Venlafaxine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: The objectives of this pilot study were to explore the changes in symptom severity, tolerability, and the pharmacodynamics of venlafaxine treatment in youths with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was a 2-week, open-label, outpatient trial of venlafaxine in children and adolescents, ages 5-17 years, with ADHD. Three dosing strata, 0.5, 1.0, and 2.0 mg/kg per day, were examined. ADHD symptom severity and improvement assessments included the ADHD Rating Scale (ARS-IV) and the Clinical Global Impressions Scale (CGI). During this study, venlafaxine, O-desmethylvenlafaxine (ODV), norepinephrine, and serotonin concentrations were obtained. RESULTS: Thirty-eight participants (33 males) were treated in this trial. Overall, parent-completed and teacher-completed ARS-IV total scores showed a statistically significant positive change at the end of the study when compared to baseline (p < 0.05). Significant increases in plasma venlafaxine concentrations were observed at day 15 when compared to day 8 (p = 0.04). In addition, plasma norepinephrine and serotonin concentrations were found to be significantly decreased from baseline at end of study (p < 0.05). Four patients ended participation in the study prematurely: lost to follow up (n = 2), withdrawal of consent (n = 1), and worsening of ADHD symptoms after 8 days of treatment (n = 1). There were no discontinuations due to other adverse events. CONCLUSIONS: Venlafaxine appeared to offer some benefit and appears to be relatively safe for the short-term treatment of ADHD in this open-label trial. The pharmacodynamics of venlafaxine in youths are consistent with serotonergic and neuradrenergic modulation.

In vitro evaluation of the potential role of sulfite radical in morphine-associated histamine release.

BACKGROUND: Intravenous morphine use is associated with elevated histamine release leading to bronchoconstriction, edema and hemodynamic instability in some patients. This study evaluated the possibility that sulfite, which is present as a preservative in many morphine preparations, might contribute to histamine release in vitro. RESULTS: The human mast cell line, HMC-1, was exposed to various morphine concentrations, in the absence of sulfite, under cell culture conditions. Clinically attained concentrations of morphine (0.018microg/ml and 0.45microg/ml) did not cause increased histamine release from mast cells. There was a significant increase in histamine release when the morphine concentration was increased by 1184-fold (668microg/ml morphine). Histamine release from mast cells exposed to morphine and/or sulfite required the presence of prostaglandin H synthetase. Histamine release in experiments using sulfite-containing morphine solutions was not statistically different from that observed in morphine-only solutions. CONCLUSION: Sulfite in sulfite-containing morphine solutions, at concentrations seen clinically, is not responsible for histamine release in in vitro experiments of the human mast cell line, HMC-1. This does not preclude the fact that sulfite may lead to elevation of histamine levels in vivo.

How low is too low? Use of cluster analysis to define low levels of mercaptopurine metabolites.

BACKGROUND: To group patients receiving treatment for acute lymphoblastic leukemia (ALL) according to their oral mercaptopurine (6-MP) metabolite levels and to establish cut-off points to screen for potential poor clinical outcome. PROCEDURE: Methodological study using 6-MP metabolite levels from 48 adolescent ALL patients enrolled in a multicenter adherence study. Cluster analysis was the primary analytical technique. We used two validation methods (a split-sampling and a simulation technique) for validating the results. RESULTS: Four clusters were retained in our initial analysis using our first group of patients (n = 27). Three clusters (labeled 1, 2, and 4) exhibited the expected negative correlation between the two metabolites, that is, "high" values of one were associated with "low" values of the other. One cluster (labeled 3) had "low" levels for both TGN and MMP. Five of the 27 adolescents had their 6-MP "held" during the study. Post-hoc examination of the results revealed that all five grouped in Cluster 3 during the time that their medications were stopped, but grouped in other clusters at other times. The median ANC was highest in Cluster 3, consistent with low therapeutic drug levels. Parameters were reproducible with both validation methods. Values below the respective 75th centile for both TGN and MMP in Cluster 3 for the complete sample (n = 48) are suggested as representing a potentially higher risk for relapse. CONCLUSIONS: This study provides an objective method for identifying patients at risk for treatment failure due to suboptimal 6-MP therapy; the clinical significance of this approach should be examined in future studies.

Effect of chloroquine on human immunodeficiency virus (HIV) vertical transmission.

INTRODUCTION: Over 2 million children globally are HIV positive. More than 90% are infected in utero from their mothers. Current pharmacological methods to reduce the rate of vertical transmission are too expensive for the developing world. Chloroquine, a cheap, widely available drug, has anti-HIV properties. We conducted a pilot study to determine if chloroquine can reduce HIV vertical transmission. METHODS: 287 samples of stored, frozen cord blood from a cohort of Ugandan infants born to HIV positive mothers were analyzed for concentrations of chloroquine and its two major metabolites, monodesethylchloroquine and didesethylchloroquine. The HIV status of each infant was determined by ELISA with Western Blot confirmation at 15 and 18 months of age. RESULTS: 49% of samples had measurable chloroquine or metabolite. Of those with measurable drug, the higher concentrations of chloroquine and its metabolites were more frequently associated with HIV negative infants. However, only the median concentration of didesethylochloroquine was significantly higher in HIV negative infants vs. HIV positive infants (1.6 ng/ml vs. 0.9 ng/ml, p=0.05). CONCLUSIONS: Nearly half of all infants in a Ugandan cohort are exposed to chloroquine in the last trimester of pregnancy. Such random maternal chloroquine use may be associated with a decreased rate of HIV vertical transmission. The issue of maternal chloroquine use requires controlled study before any clinical conclusions may be drawn.