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  • 1
    ISSN: 1432-1912
    Keywords: MIF ; Melanostatin ; Oxotremorine ; Parkinson ; Peptides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pro-Leu-Gly-NH2 (MIF) inhibits the tremor induced by oxotremorine. Objective measurement of this tremor permits the drawing of a dose-effect curve. The inhibitory effect of the peptide increases linearly with increasing doses until an optimum is reached (between 30 and 40 mg/kg i.p.). At still higher doses the peptide is inactive. The same phenomenon is observed with analogues of MIF. This finding may have important bearings on the interpretation of clinical and experimental data obtained with MIF.
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Allergy 6 (1953), S. 0 
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
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  • 4
    ISSN: 0899-0042
    Keywords: thalidomide enantiomers ; in vitro kinetics ; blood distribution ; human serum albumin ; chiral inversion ; plasma protein binding ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The aim of this investigation was to elucidate the distribution and reactions of the enantiomers of thalidomide at their main site of biotransformation in vivo, i.e., in human blood. Plasma protein binding, erythrocyte: plasma distribution, and the kinetics of chiral inversion and degradation in buffer, plasma, and solutions of human serum albumin (HSA) were studied by means of a stereospecific HPLC assay. The enantiomers of thalidomide were not extensively bound to blood or plasma components. The geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. The corresponding geometric mean blood:plasma concentration ratios were 0.86 and 0.95 (at a haematocrit of 0.37) and erythrocyte:plasma distributions were 0.58 and 0.87. The rates of inversion and hydrolysis of the enantiomers increased with pH over the range 7.0-7.5. HSA, and to a lesser extent human plasma, catalysed the chiral inversion, but not the degradation, of (+)-(R)- and (-)-(S)-thalidomide. The addition of capric acid or preincubation of HSA with acetylsalicylic acid or physostigmine impaired the catalysis to varying extents. Correction for distribution in blood enhances previously observed differences between the pharmacokinetics of the enantiomers in vivo. The findings also support the notion that chiral inversion in vivo takes place mainly in the circulation and in albumin-rich extravascular spaces while hydrolysis occurs more uniformly in the body. In addition, the chiral inversion and hydrolysis of thalidomide apparently occur by several different mechanisms. Chirality 10:223-228, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
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  • 5
    ISSN: 1573-8744
    Keywords: ketamine ; midazolam ; mass balance ; brain ; cerebral blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF)by one third, as measured by intermittent 133Xewashout. By means of pharmacodynamic models, the effects on the CBFcould be predicted from the arterial drug concentrations. The high-resolution CBFvs. time curves thus generated allowed the calculation of cerebral drug levels from arteriovenous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF,ketamine and midazolam decreasetheir own rateof transport to the brain, the immediate 30-35% drops in CBFgiving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBFis determined mainly by the effects of the anesthetics and by the arterial CO 2 tension. CBFchanges in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.
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  • 6
    ISSN: 1573-8744
    Keywords: concentration–effect relationship ; enantiomers ; stereospecific analysis ; chiral inversion ; thalidomide ; sedative effects ; continuous reaction times ; logistic regression ; Cox regression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract This study investigated the sedative effects of the enantiomers of thalidomide in humans. Since the enantiomers undergo chiral inversion in vivo this entailed application of suitable statistical methodology to distinguish the effects of each enantiomer in the presence of the other one. Six healthy male volunteers received single oral doses of (+)-(R)-thalidomide, (−)-(S)-thalidomide or racemic thalidomide in a double-blind study, and the results of this study were compared with those of a similar study where three subjects received (+)-(R)-thalidomide, (−)-(S)-thalidomide or placebo in a double-blind fashion. Blood samples for analysis of (+)-(R)-thalidomide and (−)-(S)-thalidomide were obtained. Prior to sampling it was noted whether the subject was awake or asleep, and his feelings of tiredness and heaviness were estimated using Borg scales. After blood sampling continuous reaction time was measured by a 10-min series of auditory signals. The concentration–effect relationships were analyzed by logistic regression techniques and Cox regression for the reaction time data. The (+)-(R)-thalidomide concentrations, but not the (−)-(S)-thalidomide concentrations, exhibited significant positive influences on all sedative effects studied (sleep, tiredness, and reaction times). In some of the analyses of reaction times the (−)-(S)-thalidomide concentrations had a significant effect in the opposite direction. The time course and intensity of sedative effect is thus influenced by which enantiomer is administered and by the kinetics of in vivo chiral inversion.
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  • 7
    ISSN: 1573-8744
    Keywords: fentanyl ; alfentanil ; physiological models ; regional blood flow ; tissue distribution ; tissue diffusion ; rats ; humans
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The objectives of this investigation were to characterize the disposition of fentanyl and alfentanil in 14 tissues in the rat, and to create physiological pharmacokinetic models for these opioids that would be scalable to man. We first created a parametric submodel for the disposition of either drug in each tissue and then assembled these submodels into whole-body models. The disposition of fentanyl and alfentanil in the heart and brain and of fentanyl in the lungs could be described by perfusion-limited 1-compartment models. The disposition of both opioids in all other examined tissues was characterized by 2- or 3-compartment models. From these models, the extraction ratios of the opioids in the various tissues could be calculated, confirming the generally lower extraction of alfentanil as compared to fentanyl. Assembly of the single-tissue models resulted in a whole-body model for fentanyl that accurately described its disposition in the rat. A similar assembly of the tissue models for alfentanil revealed non-first-order elimination kinetics that were not apparent in the blood concentration data. Michaelis-Menten parameters for the hepatic metabolism of alfentanil were determined by iterative optimization of the entire model. The parametric models were finally scaled to describe the disposition of fentanyl and alfentanil in humans.
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  • 8
    ISSN: 1573-8744
    Keywords: fentanyl ; alfentanil ; physiological models ; regional blood flow ; tissue distribution ; tissue diffusion ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Traditionally, physiological pharmacokinetic models assume that arterial blood flow to tissue is the rate-limiting step in the transfer of drug into tissue parenchyma. When this assumption is made the tissue can be described as a well-stirred single compartment. This study presents the tissue washout concentration curves of the two opioid analgesics fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharmacokinetics, modeling each of the 12 tissues separately, by means of either a one-compartment model or a unit disposition function. The tissue and blood concentrations of the two opioids were measured by gas-liquid chromatography. The well-stirred one-compartment tissue model could reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the brain and heart only. In most other tissues, the initial uptake of the opioids was considerably lower than predicted by this model. The unit disposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentration times tissue blood flow as the input and measured tissue concentrations as the response function. The observed zero-time intercepts of the unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl. These findings can be explained by the existence of diffusion barriers within the tissues and they also indicate that alfentanil is less efficiently extracted by the tissue parenchyma than the more lipophilic compound fentanyl. The individual unit disposition functions obtained for fentanyl and alfentanil in 12 rat tissues provide a starting point for the development of models of intratissue kinetics of these opioids. These submodels can then be assembled into full physiological models of drug disposition.
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