Single- vs Multiple-Dose Pharmacokinetics of Clozapine in Psychiatric Patients

Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.     

Interpreting cerebrospinal fluid pleocytosis in HIV in the era of potent antiretroviral therapy

Background  

Cerebrospinal fluid (CSF) pleocytosis may be seen in asymptomatic HIV-infected individuals. This finding complicates interpretation of CSF abnormalities when such individuals are evaluated for other central nervous system infections. The goal of this study was to determine the relationship between CSF pleocytosis, central nervous system (CNS) antiretroviral penetration, adherence to antiretroviral medication regimens, neurological symptoms and performance on neuropsychological tests.     

Differential induction of cytochrome P-450 by the enantiomers of trans-stilbene oxide

Optically pure (+)- and (-)-trans-stilbene oxide (TSO) enantiomers were administered to immature male Sprague-Dawley rats. (+)-TSO was the more potent inducer of liver microsomal cytochrome P-450-dependent monooxygenases. The greater potency of (+)-TSO may be explained on the basis of stereoselective metabolism since a far greater concentration of TSO was found in liver microsomes of (+)-TSO-treated rats. Furthermore, of the enzymes known to metabolize TSO, cytosolic epoxide hydrolase turned over the (-)-TSO enantiomer at a faster rate, consistent with the greater persistence of the (+)-enantiomer. Although this report is of chiral effects in potency of enzyme induction, stereoselective metabolism (i.e. disposition) rather than inherent structural characteristics (recognition) may be responsible for these effects.     

Deaths of heroin users in a general practice population

Recent evidence suggests that heroin users in the UK are 16 times more likely to die than otherwise expected, although causes of death are varied. The present investigation examines deaths of heroin users at a large Scottish general practice over a four-year period prior to 1 July 1985. A mortality rate of 9.72 per 1000 heroin-user patients per year was observed, roughly half that previously reported, although this difference did not prove to be statistically significant. A higher proportion of the observed deaths were attributed to heroin, and fewer to the misuse of other drugs, and it is speculated that this may reflect the practice's policy of not prescribing opiates to heroin users. Factors associated with heroin-user deaths are examined and areas identified where general practitioners may help to avert some of these deaths.     

Ethics and Economics in Search of a Common Language

Book reviewed in this article: The Needs of Strangers . By Michael Ignatieff. The Health Economy . By Victor Fuchs. Just Health Care . By Norman Daniels     

Levels of Psychological Distress Experienced by Family Carers of Children and Adolescents with Intellectual Disabilities in an Urban Conurbation

Background The aim of the present study was to identify factors associated with the level of psychological distress reported by family carers of children with intellectual disability living in a large urban conurbation. Method Information was collected by postal questionnaire (or interview for family carers who did not have English as their first language) from the family carers of 408 children with intellectual disability (31% of all children within the area administratively identified as having an intellectual disability). Results Results indicated that 47% of primary carers scored above the threshold for psychological distress on the GHQ and that scoring above the threshold was strongly related to the emotional and behavioural needs of the index child and South‐Asian ethnicity and moderately associated with the severity of the child's delay in communication. Conclusions The rates of psychological distress (47% overall, 70% among South‐Asian carers) were markedly higher than that found in previous studies of carers supporting a child with intellectual disabilities. It is suggested that these elevated rates of psychological distress may be mediated by socio‐economic deprivation.     

Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses.

OBJECTIVE: To assess the efficacy and safety of aripiprazole for psychosis associated with Alzheimer dementia (AD). METHODS: In this double-blind, multicenter study, 487 institutionalized patients with psychosis associated with AD were randomized to placebo or aripiprazole, 2, 5 or 10 mg/day. Primary efficacy assessment was the mean change from baseline to week 10 on the Neuropsychiatric Inventory-Nursing Home (NPI-NH) version Psychosis Subscale score. Secondary measures included NPI-NH Total, Clinical Global Impression-Severity of Illness (CGI-S), Brief Psychiatric Rating Scale (BPRS) Core and Total, and the Cohen-Mansfield Agitation Inventory (CMAI) scores. RESULTS: Aripiprazole 10 mg/day showed significantly greater improvements (mean change [2 x SD]) than placebo on the NPI-NH Psychosis Subscale (-6.87 [8.6] versus -5.13 [10.0]; F = 6.29, df = 1, 422, p = 0.013 by analysis of covariance [ANCOVA]); CGI-S (-0.72 [1.8] versus -0.46 [1.6]; F = 4.68, df = 1, 419, p = 0.031 [ANCOVA]); BPRS Total (-7.12 [18.4] versus -4.17 [21.6]; F = 4.72, df = 1, 399, p = 0.030 [ANCOVA]); BPRS Core (-3.07 [6.9] versus -1.74 [7.8]; F = 7.30, df = 1, 407, p = 0.007 [ANCOVA]); CMAI (-10.96 [22.6] versus -6.64 [28.6]; F = 5.23, df = 1, 410, p = 0.023 [ANCOVA]), and NPI-NH Psychosis response rate (65 versus 50%; chi(2) = 5.52, df = 1, p = 0.019 [CMH]). Aripiprazole 5 mg/day showed significant improvements versus placebo on BPRS and CMAI scores. Aripiprazole 2 mg/day was not efficacious. Cerebrovascular adverse events were reported: aripiprazole 2 mg/day, N = 1; 5 mg/day, N = 2; 10 mg/day, N = 4; placebo, N = 0. No deaths in any group (aripiprazole 2 mg/day, 3%; 5 mg/day, 2%; 10 mg/day, 7%; placebo, 3%) were considered to be treatment-related. CONCLUSION: Aripiprazole 10 mg/day was efficacious and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression. However, clinicians should be aware of the safety considerations of atypical antipsychotic uses in this population.