Importance of Pharmacokinetic Data for Clinical Practice

Amrein, R.; Leishman, B.

doi:10.1007/978-94-011-7238-7_6

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…In the two‐compartment model, the brain is usually considered as part of the central compartment. The high plasma diazepam concentrations achieved during the initial distribution phase fall within the therapeutic range, and are associated with strong sedative properties of diazepam [27]. In the present study, this phase was characterized by termination of convulsions and decline in the level of consciousness in 41% of children given diazepam i.v.…”

Section: Discussionmentioning

confidence: 52%

Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions

Ogutu

Newton

Crawley

et al. 2002

Brit J Clinical Pharma

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Aims Convulsions are a common complication of severe malaria in children and are associated with poor outcome. Diazepam is used to terminate convulsions but its pharmacokinetics and pharmacodynamics have not been studied in this group. Accordingly, we carried out a comparative study of the pharmacokinetics of intravenous (i.v.) and rectal (p.r.) diazepam. Methods Twenty-®ve children with severe malaria and a convulsion lasting >5 min were studied. Sixteen children received diazepam intravenously (i.v.; 0.3 mg kg x1 ) and nine rectally (p.r.; 0.5 mg kg x1 ). Plasma diazepam concentrations were measured by reversed phase high-performance liquid chromatography. The duration of convulsions, depth of coma, respiratory and cardiovascular parameters were monitored. Results Median maximum plasma diazepam concentrations of 634 (range 402±1507) ng ml x1 and 423 (range 112±1953) ng ml x1 were achieved at 5 and 25 min following i.v. and p.r. administration, respectively. All patients except three (one i.v. and two p.r.) achieved plasma diazepam concentration >200 ng ml x1 within 5 min. Following p.r. administration, plasma diazepam concentrations were more variable than i.v. administration. A single dose of i.v. diazepam terminated convulsions in all children but in only 6/9 after p.r. administration. However, nine children treated with i.v. and all those treated with p.r. diazepam had a recurrence of convulsions occurring at median plasma diazepam concentrations of 157 (range: 67±169) and 172 (range: 74±393) ng ml x1 , respectively. All the children in the i.v. and four in the PR diazepam group who had recurrence of convulsions required treatment. None of the children developed respiratory depression or hypotension. Conclusions Administration of diazepam i.v. or p.r. resulted in achievement of therapeutic concentrations of diazepam rapidly, without signi®cant cardio-respiratory adverse effects. However, following p.r. administration, diazepam did not terminate all convulsions and plasma drug concentrations were more variable.

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Section: Discussionmentioning

confidence: 52%

Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions

Ogutu

Newton

Crawley

et al. 2002

Brit J Clinical Pharma

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“…The /8 half-life, however, is an inadequate means of characterization as the decline in plasma concentration is tied to two different processes, namely, the distribution of the active substance to other tissues (concentration reduction by dilution) and the elimination by metabolism. For some benzodiazepines, the distribution phase plays a relatively minor role but for others, distribution processes are the major reason for the rapid initial decline in plasma concentration (Amrein & Leishman, 1980). Figure 2 describes three theoretical benzodiazepine models with fast absorption and no distribution phase.…”

Section: Measures Taken To Remedy Sleep Disordersmentioning

confidence: 99%

“…Figure 4 shows the plasma concentration profile of four benzodiazepines used for sleep induction (Knowles & Ruelius, 1972;Cano et al, 1977;Klotz et al, 1977;Boxenbaum et al, 1978;Heizmann et al, 1983). It can be seen that the half-life of elimination alone is insufficient to describe the course of plasma concentration during the period most relevant to the clinical effect (Amrein & Leishman, 1980 From the point of view of pharmacokinetics, two time points are of particular significance in this connection: the time at which maximum concentration is reached and the mid-point between two administrations, i.e. 12 h after intake in the case of hypnotics.…”

Section: Measures Taken To Remedy Sleep Disordersmentioning

confidence: 99%

Pharmacokinetic and clinical considerations in the choice of a hypnotic.

Amrein¹,

Eckert²,

Haefeli³

et al. 1983

Brit J Clinical Pharma

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Not only has insomnia become much more frequent in the last hundred years but its causes have also changed considerably. In the treatment of insomnia, benzodiazepines‐because of their additional anxiolytic effect‐offer substantial advantages over other sleep‐inducing agents. The residual fraction‐the quotient of plasma concentration at 12 h after drug intake to maximum plasma concentration‐makes it possible to differentiate between the benzodiazepines according to their suitability as anxiolytics or hypnotics. Midazolam has the lowest residual fraction of all known benzodiazepines and thus, administered in the appropriate dosage, also has the shortest duration of activity.

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“…With respect to diazepam, no study has demonstrated the anxiolytic efficacy of a single daily dose. On the contrary, a form with delayed absorption ("Valrelease") has been developed in order to decrease the sedative effects and obtain a steadier anxiolytic effect during the daytime (Amrein and Leishman 1980;Bergamo and Sudol 1982). Studies with a single daily dose of clorazepate, which like prazepam is a prodrug of desmethyldiazepam, showed anxiolytic efficacy equivalent to that of divided daily doses (Dureman et al 1978) and to diazepam in single or divided doses (Magnus 1973;Burrows et al 1977;Magnus et al 1977).…”

Section: Discussionmentioning

confidence: 99%

Duration of benzodiazepine clinical activity: Lack of direct relationship with plasma half-life

et al. 1984

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The anxiolytic activity and tolerance of two dosage schedules of prazepam, a long plasma half-life benzodiazepine, were compared under double-blind conditions in two groups of 10 inpatients each who met Research Diagnostic Criteria for Generalized Anxiety Disorder and presented chronic and severe symptomatology. Patients received prazepam 40 mg per day on one of two dosage schedules: divided dosage (DD) - 10 mg in the morning and at noon and 20 mg in the evening; or single dosage (SD) - 40 mg in the evening. The 3 weeks of therapy were preceded and followed by 1 week of wash-out for baseline and follow-up assessments, which were performed weekly with the Hamilton Anxiety Scale, Clinical Global Impression, rating of morning drowsiness and evening worsening of symptoms, and patient self-rating of anxiety by means of a visual analogue scale performed both in the morning and in the afternoon. The results showed a clear superiority of the DD over the SD schedule: better anxiolytic efficacy on the Hamilton Anxiety Scale (P less than 0.0005) and on both morning and afternoon visual analogue scales (P less than 0.01 and P less than 0.0002); less morning drowsiness (P less than 0.0001); and steadier anxiolytic effect during the daytime, as globally rated by the investigator (P less than 0.0001) or measured by morning-afternoon differences on the visual analogue scale (P less than 0.005). These results suggest that plasma pharmacokinetics alone may not be sufficient to predict the duration of benzodiazepine anxiolytic activity.

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Importance of Pharmacokinetic Data for Clinical Practice

Cited by 6 publications

References 29 publications

Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions

Pharmacokinetics and anticonvulsant effects of diazepam in children with severe falciparum malaria and convulsions

Pharmacokinetic and clinical considerations in the choice of a hypnotic.

Duration of benzodiazepine clinical activity: Lack of direct relationship with plasma half-life

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