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  1. Article: Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure.

    Barré, J / Ledudal, P / Oosterhuis, B / Brakenhoff, J P G / Wilkens, G / Sollie, F A E / Tran, D

    Biopharmaceutics & drug disposition

    2003  Volume 24, Issue 4, Page(s) 159–164

    Abstract: Objectives - To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily.Methods- Study 1: Twelve healthy elderly subjects (CL(creat) 72+/-8 ml/min, 72+ ...

    Abstract Objectives - To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily.Methods- Study 1: Twelve healthy elderly subjects (CL(creat) 72+/-8 ml/min, 72+/-4 years mean+/-SD) and eight young volunteers (CL(creat) 134+/-18 ml/min, 25+/-8 years) received TMZ MR 35 mg b.i.d. (eight doses). Study 2: eight patients with severe renal failure (CL(creat.) 17+/-5 ml/min, 54+/-10 years), five patients with moderate renal failure (CL(creat.) 39+/-6 ml/min, 54+/-15 years) and eight volunteers (CL(creat.) 104+/-17 ml/min, 53+/-9 years) received TMZ MR 35 mg b.i.d. (patients: ten doses, volunteers: eight doses). Serial blood and urine samples were obtained following administration of the last dose in each study. TMZ plasma and urine concentrations were determined by gas chromatography (NPD-detector). The resulting data were analysed using standard non-compartmental pharmacokinetic methods.Results- Study 1: Elimination half-life of TMZ was significantly longer and renal clearance significantly lower in the elderly subjects. Study 2: In patients with either moderate or severe renal failure, exposure (AUC(0-24)) was significantly increased and renal clearance (CL(R)) was significantly decreased. Significant correlations were observed between CL(creat) and CL(R) (r=0.94) and between CL(creat) and AUC(0-24) (r=-0.94). Conclusion - With repeated administration of TMZ MR 35 mg b.i.d., a decrease in CL(creat) is directly related to a decrease in CL(R) and results in an increase in exposure to TMZ.
    MeSH term(s) Adolescent ; Adult ; Age Factors ; Aged ; Aging/metabolism ; Delayed-Action Preparations ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Renal Insufficiency/drug therapy ; Renal Insufficiency/physiopathology ; Tablets ; Trimetazidine/administration & dosage ; Trimetazidine/pharmacokinetics
    Chemical Substances Delayed-Action Preparations ; Tablets ; Trimetazidine (N9A0A0R9S8)
    Language English
    Publishing date 2003-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 603014-2
    ISSN 1099-081X ; 0142-2782
    ISSN (online) 1099-081X
    ISSN 0142-2782
    DOI 10.1002/bdd.350
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1520: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  2. Article: Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria.

    Looareesuwan, S / Oosterhuis, B / Schilizzi, B M / Sollie, F A E / Wilairatana, P / Krudsood, S / Lugt, Ch B / Peeters, P A M / Peggins, J O

    British journal of clinical pharmacology

    2002  Volume 53, Issue 5, Page(s) 492–500

    Abstract: Aims: The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard ...

    Abstract Aims: The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether.
    Methods: In part I of the study three different artemotil dose regimens were explored in three groups of 6-9 patients for dose finding: 3.2 mg kg-1 on day 0 and 1.6 mg kg-1 on days 1-4 (treatment A), 1.6 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment B), 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20-22 patients with standard i.m. artemether treatment: 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment R).
    Results: Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment.
    Conclusions: The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.
    MeSH term(s) Acute Disease ; Adolescent ; Adult ; Animals ; Antimalarials/administration & dosage ; Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Artemether ; Artemisinins/administration & dosage ; Artemisinins/pharmacology ; Artemisinins/therapeutic use ; Dose-Response Relationship, Drug ; Female ; Humans ; Injections, Intramuscular ; Malaria, Falciparum/blood ; Malaria, Falciparum/drug therapy ; Male ; Middle Aged ; Sesquiterpenes/administration & dosage ; Sesquiterpenes/pharmacology ; Sesquiterpenes/therapeutic use
    Chemical Substances Antimalarials ; Artemisinins ; Sesquiterpenes ; Artemether (C7D6T3H22J) ; artemotil (XGL7GFB9YI)
    Language English
    Publishing date 2002-05
    Publishing country England
    Document type Clinical Trial ; Clinical Trial, Phase II ; Comparative Study ; Journal Article ; Randomized Controlled Trial
    ZDB-ID 188974-6
    ISSN 1365-2125 ; 0306-5251 ; 0264-3774
    ISSN (online) 1365-2125
    ISSN 0306-5251 ; 0264-3774
    DOI 10.1046/j.1365-2125.2002.01590.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1118: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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