2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission--II. Biochemical properties.

Two models have been chosen to study the effect of 2-amino-6-trifluoromethoxy benzothiazole (PK 26124) on excitatory amino acid neurotransmission: the pool of cyclic guanosine monophosphate (cGMP) in the cerebellum and the release of acetylcholine in the striatum and olfactory tubercles. The release of acetylcholine induced by N-methyl-DL-aspartate in the striatum and olfactory tubercles was antagonized by PK 26124 which was less potent on the release of acetylcholine induced electrically. The increase in levels of cGMP in the cerebellum induced by excitatory amino acids such as glutamate and quisqualate was antagonized by PK 26124, but the drug was inactive against N-methyl-DL-aspartate, L-aspartate, kainate and cysteine sulphinate. In vivo it antagonized the increases of cGMP in the cerebellum elicited by all these excitatory compounds. All these results are compatible with a possible antagonism by PK 26124 of the excitatory amino acid neurotransmission and may explain its anticonvulsant properties.

Autoradiographic studies of RP 62203, a potent 5-HT2 receptor antagonist. In vitro and ex vivo selectivity profile.

In this study, quantitative autoradiography was used to determine the selectivity of RP 62203, a novel naphtosultam derivative, for 5-HT2 receptors in vitro and ex vivo, using [125I]7-amino-8-iodo-ketanserin ([125I]AMIK) and [3H]mesulergine as radioligands. The density of [125I]AMIK or [3H]mesulergine binding sites was determined by quantitative image analysis. In in vitro experiments, RP 62203 displaced [125I]AMIK from 5-HT2 receptors with an IC50 of 0.21 nM in rat frontal cortex. Its affinity for 5-HT1C receptors was 100-fold lower (IC50 25 nM versus [3H]mesulergine in rat choroid plexus). RP 62203 showed moderate affinity for alpha 1-adrenoceptors in the rat thalamus (IC50 14 nM) and for histamine H1 receptors in the guinea-pig cerebellum (IC50 13 nM). The tetrabenazine sites were not affected by RP 62203 at a concentration of 30 nM. In ex vivo experiments, RP 62203 was about 4 times more potent than ritanserin in displacing [125I]AMIK from 5-HT2 receptors (ED50 0.58 mg/kg p.o.). A dose of 10 mg/kg of RP 62203 did not displace [3H]mesulergine from 5-HT1C receptors or [125I]AMIK from alpha 1-adrenoceptors and tetrabenazine sites in the rat brain and from histamine H1 receptors in the guinea-pig brain. These results demonstrate that RP 62203 specifically recognizes 5-HT2 receptors in rodent brain.

Autoradiographic studies of RP 62203, a potent 5-HT2 receptor antagonist. Pharmacological characterization of [3H]RP 62203 binding in the rat brain.

The binding properties and localization of [3H]RP 62203, a novel ligand for 5-HT2 receptors, were investigated on rat brain sections. The specific binding of this 5-HT2 receptor antagonist was reversible and could be displaced by ritanserin (1 microM). Saturation experiments revealed a single class of binding sites with a KD of 0.128 +/- 0.018 nM and a Bmax of 1.67 +/- 0.06 pmol/mg protein. Pharmacological specificity was demonstrated by the potency order of displacing agents: RP 62203 > ritanserin > spiperone > methysergide > mianserin > pipamperone > cinanserin > 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Quantitative autoradiography showed a heterogeneous distribution of [3H]RP 62203 binding sites, with the highest densities in the frontal, parietal and auditory cortices (layer IV), claustrum and olfactory bulb. Binding densities in the occipital cortex, caudate putamen and thalamic nuclei were moderate, whereas the hippocampus and substantia nigra displayed a very low density of binding sites. The cerebellar cortex appeared almost devoid of [3H]RP 62203 binding sites. The anatomical distribution of binding sites demonstrated that [3H]RP 62203 essentially bound only to rat brain regions known to contain 5-HT2 receptors. This ligand could thus be a useful tool to visualize 5-HT2 receptors.

Arteritis due to Salmonella with aneurysm formation: two cases.

Although arterial infection due to Salmonella is rare, it remains one of the most common causes of primary mycotic aneurysms. The presentation is one of sepsis, cultures positive for Salmonella and rapid expansion or rupture of the aneurysm. The authors' experience at Victoria Hospital, London, Ont., includes two cases of aneurysms infected with Salmonella--one aneurysm of the aorta and the other of the common femoral artery. Both patients were treated by excision of the aneurysm, extra-anatomic reconstruction in an area remote from the infected field and long-term administration of appropriate antibiotics. One patient was alive and well 36 months after resection. The other died of multiple organ failure 10 days after resection. From a review of the English and French literature since 1948, 64 cases of abdominal aortic aneurysms infected with Salmonella were found; half of the patients survived the perioperative period. The diagnosis of mycotic aneurysm must be considered in any patient with an aneurysm and culture specimens positive for Salmonella. The authors favour wide débridement of the infected aneurysm with extra-anatomic reconstruction. This view is supported by a review of the literature. The appropriate antibiotic therapy is bactericidal rather than bacteriostatic.