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  • 1
    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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  • 2
    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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  • 3
    ISSN: 0899-0042
    Keywords: thalidomide enantiomers ; stereospecific analysis ; high-performance liquid chromatography ; in vitro kinetics ; chiral inversion ; stereoselective pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The purposes of this work were (1) to develop a high performance liquid chromatographic (HPLC) assay for the enantiomers of thalidomide in blood, (2) to study their inversion and degradation in human blood, and (3) to study the pharmacokinetics of (+)-(R)- and (-)-(S)-thalidomide after oral administration of the separate enantiomers or of the racemate to healthy male volunteers. The enantiomers of thalidomide were determined by direct resolution on a tribenzoyl cellulose column. Mean rate constants of chiral inversion of (+)-(R)-thalidomide and (-)-(S)-thalidomide in blood at 37°C were 0.30 and 0.31 h-1, respectively. Rate constants of degradation were 0.17 and 0.18 h-1. There was rapid interconversion in vivo in humans, the (+)-(R)-enantiomer predominating at equilibrium. The pharmacokinetics of (+)-(R)- and (-)-(S)-thalidomide could be characterized by means of two one-compartment models connected by rate constants for chiral inversion. Mean rate constants for in vivo inversion were 0.17 h-1 (R to S) and 0.12 h-1 (S to R) and for elimination 0.079 h-1 (R) and 0.24 h-1 (S), i.e., a considerably faster rate of elimination of the (-)-(S)-enantiomer. Putative differences in therapeutic or adverse effects between (+)-(R)- and (-)-(S)-thalidomide would to a large extent be abolished by rapid interconversion in vivo. © 1995 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
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  • 4
    ISSN: 1573-739X
    Keywords: Drug handling ; Drug use ; Nurses ; Physicians ; Problem detection study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract As a first step toward obtaining quality assurance regarding use and handling of drugs at Malmö University Hospital, a problem detection study (PDS) was performed, drug related problems being collected from nurses, physicians and pharmacists. Problem questionnaires relevant for physicians (67 items) and nurses (82 items) were prepared and sent to chief physicians and head nurses for distribution to colleagues. The problems identified covered all aspects of drug use and handling such as availability, prescription, dispensing, information and monitoring. Fifty‐six per cent (79/141) of the physicians and 68 per cent (88/130) of the nurses responded. The main problems were related to information, chart order sheets and follow up. The item 'Uncertain whether patients take their medicine correctly after discharge' scored highest among physicians. The two main problems for the nurses were that 'newly licensed drugs and drugs used on a named‐patient basis are not included in FASS' (the Swedish national formulary). The problem detection technique proved useful for the identification of drug‐related problems, and the results will provide a basis for further improvement in quality assurance in pharmacotherapy at the hospital.
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