Vein of Galen Aneurysmal Malformation: An Updated Review

Vein of Galen aneurysmal malformation (VGAM) is a rare intracranial vascular anomaly in the choroidal arteries characterized by the persistence of the embryonic median prosencephalic vein of Markowski (MProsV). It is common in children with high mortality and disability rates. VGAM-associated clinical presentations include heart failure, hydrocephalus, and neurological symptoms, which make it difficult for diagnosis. Simultaneously, the complex VGAM vascular architecture, characterized by a wide interindividual variability, makes the management of this condition challenging to clinicians. Thus, timely diagnosis and treatment of VGAM are crucial. In this review article, we elucidated the latest research progresses of VGAM in the aspects of the pathogenesis, classification, clinical features, imaging, management, and prognosis based on recent relevant literatures. It is beneficial to raise the awareness of VGAM and improve the level of management and treatment.

Systematic Therapeutic Drug Monitoring for Linezolid: Variability and Clinical Impact

ABSTRACT Linezolid serum trough (C min) and peak (C max) levels were determined prospectively in 90 patients. Adequate exposure was defined as a C min of 2 to 8 mg/liter. Therapy was empirical (73.3%) or targeted (26.7%). Wide interindividual variability in linezolid C min levels was recorded (0.1 to 25.2 μg/ml). Overall, 65.5% of the patients had out-of-range, 41.1% had subtherapeutic, and 24.4% had supratherapeutic trough levels. We did not find a correlation between abnormal levels and adverse events, in-hospital mortality, or overall poor outcome.

Abstract 19040: Exome Sequencing of Extreme Phenotypes Identifies B4GALT2 as a Determinant of Clopidogrel Response Variability

There is wide interindividual variability in platelet aggregation in response to clopidogrel and high/low on-treatment platelet reactivity (HPR/LPR) is associated with more frequent adverse cardiovascular events. The CYP2C19*2 allele is the major genetic determinant of clopidogrel responsiveness but only accounts for ~12% of the variation thus urging for identification of additional variants. In a cohort of 636 coronary artery disease (CAD) patients, those with the most extreme pharmacodynamic response to clopidogrel were identified as LPR (P2Y12 reaction units (PRU)<50 and ADP-induced residual platelet aggregation (RPA)<5%) vs HPR (PRU>235 and RPA>60%). Four patients from each group with wild-type CYP2C19 ( *1/*1) were subjected to exome sequencing (average 70X). Identified variants that clustered in the LPR or HPR groups (3 or 4 carriers vs. 0) were identified and the probabilities of observing the clustering of each variant according to reported European minor allele frequencies (MAF) were calculated. Forty-nine of the identified variants with the lowest probablilities (18 LPR, 31 HPR, p<0.001) were genotyped across the remaining 628 coronary patients, which identified a significant association between two B4GALT2 variants (c.909C>T; p.Ile303= and c.366G>C; p.Gln122His, D’=0.68, r 2 =0.30) and treatment response. Carriers of c.909C>T (MAF=0.102) had lower PRU (p=0.0077) and RPA (p=0.0008) compared to non-carriers, as did carriers of c.366G>C (MAF=0.070) with lower PRU (p=0.0211) and RPA (p=0.0046). Notably, these effects were independent of CYP2C19*2 , suggesting an alternative biological pathway from clopidogrel metabolism. B4GALT2 is a platelet galactosyltransferase that catalyzes the biosynthesis of glycoconjugates and is involved in intercellular recognition and/or adhesion. Taken together, these data implicate B4GALT2 c.909C>T and c.366G>C as genetic determinants of clopidogrel sensitivity by directly influencing platelet aggregation. Their impact on clinical outcomes of CAD patients deserves further investigation.

Randomized Cross-Over Evaluation of Body-Surface Area–Based Dosing Versus Flat-Fixed Dosing of Paclitaxel

Purpose: Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition. Patients and Methods: Paclitaxel pharmacokinetics were prospectively studied in 12 patients that were treated in a randomized cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m2 in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel. Results: The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values ± SD (A v B) of 1.34 ± 0.158 versus 1.30 ± 0.329 μM•h, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various body-size measures, including BSA (R ≥ 0.617; P ≤ .033), weight (R ≥ 0.621; P ≤ .031), and lean-body mass (r ≥ 0.630; P ≤ .028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA. Conclusion: This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug.

Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies.

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

Thickness of the Lateral Surface of the Temporal Bone in Children

The placement of implantable auditory prostheses in children has raised questions concerning the thickness of the temporal bone in the region of implantation. The purpose of this study is to describe the thickness at specific sites of the lateral surface of the temporal bone in children of different ages. One hundred twenty-five intact temporal bones from 83 children of known sex, race, and age between birth and 20 years were measured. Thickness was measured with a specially designed micrometer at specific locations from a fixed reference point by use of a surface projected grid for site identification. Thickness was plotted against age on scattergraphs for each site, and regression analysis revealed a bimodal linear relationship. Sites medial to the temporalis muscle were the thinnest; sites associated with the posteroinferior insertion of the temporalis muscle, along the supramastoid crest, were the thickest. However, wide interindividual variability was the rule.

Microbial Amino Acid Metabolites and Bladder Cancer: No Evidence of Promoting Activity in Man

1 Indole, p-cresol and phenol are microbial amino acid metabolites which show co-carcinogenic or promoting activity in animal studies. Their involvement in the development of human bladder cancer has been determined by measuring the urinary excretion of indican (indoxyl sulphate) and conjugated phenols. 2 Thirty-two patients (22 males, 10 females) with histologically confirmed carcinoma of the urinary bladder and a similar number of age and sex matched controls took part in the study. The excretion of indican, p-cresol and phenol showed wide interindividual variability, but did not differ significantly between the two groups. 3 The findings indicate that these endogenous metabolites do not contribute significantly to the development of human bladder cancer.

Erythrocyte Catechol-O-Methyltransferase Activity and Indices of Sympathetic Activity in Man

1. Erythrocyte catechol-O-methyltransferase was studied in a population sample of 147 subjects. 2. There was a wide interindividual variability of catechol-O-methyltransferase activity, which was not unimodally distributed. Catechol-O-methyltransferase activity was not influenced by blood pressure, age or sex, nor was it related to plasma noradrenaline or urinary catecholamines or metanephrines. 3. It is not likely that inactivation of noradrenaline by O-methylation at least by erythrocytes is an important mechanism determining plasma noradrenaline, let alone arterial pressure.