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Paul-Georg Germann

Publications and source records attributed to Paul-Georg Germann.

10 recordsLinked to original sources
PubMed2005

Harmonization of immunotoxicity guidelines in the ICH process--pathology considerations from the guideline Committee of the European Society of Toxicological Pathology (ESTP) .

As part of the ICH process of harmonization of testing guidelines for immunotoxicity, the European Society of Toxicologic Pathology (ESTP) has contributed to the scientific discussion on methods and evaluation of immunotoxicity studies with technical and scientific recommendations on toxicologic pathology. The weighing and sampling of immune organs is discussed taking into consideration specifically the value of lymph node weighing and the selection of appropriate lymph nodes for the detection of local and systemic effects. The different techniques of bone marrow preparation are considered for routine and extended investigations. Criteria are given for the gross and histopathological detection of effects in Peyer's patches. For the histopathological evaluation it is strongly recommended that each compartment within the different lymphoid organs is investigated separately and semiquantitatively since this approach has shown to increase the sensitivity and specificity of immunohistopathology.

Animals↗
PubMed2003

Cyclooxygenase-inhibition enhances the effects of rSP-C surfactant therapy in a rat lavage model of acute respiratory distress syndrome (ARDS).

UNLABELLED: The effects of additional i.v. therapy with a cyclooxygenase-inhibitor Eltenac to a recombinant surfactant protein C (rSP-C) based surfactant were investigated in a rat lung lavage model of acute lung injury. Treatment was done at 60 min after the induction of acute lung injury by lavage. The influence of the different treatments were tested with regard to improving oxygenation, histopathological changes (hyaline membrane formation and alveolar influx of neutrophil leukocytes). These effects were further compared to a fixed combination of Eltenac with rSP-C surfactant which was administered intratracheally (i.tr.), 60 min after lavage. To prove that fibrinogen is involved in the formation of hyaline membranes in this animal model confocal microscopy was applied. Furthermore, for selected cases the influence of Eltenac or rSP-C surfactant on fibrinogen leakage was investigated by using confocal microscopy. Results of additional i.v. therapy exhibited an improved oxygenation with rSP-C surfactant, while a high dose of Eltenacalone did not influence oxygenation as compared to untreated controls. Addition of Eltenac lead to improved oxygenation using the low dose of rSP-C surfactant. The rSP-C surfactant prevented further hyaline membrane formation. Furthemore, addition of Eltenac to the low dose of rSP-C surfactant lead to improved hyaline membrane formation at a dose of 100 micromol/kg b.w. Results of combined i.tr. therapy confirmed the results of the additional therapy. Again, rSP-C surfactant improved oxygenation and further hyaline membrane formation, while even the high dose of i.tr. administered Eltenacalone only prevented further hyaline membrane formation. Using the low dose of rSP-C surfactant, combined treatment with Eltenac showed additional effects on oxygenation and inhibition of hyaline membrane formation. The maximum therapeutic effect of combined treatment was achieved at 0.3 mg Eltenac per kg b.w. which is equivalent to approximately 1 micromol. The inflammatory cell infiltration into the lung was not influenced by any of the therapeutic approaches. Confocal microscopy gave evidence that fibrinogen is involved in hyaline membrane formation in this animal model. Furthermore, as was shown by the explorative investigations with confocal microscopy, addition of the cyclooxygenase-inhibitor decreases the diffuse interstitial leakage of fibrinogen into the lung while surfactant monotherapy did not exhibit any influence on the fibrinogen influx into the alveoli. CONCLUSIONS: Confocal microscopy may be an effective method to investigate the connection between fibrinogen leakage and hyaline membrane formation. Effects of additional or combined treatment were superior when compared to each treatment alone leading to the conclusion that a rSP-C surfactant containing a cyclooxygenase-inhibitor, acts synergistically in this animal model of acute lung injury. Lower doses of Eltenac could be used to reach similar effects on oxygenation and prevention of hyaline membrane after combined i.tr. treatment than after additional i.v. treatment together with surfactant. This leads to the conclusion that a fixed combination of rSP-C surfactant and a cyclooxygenase-inhibitor may be an effective treatment. Further testing may be warranted to prove whether this is a promising treatment for patients with acute lung injury.

Acute Disease↗
PubMed2003

Effects of epithelial growth factor receptor (EGFR) kinase inhibitors on genetically reconstituted mouse mammary glands.

