine amide tissue factor/factor VIIa inhibitors.

Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide tissue factor/factor VIIa inhibitors with low nanomolar affinity and good selectivity against other serine proteases of the coagulation cascade were designed, using the guidance of X-ray structural analysis and molecular modelling.

Drug Design↗
PubMed2005

Chemistry for chemical genomics.

New methods and strategies have been developed to design and use small molecules that allow the functional dissection of molecular pathways, cells, and organisms by selective small-molecule ligands or modulators. In this overview, we are focusing on diversity aspects, design methods, and chemical synthesis strategies for the application of small molecules as tools for chemical genomics. Examples for different successful chemical-genomics strategies include the selection of diverse drug-like molecules, target family-focused compound libraries, natural-product chemistry, and diversity-oriented synthesis.

Chemical Engineering↗
PubMed2005

Solitary cutaneous dendritic cell tumor in a child: role of dendritic cell markers for the diagnosis of skin Langerhans cell histiocytosis.

We describe a child with a solitary dendritic cell (DC) tumor positive for S-100 protein, CD1a, and HLA-DR with the clinical and histopathologic features of a so-called solitary variant of congenital self-healing Hashimoto-Pritzker reticulohistiocytosis (CSHRH). CSHRH is a spontaneously regressing, benign form of Langerhans cell histiocytosis (LCH) and was thought to be a histiocytosis consisting of precursor Langerhans cells. In our study the tumor cells did not express CD68, indicating that they represent mature DCs. Because of the negative finding for Langerin, it cannot be assessed whether the tumor consists of terminally mature Langerhans cells that have lost Langerin expression upon maturation or of mature dermal DCs. This case demonstrates that the progress in DC biology necessitates reevaluation of our knowledge of LCH to better understand the different variants of the disease. Therefore the literature on CSHRH is reviewed in light of present knowledge on cutaneous DC immunology.

Dendritic Cells↗
PubMed2004

Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator.

A solution phase parallel synthesis approach was undertaken to rapidly explore the structure-activity relationship of an inhibitor of the Ras/Raf protein interaction identified from a small molecule compound library. Evaluation of the MAPK pathway signaling inhibitory activity of the synthesized analogues as well as their antiproliferative activity and ability to inhibit soft agar growth were performed.

Animals↗
PubMed2004

Immunosuppressive drug monitoring of sirolimus and cyclosporine in pediatric patients.

Sirolimus is primarily used as a rescue agent in pediatric transplant recipients, particularly in cases of cyclosporine or tacrolimus toxicity. Preliminary data indicate a higher apparent oral clearance in younger children (4-10 years of age). Various drug interactions have been described between sirolimus and drugs that are substrates/inhibitors or inducers of CYP3A and the P-glycoprotein transporter. Close monitoring of trough sirolimus blood levels is therefore recommended for pediatric transplant recipients. In de novo adult kidney transplant recipients on triple therapy with cyclosporine, corticosteroids and sirolimus, a therapeutic window of 4-12 microg/l is recommended for sirolimus trough concentrations determined by HPLC or LC/MS-MS. In maintenance adult patients after conversion to a calcineurin inhibitor-free regimen, sirolimus trough concentrations of 5-10 microg/l are proposed in combination with mycophenolate mofetil. These therapeutic ranges may also serve as a guide for pediatric renal transplant recipients. The concept of C2 monitoring still needs to be critically evaluated in pediatric patients. The crucial importance of achieving an adequate cyclosporine exposure early after transplantation has been demonstrated for adult transplant recipients. A cyclosporine concentration taken 2 h after dosing is a good surrogate marker of the AUC0-4h in adults. Various clinical studies have shown that in pediatric patients, the C2 concentration shows a substantially better correlation with cyclosporine exposure compared to the trough level (C0). In an outcome study with pediatric renal transplant recipients, it could be demonstrated that the AUC(0-4h) was a predictor of acute rejection in the first 3 weeks after transplantation, whereas C2 levels showed no significant association. Abbreviated AUC strategies may be preferable for optimization of CsA exposure in pediatric patients.

