Xylopyranoside-based agonists of D-myo-inositol 1,4,5-trisphosphate receptors: synthesis and effect of stereochemistry on biological activity.

The synthesis of a series of tetrahydrofuranyl alpha- and beta-xylopyranoside trisphosphates, designed by excision of three motifs of adenophostin A is reported. The synthetic route features improved preparations of allyl alpha-D-xylopyranoside and its 2-O-benzyl ether, and gives access to four diastereoisomeric trisphosphates, which show a range of abilities to mobilise Ca2+ from the intracellular stores of hepatocytes. A comparison of the potencies of the four trisphosphates provides useful information relating to the effects of stereochemical variation on the recognition of carbohydrate-based trisphosphates by D-myo-inositol 1,4,5-trisphosphate receptors. 1-O-[(3'S,4'R)-3-hydroxytetrahydrofuran-4-yl] alpha-D-xylopyranoside 3,4,3'-trisphosphate (8) is the most active member of the series with a potency close to Ins(1,4,5)P3; a beta-linked analogue, 1-O-[(3'R,4'S)-3-hydroxytetrahydrofuran-4-yl] beta-D-xylopyranoside 3,4,3'-trisphosphate, is ca. 20-fold weaker than Ins(1,4,5)P3, and the other compounds are much less active. While no compound attained a potency close to that of adenophostin A, we believe that 8 represents the minimal structure for potent Ca2+-releasing activity in this type of carbohydrate-based analogue.

C-glycoside based mimics of D-myo-inositol 1,4,5-trisphosphate.

Epimeric C-glycoside based polyphosphates, alpha- and beta-D-glucopyranosylmethanol 3,4,1'-trisphosphates (8 and 9) were prepared from D-glucose. The key intermediate, allyl 2,6-di-O-benzyl-alpha-D-glucopyranoside, was prepared in five steps (67% yield) from allyl alpha-D-glucopyranoside without the need for chromatography. Compounds 8 and 9 were shown to be full agonists at the Ins(1,4,5)P3 receptors of permeabilised hepatocytes, but with markedly different potencies. Such C-glycoside analogues are worthy of further development as Ins(1,4,5)P, receptor ligands.

A comparative study of trauma and posttraumatic stress disorder prevalence in epilepsy patients and psychogenic nonepileptic seizure patients.

PURPOSE: This study tests the hypothesis that trauma histories, including histories of physical and sexual abuse, and posttraumatic stress disorder (PTSD) are more prevalent in psychogenic non-epileptic seizure (NES) patients than in epilepsy patients. METHODS: Thirty-five inpatients with intractable seizures were evaluated for trauma history and PTSD. After these assessments, patients were diagnosed as having either epileptic or nonepileptic seizures through EEG monitoring. RESULTS: NES diagnosis correlated with PTSD and total number of lifetime traumas, adult traumas, and abuse traumas. Contrary to previous hypotheses, reported childhood sexual abuse (CSA) did not correlate significantly with NES diagnosis. However, CSA predicted PTSD in a discriminant analysis. CONCLUSIONS: We found evidence for the hypothesized relations between trauma, abuse, PTSD, and NES diagnosis. However, elevated levels in both seizure-disorder groups suggest that routine assessment for abuse, trauma, and PTSD might facilitate medical care and treatment for all intractable seizure patients.

The relationship between trauma, PTSD, and medical utilization in three high risk medical populations.

OBJECTIVE: Increased use of medical and psychiatric services has been reported as a correlate of exposure to trauma. Recent studies suggest that: 1) physical and sexual abuse traumas are particularly associated with increased utilization and 2) posttraumatic stress disorder (PTSD), a common sequela of abuse, mediates the relationship between trauma exposure andelevated utilization. The goal of this study was to explore the relationships between trauma, abuse, PTSD, and medical utilization in three medical help seeking groups reported to be at high risk for trauma exposure. METHOD: One hundred and seven patients receiving care at a university-affiliated medical center were surveyed for trauma history and PTSD using the Trauma History Questionnaire (THQ) and the PTSD Checklist (PCL). The sample included: forty-eight gynecologic outpatients, thirty-five inpatients with seizure disorders, and twenty-four psychiatric inpatients with non-PTSD admitting diagnoses. Medical utilization data were obtained from a computerized medical center data base. RESULTS: Ninety-six patients reported a trauma history. Of these patients, sixty-six reported abuse and forty-five qualified for PTSD diagnoses. Total number of traumas and reported sexual and physical abuse correlated significantly with elevated medical utilization and PTSD prevalence. PTSD diagnosis was not significantly correlated with utilization, but the five highest utilizers received PTSD diagnoses. CONCLUSIONS: Study results supported hypotheses regarding the relation of trauma exposure to medical utilization, but were less clear about the mediating role of PTSD. These findings suggest that routine screening of high-risk patient groups might promote timely identification of trauma history and PTSD, and subsequently impact health care utilization.