Biomedical subjects

Lutz Weber

Publications and source records attributed to Lutz Weber.

7 recordsLinked to original sources

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↗

PubMed2001

The IKK-2/Ikappa Balpha /NF-kappa B pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts. A critical link to dermatitis in Ikappa Balpha -deficient mice.

Tumor necrosis factor (TNF)-alpha-induced phosphorylation of the IkappaB proteins by the IkappaB kinase (IKK) complex containing IKK-2 and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation, resulting in the stimulation of a variety of pro-inflammatory target genes. The C-C chemokine eotaxin-1 is a potent chemoattractant for eosinophils and Th2 lymphocytes, may play an important role in the pathogenesis of atopic dermatitis, and acts via binding to its receptor CCR3. To investigate the role of NF-kappaB signaling in the regulation of these genes, we stably expressed a transdominant mutant of IkappaBalpha and a constitutively active mutant of IKK-2 in mouse NIH3T3 fibroblasts. The transdominant IkappaBalpha mutant completely inhibited TNF-alpha-mediated induction of both eotaxin-1 and CCR3, whereas expression of constitutively active IKK-2 was sufficient to drive almost full expression of these two genes in the absence of TNF-alpha. Moreover, we observed elevated expression levels of CCR3 and eotaxin-1 protein levels in the skin of IkappaBalpha-deficient mice characterized by a widespread dermatitis. Finally, using dermal fibroblasts derived from IkappaBalpha-deficient mice, we observed elevated basal expression, enhanced inducibility by TNF-alpha, and attenuated down-regulation upon TNF-alpha withdrawal of both CCR3 and eotaxin-1 mRNA levels. These results demonstrate that the IKK-2/IkappaBalpha/NF-kappaB pathway plays a critical role for CCR3 and eotaxin-1 expression in fibroblasts and suggests a critical link to the pathogenesis of atopic dermatitis.

3T3 Cells↗