UNLABELLED: The aim of the study was to determine the effects of a specific epithelial growth factor Receptor kinase inhibitor (EGFR-KI) and Taxol on tumor growth in a novel tumor model. MATERIAL & METHODS: A genetically engineered tumor model which uses "transgenic" organs in immune competent mice was used. NeuT-transfected immortalized HC11 epithelial cells and primary mouse mammary epithelial cells have been transplanted into the gland-free mammary fat pad of female BALB/c mice. Mammary tumors developed after a latency period of three to four weeks. The mice were thereafter daily orally treated over a 19 or 22-day period with 0, 38, 75, 2 x 75 mg/kg body weight (b.w.) EGFR-KI (n: 7-9 per group) or intravenously with 10 mg/kg b.w. Taxol. After necropsy the histopathological evaluation of the tumors was performed in a coded manner. The proliferation activity of tumor cells was analyzed by laser scanning cytometry (LSC) using anti-Ki67-antibodies. RESULTS: Oral Treatment with EGFR-KI in this transgenic organ model showed clear antitumor efficacy in a dose-dependent manner in the range between 38 and 75 mg/kg b.w. This antiproliferative effect appears to be minimally increased at 75 mg/kg/day twice per day. For all treatments a strong correlation between the biological behavior of the tumor, histopathology and cell proliferation could be established. In contrast, treatment with Taxol showed no significant reduction of tumor growth or cell proliferation in this model. This new transgenic organ model comprising histopathological evaluation and cell proliferation analysis appears to be a suitable test system for drug candidates that affect specific biochemical pathways. It may have greater predictive nature for clinical effects in humans as compared to conventional tumor models because of its c-erb B2 gene overexpression.

Administration, Oral↗
PubMed2002

Combination of low-dose valsartan and enalapril improves endothelial dysfunction and coronary reserve in Nomega-nitro-L-arginine methyl ester-treated spontaneously hypertensive rats.

Combination of nonhypotensive doses of valsartan and enalapril markedly improved survival (+87%) compared with untreated animals (37%) in spontaneously hypertensive rats (SHRs) with endothelial dysfunction. However, the combination had no effect on kidney function, and proteinuria persisted over the 12 weeks of the study. It was hypothesized that the greater survival was due to improvement in endothelial function or coronary vasculature despite blockade of nitric oxide synthase and high blood pressure. Therefore, endothelial function was evaluated in isolated aortic ring and maximal coronary blood flow was studied in isolated perfused SHR hearts (20-24 weeks) treated with -nitro-l-arginine methyl ester (L-NAME) (50 mg/l) for 4 weeks. The animals received vehicle, valsartan 5 mg/kg/d, enalapril 1 mg/kg/d, valsartan 50 mg/kg/d, or the combination valsartan 5 mg/kg/d with enalapril 1 mg/kg/d in drinking water. Normotensive Wistar-Kyoto (WKY) rats were used as control. Blood pressure was measured by telemetry. Histopathology was performed on heart, kidney (hematoxylin-eosin), and aorta (Masson trichrome). L-NAME elevated blood pressure by 50 mm Hg after vehicle (199 +/- 5 mm Hg). Valsartan 50 mg/kg/d completely abolished this increase (150 +/- 4 mm Hg) whereas the valsartan-enalapril combination synergistically decreased blood pressure (-37 mm Hg at 162 +/- 7 mm Hg) compared with monotherapy (valsartan 5 mg/kg/d -10 mm Hg; enalapril 1 mg/kg/d -15 mm Hg). All treatments improved the histopathology, most markedly in those receiving the valsartan-enalapril combination. The severity mean grades for lesions were 2.1, 1.9, 1.7, 1.1, and 0.9 in vehicle-treated SHRs, enalapril 1 mg/kg/d, valsartan 5 mg/kg/d, valsartan 5 or 50 mg/kg/d, and the valsartan-enalapril combination, respectively, compared with 0.02 in WKY rats. Acetylcholine-induced relaxation was significantly greater in treated SHRs than after vehicle (-40% at 0.1 mmol acetylcholine) but the combination induced the maximal relaxation (-85%). The ratio of maximal tension induced by serotonin in rings with and without endothelium was 1.4 and 1.3 in vehicle and valsartan 5 mg/kg/d-treated rats whereas it did not differ from 1 in WKY rats and all other treated groups. The cardiac hypertrophy (+27%) was prevented by valsartan 50 mg/kg/d and the valsartan-enalapril combination. Coronary reserve was significantly increased by valsartan 50 mg/kg/d (+85% at 7.8 +/- 0.7 ml/min/g) and the valsartan-enalapril combination (+42% at 6.0 +/- 0.4 ml/min/g) compared with 4.2 +/- 0.5 (vehicle). This was not different of 8.8 +/- 0.5 (WKYs). Despite the maintenance of a high blood pressure, low-dose valsartan-enalapril significantly improved endothelial function and histopathology and increased coronary reserve in SHRs chronically receiving L-NAME.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Practical aspects of discovery pathology.

