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111.
BACKGROUND: In pharmacodynamic studies with antiplatelet agents, platelets are usually activated in vitro with single agonists (e.g., ADP) solely. We questioned whether differences occur between single and combined stimulation of platelets [involving the major thrombin-receptors, protease-activated receptors (PAR)1 and PAR4], and whether the pharmacodynamic response to common antiplatelet drugs vary when a combined stimulus is applied instead of a single agonist. METHODS: We investigated the influence of different antiplatelet agents (aspirin [500 mg]) in vivo, the P2Y12-antagonist AR-C 69931MX (4 nM) and the GPII/IIIa-antagonist (abciximab ([5 microg/ml] in vitro) on the degranulation response (CD62) and expression of the activated GPIIb/IIIa-receptor (PAC-1) after stimulation with ADP (2 microM), collagen (4 microg/ml), a PAR1-activating peptide (3 microM TRAP) and a PAR4-activating peptide (200 microM AYPGKF) alone or in a combination of each two agonists by flow cytometry in healthy subjects. RESULTS: (1) Combined activation of TRAP with AYPGKF resulted in synergistic CD62 and PAC-1 expression. Only AYPGKF but neither TRAP nor ADP acted synergistically with collagen. (2) AR-C 69931MX inhibited platelet degranulation (CD62) in all inducer combinations with ADP or the combination TRAP with AYPGKF. The effect was considerably smaller or absent for the combination of collagen with a second inducer. (3) Aspirin intake reduced platelet degranulation and PAC-1 expression only for AYPGKF costimulation with collagen. CONCLUSION: Because a variety of different agonists influence platelet activation and its distinct functions at a time, investigations which regard the concert of these agonists might be closer to the in vivo situation and better reflect the pharmacodynamic profile of an antiplatelet agent than using one single inducing agent. 相似文献
112.
Early age of onset in fatal familial insomnia 总被引:2,自引:0,他引:2
Harder A Gregor A Wirth T Kreuz F Schulz-Schaeffer WJ Windl O Plotkin M Amthauer H Neukirch K Kretzschmar HA Kuhlmann T Braas R Hahne HH Jendroska K 《Journal of neurology》2004,251(6):715-724
Abstract.
Fatal familial insomnia (FFI) is a prion disease exhibiting the PRNP D178N/129M genotype. Features of this autosomal dominant illness are progressive insomnia, dysautonomia, myoclonus, cognitive decline and motor signs associated with thalamic nerve cell loss and gliosis. In contrast to the new variant of Creutzfeldt-Jakob disease (vCJD) the onset of FFI is in middle to late adulthood. We report two male patients who belong to a large German FFI kindred. They were examined clinically, and postmortem neuropathological examination was carried out in collaboration with the German reference centre for prion disease. Additionally, the prion protein gene (PRNP) was analysed. To identify further patients with disease onset under 30 years of age a comprehensive literature review was carried out. Two male patients presented with typical symptoms of FFI at the age of 23 and 24 years. In their kindred, the age of onset has never before been under 44 years of age. Our literature review identified five additional early onset cases who died at age 21 to 25 years. In all 22 reviewed FFI families the median manifestation age was 49.5 years. Although phenotypic variability of FFI is common, age of onset under 30 years has been considered to be a hallmark of vCJD with a mean manifestation at 27 years of age. Our findings underline that in addition to vCJD, FFI must be considered in cases of young-onset prion disease. This has considerable impact on clinical management and genetic counselling.* These two authors contributed equally 相似文献
113.
