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  • 1
    Online Resource
    Online Resource
    Stereochemical Aspects of Drug Action and Disposition. (2003)
    Berlin, Heidelberg :Springer Berlin / Heidelberg,
    Details
    Keywords: Chirality. ; Electronic books.
    Type of Medium: Online Resource
    Pages: 1 online resource (454 pages)
    Edition: 1st ed.
    ISBN: 9783642558429
    Series Statement: Handbook of Experimental Pharmacology Series ; v.153
    URL: https://ebookcentral.proquest.com/lib/geomar/detail.action?docID=3090370
    DDC: 572.79999999999995
    Language: English
    Note: Handbook of Experimental Pharmacology Volume 153 -- Stereochemical Aspects of Drug Action and Disposition -- Copyright -- Preface -- List of Contributors -- Contents -- Section I Chemical Aspects -- CHAPTER 1 Recent Developments in Asymmetric Organic Synthesis: Principles and Examples -- CHAPTER 2 Stereoselective Separations: Recent Advances in Capillary Electrophoresis and High-Performance Liquid Chromatography -- CHAPTER 3 Stereochemical Issues in Bioactive Natural Products -- CHAPTER 4 Drug Racemization and Its Significance in Pharmaceutical Research -- CHAPTER 5 Physical Properties and Crystal Structures of Chiral Drugs -- Section II Experimental Pharmacology -- CHAPTER 6 Chiral Recognition in Biochemical Pharmacology: An Overview -- CHAPTER 7 Enantioselectivity in Drug-Receptor Interactions -- CHAPTER 8 Mechanisms of Stereoselective Binding to Functional Proteins -- CHAPTER 9 Stereoselective Drug-Channel Interactions -- CHAPTER 10 Stereoselective Bioactivation and Bioinactivation - Toxicological Aspects -- Section III Drug Absorption, Distribution, Metabolism, Elimination -- CHAPTER 11 Intestinal Drug Transport: Stereochemical Aspects -- CHAPTER 12 Enantioselective Plasma and Tissue Binding -- CHAPTER 13 Stereoselective Drug Metabolism and Drug Interactions -- CHAPTER 14 Metabolic Chiral Inversion of 2-Arylpropionic Acids -- CHAPTER 15 Stereoselective Renal Elimination -- Section IV Implications for Drug Development and Therapy -- CHAPTER 16 Regulatory Requirements for the Development of Chirally Active Drugs -- CHAPTER 17 Improving Clinical Risk/Benefit Through Stereochemistry -- Subject Index.
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  • 2
    Electronic Resource
    Electronic Resource
    Determination of monoureides in biological fluids by high-pressure-liquid-chromatography (1978)
    Springer
    Archives of toxicology 41 (1978), S. 187-193 
    Details
    ISSN: 1432-0738
    Keywords: High-pressure-liquid-chromatography ; Bromisoval ; Carbromal ; Methaqualone ; Hochdruckflüssigchromatographie ; Bromisoval ; Carbromal ; Methaqualon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Eine spezifische und empfindliche Methode zur gleichzeitigen Bestimmung von Bromisoval, Carbromal und Methaqualon wird beschrieben. Sie beruht auf der Anlagerung der Substanzen an Aktivkohle bei pH 11 und anschließener Elution von der Aktivkohle mit einem Lösungsmittelgemisch. Die Auftrennung des Eluates erfolgt mittels Hochdruckflüssigchromatographie auf einer Reverse-Phase (RP 18)-Säule. Als mobile Phase dient ein Acetonitril: Wassergemisch (26 ∶ 74). Der Nachweis der eluierten Komponenten erfolgt mittels UV-Absorption bei 210 nm. Die Methode besitzt eine Empfindlichkeit von 0,05 μg Bromisoval und 0,2 μg Carbromal pro ml Serum. Die Repetierbarkeit und Reproduzierbarkeit ist mit Variationskoeffizienten, die in Abhängigkeit von der Konzentration zwischen ± 3,0 und ± 7,6% liegen, als gut anzusehen. Auch die Genauigkeit der Methode ist mit einem Korrelationskoeffizienten von 0,98 für Bromisoval, 0,99 für Carbromal und 0,989 für Methaqualon gut.