Absorption↗
PubMed2004

Rat growth plate chondrocytes express low levels of 25-hydroxy-1alpha-hydroxylase.

Long standing disturbances of Vitamin D-metabolism as well as null-mutant animals for 25-hydroxy-1alpha-hydroxylase results in disorganised growth plates. Cultured chondrocytes were shown to be target for the hydroxylated Vitamin D-metabolites 1alpha,25(OH)(2)D(3) and 24,25(OH)(2)D(3). Because studies on production of these metabolites were inconclusive in in vitro systems, the expression of the Vitamin D-system was examined in rat growth plate chondrocytes in vitro as well as ex vivo. Gene expression for 25-hydroxy-1alpha-hydroxylase, 25-hydroxy-24-hydroxylase as well as Vitamin D-receptor and collagen II and X were analysed on mRNA level by RT-PCR and quantitative real-time PCR, on protein level by western blotting and by immunohistochemistry in isolated growth plate chondrocytes or intact growth plates. Compared to UMR or CaCo(2) cells and renal homogenates cultured growth plate chondrocytes expressed low levels of 25-hydroxy-1alpha-hydroxylase mRNA and 25-hydroxy-24-hydroxylase mRNA. The expression of both was modulated by 25(OH)D(3), but 1alpha,25(OH)(2)D(3) affected only 25-hydroxy-24-hydroxylase. These data were confirmed by Western blotting. Immunohistochemistry demonstrated predominant staining for 25-hydroxy-1alpha-hydroxylase in chondrocyte nodules and cells embedded in matrix in vitro. Ex vivo, 25-hydroxy-1alpha-hydroxylase was detected predominantly in late proliferative and hypertrophic zone of the growth plate. In conclusion, growth plate chondrocytes express the key components for a paracrine/autocrine Vitamin D-system.

Animals↗
PubMed2003

Cultured rat growth plate chondrocytes express low levels of 1alpha-hydroxylase.

Growth plate chondrocytes are the target of the hydroxylated vitamin D metabolites 1alpha,25(OH)2D3 and 24,25(OH)2D3. Because studies on the production of these polar metabolites were inconclusive in various in vitro systems, the expression of a potential paracrine/autocrine vitamin D system was examined in primary cultures of rat growth plate chondrocytes using real-time RT-PCR. Compared to UMR cells and renal homogenates primary cultures of growth plate chondrocytes expressed low levels of 25-hydroxy-1alpha-hydroxylase as well as 25-hydroxy-24-hydroxylase. The expression of both is modulated by 25 vitamin D3, but 1alpha,25(OH)2D3 affected only 25-hydroxy-24-hydroxylase. If these findings are confirmed in intact growth plates, the polar vitamin D metabolites could act in a paracrine/autocrine fashion within the growth plate.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2002

Multi-component reactions and evolutionary chemistry.

Multi-component reactions (MCRs) provide a new approach towards the efficient synthesis of diverse compounds and compound libraries. MCRs are evolving from being purely a chemistry curiosity to being recognized as having increasing relevance for drug discovery in terms of lead discovery and optimization. The combination of MCR-type chemistry-planning with evolutionary in silico and in vitro prediction of drug potential or biological properties is a new and powerful tool in drug discovery.

Combinatorial Chemistry Techniques↗
PubMed2002

The role of ultrasound in detection and management of regional disease in melanoma patients.

