Antimalarial simplified 3-aryltrioxanes: synthesis and preclinical efficacy/toxicity testing in rodents.

A streamlined five-step chemical synthesis of rationally designed, simplified 3-aryltrioxane 8a is described. A noteworthy feature of this synthetic scheme is use of air rather than expensive molecular oxygen as the source of the pharmacologically critical peroxide unit in trioxane 8a. This simplified acetal trioxane carboxylic acid 8a is thermally stable, and it is hydrolytically stable in water even at 40 degrees C and pH 7.4 for at least 7 days. Preclinical evaluation of this water-soluble synthetic trioxane 8a in rodents shows it to have at least as good a therapeutic index (efficacy/toxicity) as that of water-soluble semisynthetic trioxane artelinic acid (5).

Observation of metabolic changes in chronic schizophrenia after neuroleptic treatment by in vivo hydrogen magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: The authors investigate: (1) whether there is a lateral effect of hydrogen (1H) magnetic resonance (MR) spectroscopy observable metabolite ratios between the right and the left prefrontal lobe in chronic schizophrenia; (2) whether there is a change of proton metabolite ratios in chronic schizophrenia after neuroleptic treatment; (3) whether there is a relation between changes in 1H MR spectra and the clinical assessment of Brief Psychiatric Rating Scale (BPRS); and (4) to investigate a hypofrontality hypothesis in schizophrenia in terms of neurochemical aspects. METHODS: Localized in vivo 1H MR spectroscopy was used to measure the metabolite levels in the prefrontal lobes of control persons (n = 20) and of chronic patients before and after neuroleptic treatment (n = 34). The MR spectra of 8 cm3 voxels were compared with clinical assessment of BPRS in each subject. RESULTS: No significant metabolic lateral effect was established in both schizophrenia and control groups (P > 0.05). After neuroleptic treatment, chronic schizophrenic patients generally demonstrated a decrease of the complex of gamma-aminobutyric acid (GABA) and glutamate (Glu) containing (GABA + Glu)/creatine (Cr) ratio. CONCLUSIONS: The current follow-up 1H MR spectroscopy study shows a significant correlation between alterations of (GABA + Glu)/Cr ratio and BPRS, and supports a hypofrontality hypothesis in chronic schizophrenia. The reduction of (GABA + Glu)/Cr ratio after neuroleptic treatment may implicate the recovery of normal neuronal function in neurotransmitters. In vivo 1H MR spectroscopy may be a useful modality in follow-up evaluation of neuroleptic treatment in chronic schizophrenia.