    Notes: Abstract A sensitive and specific method for the simultaneous determination of bromisoval, carbromal, and methaqualone is described. The drugs are adsorbed from serum onto charcoal at pH 11 and eluted from it with organic solvent. The eluate is separated by high-pressure liquid-chromatography on reverse phase (RP 18) column using acetonitrile: water (26 ∶ 74 by volume) as mobile phase. The eluted drugs are detected by uv-absorption at 210 nm. The method is sensitive, specific, precise, and accurate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00354090
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  • 3
    Electronic Resource
    Electronic Resource
    Identification of N2 as a metabolite of acetylhydrazine in the rat (1996)
    Springer
    Archives of toxicology 70 (1996), S. 300-305 
    Details
    ISSN: 1432-0738
    Keywords: Key words Acetylhydrazine ; Isoniazid ; [15N]-Nitrogen ; Laser magnetic resonance spectroscopy ; Cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In the pathogenesis of isoniazid-induced hepatic injury, cytochrome P450-dependent metabolic activation of the metabolite, acetylhydrazine (AcHz), is the crucial step. Exhalation of [14C]-carbon dioxide has previously been used to quantify indirectly this pathway. In contrast, according to the current concept of AcHz bioactivation, molecular nitrogen is produced directly, but has not yet been identified. Here, we measured [15N]-nitrogen and 14CO2 exhalation, after the administration of [15N2]-[14C]-AcHz, in rats. Laser magnetic resonance (LMR) spectroscopy, a new sensitive and specific technique for the measurement of 15N and 14N in gas samples, was used. To demonstrate the involvement of cytochrome P450, rats were treated with phenobarbital (PB) or PB + cobalt(II) chloride (CoCl2) (n=3 in each group). Time-dependent 15N2 exhalation differed significantly between treatment groups (p〈0.001). At 240 min, cumulative exhalation of 15N was 1.92±0.43% (mean±SE) of the dose in the control group, 2.53±0.23% in the PB group, and 1.00±0.15% in the PB+CoCl2 group (p〈0.05 compared to controls, p〈0.01 compared to PB). Cumulative exhalation of 14CO2 in 24 h ranged from 15.1 to 21.9%, with no significant difference between treatment groups. In conclusion, N2 is a metabolite of AcHz. N2 formation reflects the cytochrome P450-mediated activation of AcHz and can be used as an index of this pathway. Generally, LMR spectroscopy is valuable for monitoring any N2-liberating process in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050277
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  • 4
    Electronic Resource
    Electronic Resource
    When good drugs go bad (2007)
    [s.l.] : Nature Publishing Group
    Nature 446 (2007), S. 975-977 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] ...Safety issues can arise throughout the life-history of a drug — from preclinical screening through to clinical trials and, importantly, after the drug is marketed and tested for the first time on the population at large. Although serious adverse drug reactions (SADRs) that can cause ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/446975a
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  • 5
    Electronic Resource
    Electronic Resource
    PHARMACOGENOMICS AND INDIVIDUALIZED DRUG THERAPY (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 119-137 
    Details
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Pharmacogenetics deals with inherited differences in the response to drugs. The best-recognized examples are genetic polymorphisms of drug-metabolizing enzymes, which affect about 30% of all drugs. Loss of function of thiopurine S-methyltransferase (TPMT) results in severe and life-threatening hematopoietic toxicity if patients receive standard doses of mercaptopurine and azathioprine. Gene duplication of cytochrome P4502D6 (CYP2D6), which metabolizes many antidepressants, has been identified as a mechanism of poor response in the treatment of depression. There is also a growing list of genetic polymorphisms in drug targets that have been shown to influence drug response. A major limitation that has heretofore moderated the use of pharmacogenetic testing in the clinical setting is the lack of prospective clinical trials demonstrating that such testing can improve the benefit/risk ratio of drug therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.med.56.082103.104724
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  • 6
    Electronic Resource
    Electronic Resource
    Variability of cyclophosphamide uptake into human bronchial carcinoma: consequences for local bioactivation (2000)
    Springer
    Cancer chemotherapy and pharmacology 45 (2000), S. 63-68 
    Details
    ISSN: 1432-0843