Pathologists are uniquely qualified to play a central role in driving drug discovery and development programs by: 1) establishing disease models to assess potential therapies, 2) characterizing modifications in the disease state in response to therapies, 3) characterizing toxicologic mechanisms and responses to drug candidates, and 4) facilitating multidisciplinary efforts to monitor for the clinical occurrence, progression, and reversibility of adverse events. Such nontraditional deployment of resources must, to be viable, produce benefits to the pharmaceutical industry comparable to those of more conventional activities such as delivery of data in nonclinical safety studies. Additionally, benefits must be tangible from standpoints such as time savings or improved quality of research decisions, manifesting as either program acceleration or improved candidate survival.

4-Quinolones↗
PubMedDate not supplied

Laser technologies in toxicopathology.

One of the main concepts in toxicology and risk assessment is the identification of compounds with the least toxicity, gaining increased understanding of the underlying mechanisms of efficacy and toxicity so as to accelerate the early selection of compounds for development. For this purpose, "cutting-edge" technologies, such as flow cytometry (FC), laser scanning cytometry (LSC) and confocal laser scanning microscopy (CLSM), have proved to be valuable tools. FC, LSC and CLSM have been successfully applied in a wide range of areas within toxicology and research including genetics, reproduction, dermatology, pathology and target organ toxicity. The scope of this paper is to give a short overview of the usefulness of the different laser applications. Specific examples of the impact of these technologies will be presented or can be found in the references. Flow cytometry methods have been successfully applied in immunophenotyping, micronuclei scoring, polyploidy determination, apoptosis and cell cycle evaluation, cell proliferation and quantification. A three-parameter FC method for the analysis of testicular toxicity has also been established as an alternative to traditional histopathological methods. This method allows a large number of cells to be analysed in a short time and provides quantitative values to evaluate testicular damage in the rat. Laser scanning cytometry has been used in our unit for rat blood cell immunophenotyping, tumor proliferation, apoptosis and cell cycle analysis on minipig and rat skin and cardiac cells identification. The wide range of applications that can be applied with the LSC shows the enormous potential of this technology in research and development. Confocal laser scanning microscope was used in our laboratory, in collaboration with the research department, to investigate the mechanisms underlying hepatic lesions found in dogs, to detect fibrinogen influx into rat lung, to explore the mechanism of eye toxicity and to quantify dopaminergic fibers in brain sections. Integrating these technologies within discovery pathology allowed us to understand disease processes with respect to their development and subsequent consequences. It contributes to descriptive pathologic diagnostic and allows a productive interaction with research and development. These technologies offer a range of novel applications and have been shown to be useful tools in terms of specificity, sensitivity, reliability, rapidity and quantification. Expertise in cutting-edge technologies, pathology and cell and molecular biology is essential to a successful and flexible interaction across all therapeutic areas in drug discovery.

Animals↗
PubMedDate not supplied

Pheochromocytomas and ganglioneuromas in the aging rats: morphological and immunohistochemical characterization.

We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague-Dawley rats from carcinogenicity studies. Morphologically, benign pheochromocytomas were characterized by monomorphic, small, basophilic cells with almost absence of mitoses. Malignant pheochromocytomas presented a low grade of pleomorphism, higher rate of mitoses, necrosis, infiltrative growth and in 1 case metastases in the lung. Ganglioneuromas were characterized by ganglion and neuron-like cells embedded in an eosinophilic matrix containing neurites, Schwann cells, and scant fibrovascular elements. All pheochromocytomas were strongly immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Subpopulations of chromaffin cells expressed chromogranin A (CGA) positivity. Matrix and Schwann cells were positive for S-100 and for glial fibrillary acidic protein (GFAP). In focal areas of the tumors, ganglion cells and axons were positive for neurofilament proteins (NFP) and synaptophysin. Ganglion cells exhibited peripherin and beta-tubulin. Proliferative activity of the tumors was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67 and the proliferating cell nuclear antigen (PCNA). As expected, cell proliferation indices were much higher in malignant pheochromocytomas than in benign, yet ganglioneuromas remained immunonegative. Considering that Ki-67 antigen is more specific for cell proliferation, it should be regarded as marker of choice for supporting the differential diagnosis between benign and malignant pheochromocytomas.

Adrenal Gland Neoplasms↗