Harder S Graff J Klinkhardt U von Hentig N Walenga JM Watanabe H Osakabe M Breddin HK 《Thrombosis and haemostasis》2004,91(6):1137-1145
Treatment with the direct thrombin inhibitor argatroban (ARG) is often followed by vitamin K-antagonist treatment (VKA). Phenprocoumon (PC) and acenocoumarol (AC) are frequently used in Europe. The standard monitoring test for VKA, pro-thrombin time (PT), is prolonged by direct thrombin inhibitors. Therefore the International Normalized Ratio (INR) obtained during combined treatment does not reflect the true effect of the VKA. A similar interference of the VKA on the activated partial thromboplastin time (aPTT), a monitoring assay for direct thrombin inhibitors, can occur. In 39 healthy volunteers the effect of ARG alone or combined with PC or AC on PT, INR, aPTT, and Ecarin Clotting Time (ECT) was investigated. 6 groups each of 6-8 volunteers received a 5-hour infusion of either 1.0, 2.0 or 3.0 microg/kg/min ARG (days 1, 3, 4 and 5) before initiation of either PC or AC (day 1) and during continued VKA dosing (target INR 2-3). A linear relationship (INR(ARG+VKA) = intercept + slope * INR (VKA alone)) was observed between the INR measured "on" and "off" ARG. The slope depended on the argatroban dose and on the International Sensitivity Index (ISI) of the PT reagent, the steepest slope (i.e., the largest difference between INR (ARG+VKA) and INR (VKA alone)) was seen with the highest ARG dose and the PT reagent with an ISI of 2.13. There was a close correlation between plasma levels of ARG and aPTT or ECT. Under VKA the ARG-aPTT relationship indicated an increased sensitivity of the aPTT to ARG, VKA treatment had no effect on the prolongation of the ECT induced by argatroban. In conclusion, ARG at doses up to 2 microg/kg/min can be discontinued at an INR of 4.0 on combined therapy with VKA, as this would correspond to an INR between 2.2 and 3.7 for the VKA. If it is necessary to monitor ARG in the critical transition period, the ECT which is not influenced by VKA can be used as an alternative to the aPTT. 相似文献
114.
Niederer C Behra R Harder A Schwarzenbach RP Escher BI 《Environmental toxicology and chemistry / SETAC》2004,23(3):697-704
Reactive electrophilic chemicals, such as reactive organochlorine compounds or epoxides, react specifically with a broad spectrum of nucleophilic biomolecules, including proteins and DNA. Conventional toxicity tests for algae, involving the observation of growth inhibition, i.e., the inhibition of cell multiplication, after several days, yield unreliable information for risk assessment because reactive compounds hydrolyze to different extents during the exposure period. The diversity of their modes of toxic action further complicates effect assessment and calls for methods yielding additional information on the mechanisms of toxicity. One of the primary targets of reactive chemicals in cells is the tripeptide glutathione (GSH), which is important for detoxification but can also be regarded as a toxicity sensor because changes in glutathione levels indicate stress. A vital system for algae is the photosynthetic system, which is indirectly affected by reactive chemicals. The test systems developed in this study for the assessment of reactive toxicity toward algae were therefore based not only on nonspecific toxicity indicators like growth inhibition but also on indicators for disturbance of photosynthesis (inhibition of photosystem II quantum yield) and glutathione metabolism. The application of the developed test systems on Scenedesmus vacuolatus after short-term exposure of 2 h showed that these tests can be used as fast screening tests for algal toxicity and in mode-of-action-based test batteries. 相似文献
115.
Klingebiel R Djamchidi C Harder A Lehmann R Jahnke V 《ORL; journal for oto-rhino-laryngology and its related specialties》2002,64(3):223-225
Neural tissue-derived facial nerve tumours usually present as neurinomas. We describe the extremely rare occurrence of a histologically verified neurofibroma primarily arising in the mastoid segment of the facial canal in a patient not fulfilling diagnostic criteria for neurofibromatosis. The tumour showed evidence of perineural growth into the jugular foramen, as suggested by cross-sectional imaging and intraoperative findings. 相似文献
116.
117.
Harder A 《Parasitology research》2002,88(5):395-397
The chemotherapy of schistosomiasis has improved greatly in the last few decades. There are three drugs available: metrifonate (active against Schistosoma haematobium), oxamniquine (active against Schistosoma mansoni) as narrow spectrum drugs and praziquantel, which is effective against all important adult schistosome species and their immature stages, as the drug of choice. 相似文献
118.
Oertli D Marti WR Zajac P Noppen C Kocher T Padovan E Adamina M Schumacher R Harder F Heberer M Spagnoli GC 《Human gene therapy》2002,13(4):569-575
A specific cellular immune response directed against a panel of three defined tumor-associated antigen (TAA) epitopes was induced in metastatic melanoma patients by a prime-boost strategy taking advantage of an innovative recombinant vaccinia virus as evaluated by quantitative assessment of cytotoxic T lymphocytes (CTLs) with corresponding specificity. The immunization protocol consisted of the administration of psoralen-UV-treated and replication-incompetent recombinant vaccinia virus encoding the three immunodominant HLA-A*0201-restricted epitopes Melan-A(27-35), gp100(280-288), and tyrosinase(1-9) together with two costimulatory molecules, B7.1 and B7.2, in the context of systemic granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment. Boosts were subsequently applied with corresponding synthetic nonapeptides and GM-CSF. Specific CTL induction was assessed by tetramer staining and CTL precursor (CTLp) frequency evaluation. Within 12 days of injection of the recombinant vector, cytotoxic T cell responses specific for engineered epitopes were detectable in three of three patients. During the vaccination treatment, antigen-specific CTLp frequencies exceeding 1:10,000 peripheral CD8(+) T cells could be observed. Tetramer staining also revealed significant increases in specific CD8(+) T cell numbers. We conclude that active specific antitumor vaccination can raise a concurrent and specific cellular immune response against a panel of molecularly defined antigens, thereby increasing the chance of an immune hit against neoplastic cells with heterogeneous antigen expression. Data from this study emphasize the potency of a recombinant vaccinia virus vector encoding multiple minigenes and costimulatory molecules in the context of exogenously administered GM-CSF. Clinical effectiveness of this immunologically active protocol should therefore be explored in appropriately selected groups of patients. 相似文献
119.