    Keywords: Key words Cyclophosphamide ; Human lung tissue ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The alkylating cytostatic prodrug cyclophosphamide is bioactivated by the human cytochrome P450 enzyme system. Since these enzymes are not only expressed in human liver, but also in extrahepatic tissue, local bioactivation of this drug may play an important role in its antineoplastic effects, e.g., chemotherapy of lung tumors. This would require uptake of significant amounts of cyclophosphamide into tumor tissue, which has not yet been demonstrated. Methods: We used a recently developed, ex vivo isolated, ventilated and perfused human lung model to study cyclophosphamide uptake into bronchial carcinoma and healthy lung tissue. Following a standard lobectomy, lung samples containing the tumor were perfused with buffer containing 2 mM cyclophosphamide for 2 h. Cyclophosphamide concentrations in perfusate and healthy peripheral tissue were measured during the perfusion and in tumors at the end of perfusion. Results: In all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a tissue to perfusate ratio of 0.021. Moreover, in tumor samples, cyclophosphamide concentrations were significantly lower (P 〈 0.05) than in healthy lung tissue and showed pronounced interindividual variability. Median concentrations were 36.8 μg/g (26.9–44.2 μg/g) in healthy tissue and 5.1 μg/g (0.0–26.8 μg/g) in tumor samples. Tumor cyclophosphamide concentrations varied between 0 and 75% of those reached in healthy tissue. Conclusions: Our results indicate that CP tumor concentrations are modulated by factors different from dose and that expression of bioactivating enzymes in human lung or transfection of genes encoding these enzymes into tumor cells does not necessarily lead to local bioactivation of cyclophosphamide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00006745
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  • 7
    Electronic Resource
    Electronic Resource
    Influence of sequential exposure to R-verapamil or B8509-035 on rhodamine 123 accumulation in human lymphoblastoid cell lines (1993)
    Springer
    Cancer chemotherapy and pharmacology 32 (1993), S. 151-155 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Modulators for the reversal of multidrug resistance such as R-verapamil and B8509-035, a dihydropyridine, effectively overcome multidrug resistance in vitro and are currently undergoing clinical trial. One problem with their use is the application protocol; the question as to whether they should be given by continuous administration or in sequential doses in combination with the cytotoxic drugs has to be addressed. Therefore, we examined the influence of the exposure time and the sequence of modulator administration on the active transport of the fluorescent dye rhodamine 123 (R123), a substrate for the P-glycoprotein, in the resistant lymphoblastid cell line VCR1000 and the parental nonresistant cell line CCRFCEM. Our results demonstrate the importance of coadministration of R-verapamil and the cytotoxic agent for the modulation of multidrug resistance, whereas the exposure sequence does not seem to be such an essential parameter in the case of B8509-035. This observation should be considered for the further design of clinical studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685619
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  • 8
    Electronic Resource
    Electronic Resource
    Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism (1999)
    Springer
    Cancer chemotherapy and pharmacology 43 (1999), S. 263-268 
    Details
    ISSN: 1432-0843
    Keywords: Key words Cyclophosphamide ; High dose ; Pharmacokinetics ; Application schedule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. Patients and methods: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [31P]-nuclear magnetic resonance spectroscopy; [31P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/m2 infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d1 and d2. Results: (Data are given as mean values for CD and d1/d2 of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d1 of HD, but significantly increased on d2 of HD (CL: 83 and 78/115 ml/min; P 〈 0.01 for d1 versus d2). The latter was translated into an increase in formation CL of both active (+16.4 ml/min) and inactive metabolites (+17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose (P 〈 0.05 for d1 versus d2 of HD). Conclusions: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050893
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  • 9
    Electronic Resource
    Electronic Resource
    CYP3A genetics in drug metabolism (2001)
    [s.l.] : Nature Publishing Group
    Nature medicine 7 (2001), S. 285-287 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] All living organisms, including humans, are continuously exposed to approximately 10,000 chemicals present in food, drinks and the environment. Many naturally occurring compounds are toxic, such as mold aflatoxins, which are among the most potent carcinogens. Various defense mechanisms have evolved ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/85417
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  • 10
    Electronic Resource
    Electronic Resource
    Identification of the primary gene defect at the cytochrome P 450 CYP2D locus (1990)
    [s.l.] : Nature Publishing Group
    Nature 347 (1990), S. 773-776 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] These conflicting reports could possibly be explained by the limitations of the phenotyping assay used to identify affected FIG. 1 Comparison of nucleotide sequences of DNA encoding functional debrisoquine hydroxylase (dbl) and related cDNAs. The sequence for dbl and variant 'b' are taken ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/347773a0
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