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  • 11
    Electronic Resource
    Electronic Resource
    [s.l.] : Macmillian Magazines Ltd.
    Nature 402 (1999), S. 313-320 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PI3Ks are dual-specificity enzymes with a lipid kinase activity which ...
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  • 12
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 357 (1992), S. 85-89 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] **************We have described procedures for the preparation of crystals of a complex of HIV-1 reverse transcriptase, an Fab fragment, and DNA16. The same crystal form can be grown without DNA. We used a 19-base strand paired with an 18-base strand (19/18) dsDNA with a one-base overhang as a ...
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  • 13
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 380 (1996), S. 595-602 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Mammalian phosphoinositide-specific phospholipase C enzymes (PI-PLC) act as signal transducers that generate two second messengers, inositol-l,4,5-trisphosphate and diacylglycerol. The 2.4-Å structure of phospholipase Cδ1 reveals a multidomain protein incorporating modules shared by ...
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  • 14
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature structural biology 3 (1996), S. 788-795 
    ISSN: 1072-8368
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] The structure of the PH-domain truncated core of rat phosphoinositide-specific phospholipase C-δ1 has been determined at 2.4 Å resolution and compared to the structure previously determined in a different crystal form. The stereochemical relationship between the EF, catalytic, and C2 ...
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  • 15
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 449 (2007), S. 735-739 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The AAA+ ATPases are essential for various activities such as membrane trafficking, organelle biogenesis, DNA replication, intracellular locomotion, cytoskeletal remodelling, protein folding and proteolysis. The AAA ATPase Vps4, which is central to endosomal traffic to lysosomes, retroviral ...
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  • 16
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1573-8744
    Keywords: triamterene ; sulfate conjugate ; protein binding ; blood/plasma ratio ; renal clearance ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic profiles of triamterene and hydroxytriamterene sulfuric acid ester, the major metabolite of triamterene, were studied in six normal male volunteers using a newly developed specific HPLC analytical method. Following a 100 mg oral dose of triamterene, the plasma concentration time course of the sulfate conjugate parallels that of triamterene in all subjects, but concentrations of the metabolite were more than 10 times higher than unchanged triamterene concentrations at identical sampling times. Interestingly, the renal clearance of the sulfate conjugate was less than that of triamterene. These characteristic features of triamterene disposition were fitted to a compartment model incorporating a first-pass metabolic process. Unbound fractions of triamterene and metabolite in plasma were 0.39 and 0.10 (mean of 6 subjects), respectively. The low unbound fraction of the metabolite in plasma most probably accounts for the low renal clearance of the sulfate conjugate as compared with triamterene.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1573-8744
    Keywords: nitroglycerin ; dinitrate nitroglycerin metabolites ; end-product inhibition ; saturable binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Evaluation of the pharmacokinetics of nitroglycerin has been hindered in the past by the lack of specific and sensitive analytical procedures, and the unavailability of parenteral nitroglycerin and infusion sets which did not adsorb nitroglycerin. The purpose for this present study was to determine the pharmacokinetic parameters of nitroglycerin and the dinitrate metabolites after multiple intravenous infusions of nitroglycerin in healthy volunteers. Six volunteers received variable infusion rates of nitroglycerin. Generally, at 0, 40, 80, and 120 min, the infusion rates were adjusted to 10, 20, 40, and 10 μg/min, respectively. Plasma samples were drawn and analyzed for nitroglycerin and its 1,2-and 1,3-dinitraie metabolites using capillary GC. Steady-state nitroglycerin plasma concentrations attained at 10, 20, 40, and 10μg/min were 0.44±0.31, 1.32±0.71, 4.23±1.50 and 1.04±0.43 ng/ml, respectively. As the infusion rate was increased, the steady-state concentrations increased disproportionately. When the dose was decreased from 40 to 10μg/min, the steady-state nitroglycerin concentrations were always higher than those at the initial low infusion rate. Thus, in the majority of subjects, a hysteretic type of response was present. The hysteresis observed in the dose versus steady-state concentration curve may be explained by either end-product inhibition or saturable binding of nitroglycerin to blood vessels. The clearance values (5.5 to 71 l/min) were very high and far exceed the maximum possible hepatic clearance suggesting that nitroglycerin is metabolized by organs other than liver. Clearance was not directly related to plasma concentrations but was found to decrease to a constant value (approximately 11±6 l/min〈 as nitroglycerin concentrations initially increased.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1573-8744
    Keywords: disopyramide ; bioavailability ; protein binding ; nonlinear ; sustained release ; pharmacokinetics ; ultrafiltration ; immunoassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Disopyramide has nonlinear protein binding and thus the relationship between the extent of its bioavailability and AUC,the area under the plasma concentration-time curve, is (1) nonlinear and (2) absorption rate-dependent. The unbound species follows linear pharmacokinetics. A solution of disopyramide, the innovator's product, and two generic formulations were found to be statistically indistinguishable in their bioavailability of disopyramide, whether comparison was based upon AUCor area under the plasma unbound concentration-time curve (AUCu).The AUCand AUCugave similar results because of truly similar bioavailability, coupled with sufficiently similar release rates, among the four preparations chosen for study. The concentration dependence of disopyramide protein binding and the time course of unbound plasma concentrations were fit by models which then allowed prediction of AUCunder various biopharmaceutical scenarios. Nonlinear binding of disopyramide to plasma proteins renders AUCan insensitive parameter for the discrimination of products with different extents of bioavailability; immediate release products allowing bioavailabilities of 75 or 125% relative to the solution can generate AUCs86 and 112%, respectively, of that from the solution. Nonlinear binding, furthermore, leads to a tendency for AUC tooverestimate the bioavailability of slower release products in single-dose studies; if AUCwere the index of bioavailability, products permitting the same bioavailability as the solution but releasing over 12 hr could appear to allow 114% relative bioavailability. Moreover, in some situations the bias arising from the insensitivity of AUCto product differences can be reinforced by the dependence of AUCon release rate; an apparent relative bioavailability of 80% can be achieved by a 12-hr release product allowing a true relative bioavailability of a mere 58%. While multiple-dose studies appear largely to avoid the tendency to overestimate low bioavailability in slow-release products, in these studies AUCappears to be even more insensitive in resolving discrepancies between products. Assay technology now available makes AUCua feasible and more reliable index of bioavailability than AUCwhen plasma protein binding of drugs is nonlinear.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1573-8744
    Keywords: bootstrap ; individual bioequivalence ; moment-based criteria ; population bioequivalence ; probability-based criteria ; scaled criteria ; unscaled criteria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Bioequivalence of two drug formulations is currently defined by drug regulatory authorities in terms of the mean responses following administration of the test and reference formulations (average bioequivalence). However, the various potential shortcomings of average bioequivalence are now understood, and switchability, and thus individual bioequivalence, has become a reasonable expectation when changing from one pharmaceutically equivalent drug product to another. Progress has been made in developing criteria for individual bioequivalence, and an overview and classification of most of the different approaches to the assessment of individual bioequivalence have been achieved. As a consequence of this classification, the different character of scaled and unscaled bioequivalence measures has been recognized and, in turn, this leads to the proposal, made in this paper, of using both scaled and unscaled criteria for bioequivalence assessment of different classes of drugs, depending on their within-subject variability and therapeutic range. This strategy addresses the shortcomings of average bioequivalence, and, when applied to data sets from bioequivalence studies with four-period replicate crossover designs, turns out to have some satisfactory properties. Open questions and areas for further research are discussed.
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