Dissociable lexical and phonological influences on serial recognition and serial recall.

The impact of the lexicality of memory items on memory performance was compared in two paradigms, serial recall and serial recognition. Experiments 1 to 3 tested 7- and 8-year-old children. Memory accuracy was only mildly impaired in lists containing nonwords compared with words in a serial recognition task involving judgments of whether the items in two sequences were in the same order (Experiment 1), although a substantial advantage for word over nonword items from the same stimulus pool was found in serial recall (Experiment 2). A stronger influence of lexicality on serial recall than serial recognition was further demonstrated in Experiments 3A and 3B, and in 4A and 4B using adult participants. These experiments also established comparable degrees of sensitivity to the phonological similarity of the memory sequences in the two paradigms. The phonological similarity effect in serial recall was found to arise from increased phoneme order errors, whereas the lexicality effect was due principally to the greater frequency of phoneme identity errors for nonwords. It is proposed that the lexicality effect originates in the redintegration of item information just prior to recall, and that this process is largely bypassed in serial recognition.

Phonotactic influences on short-term memory.

The impact of phonotactic probabilities on serial recall was investigated in a series of experiments. In Experiments 1A and 1B, 7 and 8 year olds were tested on their serial recall of monosyllabic words and of nonwords varying in phonotactic frequencies. A recall advantage to words over nonwords remained when stimuli were balanced for phonotactic probability, but nonword recall showed superior accuracy for high over low probability nonwords, as in Experiment 2. The nonword frequency effect appears to reflect the frequency of constituent syllables rather than biphones. Both lexicality and high phonotactic frequency led to increased proportions of full over partial recall of the memory stimuli. These findings indicate that decayed memory traces in phonological short-term memory can be reconstructed using either lexical or phonotactic knowledge.

Verbal and visuospatial short-term memory in children: evidence for common and distinct mechanisms.

This study was designed to identify whether verbal and visuospatial short-term memory performance in children is served by common or distinct mechanisms. Five- and 8-year-old children were tested on their verbal recall of spoken letter names and digits, and on their recall of tapped sequences of blocks. The performance of the children on the verbal and visuospatial serial recall tasks was largely unrelated, extending evidence for dissociable memory systems found in adults. Detailed characteristics of recall, such as serial position functions, migration patterns, and distribution of error types, were similar in the tasks requiring recall of letters and of blocks, although order errors predominated in the block but not the letter recall task for the older children. These results appear to reflect the application of common processes specialized for the extraction of serial order information from the phonological and visuospatial components of short-term memory.

The prediction of steady-state plasma phenobarbitone concentrations (following low-dose phenobarbitone) to refine its use as an indicator of compliance.

1. A model for predicting the steady-state plasma concentration of phenobarbitone following low-dose phenobarbitone used as an indicator of compliance was derived using data for 10 healthy volunteers. 2. Each volunteer was given a single 30 mg oral dose of phenobarbitone and the pharmacokinetics were described. Subsequently, volunteers were given phenobarbitone 2 mg daily for 28 days and a further pharmacokinetic profile determined during and after this period. 3. An initial predicted estimate of steady-state plasma drug concentration was made using each volunteer's demographic details. This estimate was revised by Bayesian analysis using single timed samples (24, 48, 72 or 96 h) following the single dose. 4. The model was tested on a further 10 healthy volunteers given a single 8 mg dose and who were subsequently given 2 mg daily for 28 days. 5. The revised estimate of peak steady-state plasma phenobarbitone concentration utilising the 96 h post-single dose concentration (356 ng ml-1) was least biased (mean prediction error +/- 95% CI = 10.6 +/- 19.8 ng ml-1) and most precise (root mean square error +/- 95% CI = 28.3 +/- 19.0 ng ml-1). In all cases the peak or trough steady-state drug concentration was within 13% of the predicted value. 6. The model reflected compliance accurately in a further eight volunteers with simulated partial (two-thirds) compliance. 7. The use of a predictive model using Bayesian analysis to estimate expected steady-state plasma phenobarbitone concentrations could increase further the usefulness of low-dose phenobarbitone as an indicator of compliance.

A comparison of a short half-life marker (low-dose isoniazid), a long half-life pharmacological indicator (low-dose phenobarbitone) and measurements of a controlled release 'therapeutic drug' (metoprolol, Metoros) in reflecting incomplete compliance by volunteers.

1. Although, long half-life compounds appear to be more appropriate pharmacological indicators of compliance with treatment, short half-life markers or measurements of short half-life therapeutic drugs are frequently used. 2. We have compared the usefulness of low-dose phenobarbitone (a long half-life indicator), low dose isoniazid (a short half-life marker) and controlled release metoprolol (Metros) (a controlled release formulation of a short half-life 'therapeutic' drug) in seven volunteers with simulated partial (two thirds) compliance. 3. Detection of isoniazid metabolites in urine had an 83% sensitivity and 94% specificity for detecting ingestion within the previous 24 h and 100% sensitivity and 82% specificity for detecting ingestion within the past 6 h but gave no indication of the longer term pattern of compliance. 4. At 28 days (a time when steady-state would be obtained for all three drugs) phenobarbitone plasma levels were 70% (66-76%)--median and interquartile range--of the expected steady-state level if compliance had been complete. Corresponding figures for metoprolol were 82% (37-100%). 5. Measurement of phenobarbitone was much superior to isoniazid or metoprolol measurements in reflecting partial compliance over the previous 1 to 4 weeks.

