Testing an Adapted Auditory Verbal Learning Test Paradigm for fMRI to Lateralize Verbal Memory in Patients with Epilepsy.

BACKGROUND AND PURPOSE: fMRI is a noninvasive tool for predicting postsurgical deficits in candidates with pharmacoresistant temporal lobe epilepsy. We aimed to test an adapted paradigm of the Rey Auditory Verbal Learning Test to evaluate differences in memory laterality indexes between patients and healthy controls and its association with neuropsychological scores. MATERIALS AND METHODS: We performed a prospective study of 50 patients with temporal lobe epilepsy and 22 healthy controls. Participants underwent a block design language and memory fMRI. Laterality indexes and the hippocampal anterior-posterior index were calculated. Language and memory lateralization was organized into typical and atypical on the basis of laterality indexes. A neuropsychological assessment was performed with a median time from fMRI of 8 months and was compared with fMRI performance. RESULTS: We studied 40 patients with left temporal lobe epilepsy and 10 with right temporal lobe epilepsy. Typical language occurred in 65.3% of patients and 90.9% of healthy controls (P = .04). The memory fMRI laterality index was obtained in all healthy controls and 92% of patients. The verbal memory laterality index was bilateral (24.3%) more frequently than the language laterality index (7.69%) in patients with left temporal lobe epilepsy. Atypical verbal memory was greater in patients with left temporal lobe epilepsy (56.8%) than in healthy controls (36.4%), and the proportion of bilateral laterality indexes (53.3%) was larger than right laterality indexes (46.7%). Atypical verbal memory might be associated with higher cognitive scores in patients. No relevant differences were seen in the hippocampal anterior-posterior index according to memory impairment. CONCLUSIONS: The adapted Rey Auditory Verbal Learning Test paradigm fMRI might support verbal memory lateralization. Temporal lobe epilepsy laterality influences hippocampal memory laterality indexes. Left temporal lobe epilepsy has shown a higher proportion of atypical verbal memory compared with language, potentially to memory functional reorganization.

Solid-phase total synthesis of trunkamide A(1).

Marine organisms are a rich source of novel, biologically active compounds. Herein, the solid-phase total synthesis of trunkamide A, currently in preclinical trials, is presented. Trunkamide A contains a thiazoline heterocycle and two residues of Ser and Thr with the hydroxy function modified as reverse prenyl (rPr). Cornerstones of the synthesis are as follows: (i) solid-phase peptide chain elongation using a quasi-orthogonal protecting scheme with tert-butyl and fluorenyl based groups, on a chlorotrityl resin; (ii) concourse of HOAt-based coupling reagents; and (iii) cyclizations in solution. Furthermore, the following synthetic steps are discussed: (i) preparation of the reverse prenyl derivatives of Ser and Thr; (ii) introduction of precursor of thiazoline as a protected amino thionoacid derivative; and (iii) formation of the thiazoline ring with DAST. All these features make this strategy particularly suitable for the large-scale synthesis of trunkamide A and other peptides containing the same motifs.

Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man.

Ecteinascidin 743 (ET-743) is a potent anti-tumoral agent of a marine origin. It is currently being tested in phase II clinical trials using a 3-weekly 24-h i.v. infusion of 1500 microg/m(2) and 3-h infusions of 1650 microg/m(2). Knowledge of the metabolism of ET-743 is, however, still scarce. In the present study, a qualitative chromatographic discovery of metabolites of ET-743 in man is reported. ET-743 and its demethylated analog ET-729 were incubated at 37 degrees C in the presence of enzyme systems, pooled human microsomes, pooled human plasma and uridine 5'-diphosphoglucuronyltransferase, respectively, in appropriate media. Reaction products were investigated chromatographically using photodiode array and ion spray-mass spectrometric detection (LC-MS). The main reaction products in microsomal incubations of ET-743 resulted from a remarkable breakdown of the molecule. In plasma the drugs were deacetylated, and the transferase did actually yield a glucuronide of both ET-743 and ET-729. In contrast, screening of urine, plasma and bile, collected from patients treated with ET-743 at the highest dose levels, using a sensitive LC-MS assay, did not result in detection of ET-729 and metabolites which were generated in vitro. The urinary excretion of ET-743 in man was lower than 0.7% of the administered dose for a 24-h infusion.

Advances in the chemistry and pharmacology of ecteinascidins, a promising new class of anti-cancer agents.

Ecteinascidins are marine natural products consisting of two or three linked tetrahydroisoquinoline subunits and an active carbinolamine functional group. Their potent antiproliferative activity against a variety of tumor cells has made them attractive candidates for development as anticancer agents. The lead compound, ecteinascidin 743 (ET 743), is currently in phase II clinical trials but the low amounts present in its natural source, the tunicate Ecteinascidia turbinata, made it necessary to develop efficient synthetic procedures. Recent improvements on the original synthesis are reviewed as well as new strategies starting from readily available cyanosafracin B. ET 743 is known to bind to the minor groove of DNA giving rise to a covalent adduct with the exocyclic amino group at position 2 of a guanine in a fashion similar to saframycin antibiotics. Some of the resulting complexes have been studied by a variety of biochemical and spectroscopic methods and also by computer simulations. The rules for sequence specificity have been well established (preferred targets are RGC and YGG, where R and Y stand for purine and pyrimidine, respectively), and it has been shown that binding of ET 743 to DNA is accompanied by minor groove widening and DNA bending towards the major groove. Although the precise target for antitumor action remains to be unambiguously defined, a role in affecting the transcriptional regulation of some inducible genes is rapidly emerging.

Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B.

An efficient new process is described for the synthesis of ecteinascidin ET-743 (1) and phthalascidin (2), starting from readily available cyanosafracin B (3).

Synthesis and preliminary pharmacological evaluation of thiophene analogues of viloxazine as potential antidepressant drugs.

A series of eight thienyloxymethylmorpholines, thiophene analogues of viloxazine, have been synthesized by three different routes. The preliminary pharmacological evaluation of this series shows antidepressant properties on the mice models used with a light sedative action. The structure-activity relationship is established in a first approximation.

In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells.

Aplidine is a new marine anti-cancer depsipeptide isolated from the Mediterranean tunicate Aplidium albicans. We have evaluated its antiproliferative action against a variety of freshly explanted human tumour specimens. Concentration ranges of 0.01-1.0 microM and 0.0001-1.0 microM were used in short- and long-term exposure schedules respectively. After exposure for 1 h in 49 evaluable specimens, aplidine showed a clear concentration-dependent anti-tumour effect. At 0.05 microM, 85% of the specimens were markedly inhibited. Continuous exposure for 21-28 days in 54 tumour specimens also led to a concentration-dependent activity relationship. Fifty per cent and 100% tumour inhibitions were achieved with 0.001 microM and 0.05 microM respectively. A head to head evaluation assessing short vs continuous exposure was carried out, resulting in evidence of an activity-time of exposure relationship. Breast, melanoma and non-small-cell lung cancer appear to be sensitive to low concentrations of aplidine. In addition the evaluation of the effects of aplidine on haematopoietic cells showed a concentration-dependent toxicity. However, under continuous exposure, active concentrations induced mild bone marrow toxicity, indicating that a therapeutic window at marginally myelotoxic concentrations might exist.