Harder A Schmitt-Wrede HP Krücken J Marinovski P Wunderlich F Willson J Amliwala K Holden-Dye L Walker R 《International journal of antimicrobial agents》2003,22(3):318-331
There are three major classes of anthelmintics for veterinary use: the benzimidazoles/prebenzimidazoles, the tetrahydropyrimidines/imidazothiazoles, and the macrocyclic lactones. In nematodes, there are five targets for the existing anthelmintics: the nicotinergic acetylcholine receptor which is the target of tetrahydropyrimidines/imidazothiazoles and indirectly that of the acetylcholineesterase inhibitors; the GABA receptor which is the target of piperazine, the glutamate-gated chloride channel as the target of the macrocyclic lactones, and beta-tubulin as the target of prebenzimidazoles/benzimidazoles. All these anthelmintics are now in serious danger because of the worldwide spread of resistant nematodes in sheep, cattle, horses and pigs. The class of cyclooctadepsipeptides has entered the scene of anthelmintic research in the early 1990s. PF1022A, the first anthelmintically active member, is a natural compound from the fungus Mycelia sterilia that belongs to the microflora of the leaves of the Camellia japonica. PF1022A contains 4 N-Methyl-L-leucines, 2 D-lactic acids and 2-D-phenyllactic acids arranged as a cyclic octadepsipeptide with an alternating L-D-L-configuration. Emodepside is a semisynthetic derivative of PF1022A with a morpholine ring at each of the two D-phenyllactic acids in para position. The anthelmintic activity is directed against gastrointestinal nematodes in chicken, mice, rats, meriones, dogs, cats, sheep, cattle and horses. Moreover, emodepside is active against Trichinella spiralis larvae in muscles, microfilariae and preadult filariae and Dictyocaulus viviparus. PF1022A and emodepside are fully effective against benzimidazole-, levamisole or ivermectin-resistant nematodes in sheep and cattle. In Ascaris suum both cyclooctadepsipeptides lead to paralysis indicating a neuropharmacological action of these compounds. Using a PF1022A-ligand immunoscreening of a cDNA library from Haemonchus contortus a cDNA clone of 3569 base pairs could be identified. This clone codes for a novel 110 kDa heptahelical transmembrane receptor, named HC110R. Database- and phylogenetic analysis reveals that this receptor is a homolog to B0457.1 from Caenorhabditis elegans and has significant similarity to latrophilins from human, cattle and rat. HC110R is located in the plasma membrane and in lysosomes and endosomes. Alpha-latrotoxin, the poison of the black widow spider, binds at a 54 kDa aminoterminal fragment of HC110R. After binding a Ca2+-influx into HEK293 cells is induced which can be blocked by EGTA, Cd2+ or nifedipin. PF1022A or emodepside also bind to this 54 kDa aminoterminal region of HC110R and interact with the functional responses of alpha-latrotoxin. In C. elegans antibodies against the C-or N-terminus of HC110R bind to the B0457.1 protein located in the pharynx. Electrophysiological studies reveal that emodepside inhibits pharyngeal pumping of the nematodes in a concentration dependent way with an IC(50) value of about 4 nM. Thus, it is tempting to speculate that emodepside exerts its action on nematodes via a latrophilin-like receptor which might have an important regulatory function on pharyngeal pumping. 相似文献
120.
The situation regarding the treatment of human Giardia and Trichomonas infections and the intestinal and tissue stages of Entamoeba histolytica with metronidazole and other 5-nitroimidazoles is currently satisfactory (Table 1; Mehlhorn 2000). Following correct and rapid diagnosis, the parasites are eliminated reliably and completely. The situation in cases of infection with Acanthamoeba (often involving the eyes) or with Naegleria (often involving the brain) is serious, however. In both cases, there is no drug of choice available. Treatment consists of relieving the symptoms and/or preventing local degeneration. 相似文献