Melanoma follow-up programs are directed towards early detection of tumor recurrence. Because the majority of first relapses occur in the regional lymph node area, special focus is placed on this region using various techniques in addition to physical examination. During the last several years, particularly ultrasound B-scan has evolved as a technique of major importance for detection of such regional melanoma recurrences. The technique shows high sensitivity and specificity, discriminating regional or subcutaneous melanoma metastases from nonspecific nodes. Furthermore, suspicious findings can be evaluated quickly and reliably by the minimally invasive technique of ultrasound-guided fine-needle aspiration cytology (FNAC). For regional metastases located deeply or close to vulnerable structures, the new method of ultrasound-guided anchor-wire-marking facilitates subsequent surgery. In summary, ultrasound B-scan has become an essential technique in the follow-up of melanoma patients.

Biopsy, Needle↗
PubMed2002

Pharmacokinetics and protein adduct formation of the pharmacologically active acyl glucuronide metabolite of mycophenolic acid in pediatric renal transplant recipients.

The acyl glucuronide metabolite (AcMPAG) of mycophenolic acid (MPA) has been found to possess both immunosuppressive and pro-inflammatory activity in vitro. In this study its pharmacokinetics were determined in pediatric renal transplant recipients receiving cyclosporine, steroids, and mycophenolate mofetil. Twelve-hour concentration-time profiles for AcMPAG, MPA, and the phenolic glucuronide (MPAG) were determined by high-performance liquid chromatography (HPLC) in the initial (1-3 wk; n = 16) and stable (3-12 mo; n = 22) phases after transplantation. In addition, the formation of covalent adducts between AcMPAG and plasma albumin (AcMPAG-Alb) was investigated using Western Blot analysis. AcMPAG-AUC(12h) showed significant (p < 0.05) correlations with MPA-AUC(12h) (r = 0.78) and MPAG-AUC(12h) (r = 0.78). In molar equivalents the median AcMPAG-AUC(12h) was 10.3% (range, 4.6%-45.5%) of MPA-AUC(12h). Values (median [range]) of AcMPAG-AUC(12h) (10.1 [3.30-30.1] mg.h/L), AcMPAG-C(0) (0.48 [0.08-1.43] mg/L), and AcMPAG-C(max) (1.95 [0.88-5.35] mg/L) were significantly (p < 0.05) higher in the stable phase than in the initial phase: 3.54 [2.07-20.0] mg.h/L for AUC(12h); 0.25 [<0.04-0.97] mg/L for C(0), and 1.12 [0.32-2.44] mg/L for C(max). The increases in the AcMPAG pharmacokinetic variables were paralleled by significant increases in the corresponding MPA variables. In addition, a strong negative correlation (r = -0.69; p < 0.05) was found between AcMPAG concentrations and the creatinine clearance. AcMPAG-Alb adducts were detected in all patient samples. They showed considerable interindividual variation and increased significantly with time from the initial phase to the stable phase. AcMPAG-Alb correlated significantly (p < 0.05) with AcMPAG-AUC(12h) (r = 0.70) and plasma albumin (r = 0.40). AcMPAG plasma concentrations are dependent on renal function, MPA disposition, and glucuronidation. The pharmacokinetics of AcMPAG is characterized by broad interindividual variation. In some patients AcMPAG may significantly contribute to the immunosuppression during mycophenolate mofetil therapy. AcMPAG-Alb adduct formation may serve as a marker for extended AcMPAG exposure. The association of AcMPAG with adverse effects must be further investigated.

Administration, Oral↗
PubMed2002

The application of multi-component reactions in drug discovery.

Multi-component reactions (MCRs) enable the facile, automated and high throughput generation of small organic molecules. MCRs have been used to create diversity oriented and biased combinatorial libraries, to accomplish the synthesis of highly complex natural products as well as for the large-scale production of drug candidates. This provides medicinal chemists with a powerful tool to create novel chemical diversity, matching the space of biological targets with relevant chemistry. The discovery of novel MCRs has become an increasingly active area of research, yielding novel chemical scaffolds for drug discovery efforts.

Animals↗
PubMed2002

Micromoulded plastic components.

This review of applications close to the market as well as those on the horizon highlights the benefits of micromoulding technology for cost-effective large-volume production of microstructured plastic components.

Biotechnology↗