In this report, we describe seven new patients with a severe deficiency of glutaryl-CoA dehydrogenase in cultured skin fibroblasts. Three of the patients studied excreted high levels of glutaric acid. The remaining four patients presented a lack of significant glutaric aciduria. However, glutaric acid was found in increased levels in CSF. In both groups of patients, the urine glutaric acid levels were not related to their metabolic condition at the time of sampling. Hypocarnitinemia was a common finding. Some patients also showed defects on respiratory chain complexes in muscle biopsy. Only one patient has a normal psychomotor development. The other six patients are severely handicapped despite the attempts of different therapies. In patients with progressive neurological deterioration with dystonia and cerebellar signs associated with temporal lobe atrophy and bilateral basal ganglia damage on MRI, a glutaric aciduria type I (GA I) should always be investigated. The presence of glutaric acid in body fluids, especially in CSF, as well as plasma carnitine levels, should be determined. These procedures can lead to the diagnosis of glutaric aciduria type I.

No abstract

The synthesis and pharmacology of a new series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles that combine central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor blocking activity is described as potential antidepressants. Four compounds were selected for further evaluation, and the combination of both activities was found to be stereoselective, residing mainly in one enantiomer. Reversal of the loss of righting induced by the alpha(2)-agonist medetomidine in rats confirmed the alpha(2)-adrenoceptor blocking activity in vivo and also demonstrated CNS penetration. Antagonism of p-chloroamphetamine (pCA)-induced excitation as well as blockade of the neuronal 5-HT depletion induced by p-CA administration in rats confirmed their ability to block the central 5-HTT, even after oral administration. Replacement of the oxygen atom at the 5-position of the tricyclic scaffold by a nitrogen or a carbon atom, as well as O-substitution at position 7, led also to active compounds, both in vitro and in vivo.

No abstract