Poor compliance is a major factor in unstable outpatient control of anticoagulant therapy.

Control of oral anticoagulant therapy in outpatients is often unsatisfactory. The contribution of poor compliance with prescribed warfarin to unstable anticoagulant control was investigated prospectively using low-dose phenobarbitone as an indicator of compliance in 30 out-patients, 15 with stable and 15 with unstable control. Following entry to the study, there was no significant change in anticoagulation (p = 0.36) in the group with stable control. In the group who previously had unstable control, there was a significant change in INR (p = 0.0045) and anticoagulant control greatly improved. It appears that the considerable fluctuation in INR seen in many of the latter patients before the study was due to poor compliance and that entering them into the study modified their behavior. Two patients in this group who continued to have unstable anticoagulant control were shown to be poorly compliant using the phenobarbitone indicator. The results suggest that, in outpatients, poor compliance is the major cause of unstable anticoagulation with warfarin.

Measuring treatment compliance of men with non-gonococcal urethritis receiving oxytetracycline combined with low dose phenobarbitone.

Of 62 men with non-gonococcal urethritis who entered a study to assess compliance with treatment with oxytetracycline, only 33 could be evaluated. Traditional methods (interview and the absence of oxytetracycline in the urine) showed incomplete compliance in nine. Use of low dose phenobarbitone as a pharmacological marker showed incomplete compliance in a further five patients. In addition, phenobarbitone concentrations gave information on the extent to which individual patients had omitted treatment and provided direct, as opposed to circumstantial, evidence of good compliance by most (18) of those studied. Only three of the 33 patients whose compliance was assessed had evidence of continuing infection at follow up, and there was evidence of incomplete compliance in only one of these patients.

The use of a pharmacological indicator to investigate compliance in patients with a poor response to antirheumatic therapy.

Twenty-six patients with rheumatoid arthritis which was poorly controlled despite high dose D-penicillamine were studied. Compliance was assessed by standard methods (return tablet count and interview). In addition low-dose phenobarbitone was included in the penicillamine formulation as a pharmacological indicator of compliance. Using these techniques incomplete compliance was apparent in 11 patients (42%). All such patients were identified by the pharmacological marker. Only one admitted poor compliance at interview and only six returned more than a few tablets too many. The reason for the high incidence of poor compliance in this selected group is not apparent but it may represent a significant cause of failure with D-penicillamine therapy. The use of low-dose phenobarbitone may have wider applications in the investigation of patients with other conditions who fail to respond adequately to treatment.

Use of a pharmacological indicator to monitor compliance with thyroxine.

Poor compliance with medication is often suspected, but difficult to confirm. The compliance of fourteen newly diagnosed hypothyroid patients was assessed using both TSH levels and low-dose phenobarbitone as a pharmacological marker. The study confirms the value of phenobarbitone as an indicator of compliance over a protracted period and suggests that it could be used to differentiate under-treatment from poor compliance.

Pharmacokinetics of N-desmethylclobazam in healthy volunteers and patients with epilepsy.

1. The single dose pharmacokinetics of N-desmethylclobazam (NDMC) and clobazam were studied in eight healthy male volunteers. 2. Steady-state pharmacokinetic data are described from four healthy male volunteers and eight epileptic patients taking NDMC. 3. A single 30 mg dose of NDMC produced a greater Cmax (P less than 0.001) and AUC0-infinity (P less than 0.005) and a shorter tmax (P less than 0.05) and t1/2 (P less than 0.01) for NDMC than did 30 mg clobazam. 4. Mean steady-state NDMC concentrations were greater in male patients than in female patients and also in male patients compared with male volunteers. The differences between patients and volunteers might be explained by concomitant antiepileptic medication.

The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N-desmethylclobazam.

The effect of cimetidine on the single dose pharmacokinetics of orally administered clobazam and N-desmethylclobazam (NDMC) was studied in volunteers. Cimetidine inhibited the elimination of both clobazam and NDMC and inhibited the rate of formation of NDMC from clobazam. The increase in the AUC for NDMC generated from clobazam was relatively greater than that for clobazam itself. This suggests that NDMC elimination is inhibited to a relatively greater extent than clobazam elimination. The increase in AUC for NDMC generated from clobazam was also relatively greater than that for NDMC administered orally. This would suggest that cimetidine either increases the bioavailability of clobazam or reduces that of NDMC. The increases in the AUC for NDMC and for clobazam in some individuals was of a magnitude which is likely to be clinically significant.