Aims N-Desmethylclozapine and clozapine N-oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney. Methods From 15 psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2 h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis. Results The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N-desmethylclozapine 9.7%, and clozapine N-oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N-desmethylclozapine and clozapine N-oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N-desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose. Conclusions Clozapine, N-desmethylclozapine and clozapine N-oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N-demethylation and N-oxidation must make major contributions to the total fate of clozapine in patients.
The purpose of this study was to describe the language, articulation, voice and resonance characteristics in children with Goldenhar syndrome. The 4 Dutch-speaking subjects were 2 boys (age 4.5 and 10.2 years) and 2 girls (aged 5.0 and 5.4 years) with normal cognitive functioning. Language testing showed a delay in the development of morphosyntactic abilities. Speech analysis showed that these four children were capable of producing all the sounds of their mother tongue. One type of distortion error, namely dentalization, was found in 2 children. Phonological process analysis revealed the persistence of processes such as final consonant deletion, unstressed syllable deletion and cluster reduction, which are normal in young children but are suppressed with maturation. Also the substitution process of devoicing was observed in these 4 children. It is not clear how the speech and language problems demonstrated in these 4 children are to be explained. It must be taken into consideration that the Goldenhar syndrome has a variable expression. It is possible that the presence of a mandibular defect, hearing impairment, the type and severity of palatal abnormality and decreased linguistic processing skills influence articulation in an individual child. The voices of 2 children were characterized by the presence of slight roughness, corresponding with a higher jitter percentage. How the occurrence of the hoarse voices is to be explained is not quite clear. Laryngoscopic evaluation of the vocal folds showed no organic or functional voice disorder. Regarding resonance, only the child with a cleft palate showed hypernasality and nasal emission. The ENT specialist and the speech-language pathologist must be aware of these communication disorders in order to start preventive and early ‘tailor-made’ speech and language intervention as soon as possible.
A patient with Huntington’s disease developed acute dystonia whilst treated with tiapride. Sulpiride and tetrabenazine also induced dystonia. The anticholinergic biperiden depressed the syndrome but worsened psycho-pathology. Finally a combination of tetrabenazine and clozapine was successful in treatment of both chorea and dystonia. According to this observation, acute dystonia may occur in Huntington’s disease as a consequence of neuroleptic treatment.
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