Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants

BACKGROUND: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. CONCLUSION: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

PART I. ANALYTICAL APPLICATIONS OF MASS SPECTROMETRY/MASS SPECTROMETRY (MS/MS). PART II. INVESTIGATIONS OF ION-MOLECULE REACTIONS PRODUCTS BY MS/MS. PART III. THE QUESTION OF TAUTOMERISM OF ALKYLNITRILE AND ISONITRILE RADICAL CATIONS

Part I. We describe the design of a unique high resolution mass spectrometry/mass spectrometry (ms/ms) instrument having the configuration electrostatic analyzer, magnetic sector, and electrostatic analyzer (EBE). Suitable experiments are reported which evaluate the instrument in terms of the requirements for analytical ms/ms applications: high resolution mass selection, high dynamic range, and good transmission for collision-induced decomposition (CID) fragments. The unique capability of triple-sector instruments to monitor consecutive collision-induced reactions is applied to the analysis of mixtures of ions which are isobaric and isomeric, respectively. In addition, a method for the analysis of tetrachlorodibenzo-p-dioxin (TCDD) suitable for use with double or triple sector instruments is described in which the loss of COCl from the molecular ion is monitored. The precision, quality of calibration, and detection limit are evaluated directly, and the accuracy and specificity are tested by comparing the results of an analysis of soil samples with those obtained using GC/HRMS. Part II. We employ ms/ms techniques to study the ion-molecule reaction products created and collisionally-stabilized in a high-pressure ion source. By comparison of unimolecular and collision-induced dissociation spectra, it is demonstrated that the stabilized collision complex from the reaction of {o-quinodimethane}(\u27+) and styrene is shown to have the structure of 2-phenyltetralin, the anticipated product of a {4+2}-cycloaddition mechanism. The stabilized complex from the reaction of {styrene}(\u27+) and neutral styrene is shown not to have the structure of 1-phenyltetralin, and we offer evidence in favor of a formal {4+2}-cycloaddition mechanism. The stabilized complexes of {1,3-butadiene}(\u27+) and olefins are shown not to possess the structures expected for a {4+2}-cycloaddition mechanism. Part III. We use unimolecular and collision-induced dissociations to establish that the isomeric pairs {CH(,3)CN}(\u27+) and {CH(,2)CNH}(\u27+) and {CH(,3)NC}(\u27+) and {CH(,2)NCH}(\u27+) are stable, noninterconverting structures, even when activated to decompose. The same conclusion pertains to the ions {CH(,3)CH(,2)CN}(\u27+) and {CH(,3)CHCNH}(\u27+) and for {NCCH(,2)CH(,2)CN}(\u27+), {NCCH(,2)CHCNH}(\u27+), and {HNCCHCHCNH}(\u27+). The energy barrier of a {1,3}-hydrogen shift, a possible isomerization mechanism, is determined to be at least 76 kcal mol(\u27-1) for the {CH(,3)CN}(\u27+) and {CH(,2)CNH}(\u27+) pair

Source-Induced Fragmentation of Heparin, Heparan, and Galactosaminoglycans and Application

Sulfated glycosaminoglycans (GAGs) are difficult molecules for analysis by mass spectrometry due to their complexity in saccharide composition, polydispersity, and sequence heterogeneity. Structural information is typically derived from their enzymatic or chemical digests. Many analytical studies focused on the determination of disaccharide compositions. In this study a direct electrospray mass spectrometry method is described for the analysis of intact heparin, heparan sulfate, dermatan sulfate, and chondroitin sulfates. The GAGs were desalted by membrane filtration and analyzed in dilute formic acid (0.5%) in negative ion mode. At the dissociation cone voltage (defined as minimum cone voltage to dissociate all polymeric molecules), heparin, heparan sulfate, dermatan sulfate, and chondroitin sulfates produced simple mass spectra consisting primarily of monosaccharide and disaccharide ions derived from glycosidic bond cleavages. The type and abundance of the ions in the dissociation of each molecule were a good reflection of their saccharide compositions. The major ions of heparin were the hexuronic acid ion (m/z 175), glucosamine ion (m/z 240), and the disaccharide ion (m/z 416). Heparan sulfate produced the same set of fragments as heparin since they shared the same compositional saccharides. However, the formation of the m/z 175 ion dominated the source induced fragmentation process for heparan sulfate reflecting its high content of the nonsulfated disaccharide d-glucuronic acid-acetylated glucosamine (GlcA-GlcNAc). Chondroitin/dermatan sufates contained only acetylated amino sugar (acetylated galactosamine (GalNAc). Consequently, the principle mono/disaccharide ions were all acetylated with m/z values of 282 and 458, respectively. The contrast among the dissociation features of the three types of molecules were sufficient to allow their ready differentiation. Additionally, sensitive detection of chondroitin/dermatan sulfate and heparan sulfate in heparin was made possible by the same differences in the dissociation chemistry of the three types of molecules. As low as 0.5% chondroitin/dermatan sulfate and 5% heparan sulfate in heparin can be reliably detected. This method was successfully used for the detection of oversulfated chondroitin sulfate in heparin as a contaminant following reports of increased adverse events associated with heparin injections from the end of 2007 to early 2008. Heparin is an important, widely prescribed anticoagulant. In light of this contamination event, quality assurance beyond standard activity assays proves to be important. This method provides a simple and fast way for the detection of low level chondroitin, dermatan, and heparan sulfates and their oversulfated derivatives in heparin raw material or formulation