Comparative potencies of 3,4-methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5-HT transport in mammalian cell lines.

BACKGROUND AND PURPOSE: Illegal 'ecstasy' tablets frequently contain 3,4-methylenedioxymethamphetamine (MDMA)-like compounds of unknown pharmacological activity. Since monoamine transporters are one of the primary targets of MDMA action in the brain, a number of MDMA analogues have been tested for their ability to inhibit [3H]noradrenaline uptake into rat PC12 cells expressing the noradrenaline transporter (NET) and [3H]5-HT uptake into HEK293 cells stably transfected with the 5-HT transporter (SERT). EXPERIMENTAL APPROACH: Concentration-response curves for the following compounds at both NET and SERT were determined under saturating substrate conditions: 4-hydroxy-3-methoxyamphetamine (HMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 2,5-dimethoxy-4-bromophenylethylamine (2CB), 3,4-dimethoxymethamphetamine (DMMA), 3,4-methylenedioxyphenyl-2-butanamine (BDB), 3,4-methylenedioxyphenyl-N-methyl-2-butanamine (MBDB) and 2,3-methylenedioxymethamphetamine (2,3-MDMA). KEY RESULTS: 2,3-MDMA was significantly less potent than MDMA at SERT, but equipotent with MDMA at NET. 2CB and BDB were both significantly less potent than MDMA at NET, but equipotent with MDMA at SERT. MBDB, DMMA, MDOH and the MDMA metabolites HMA and HMMA, were all significantly less potent than MDMA at both NET and SERT. CONCLUSIONS AND IMPLICATIONS: This study provides an important insight into the structural requirements of MDMA analogue affinity at both NET and SERT. It is anticipated that these results will facilitate understanding of the likely pharmacological actions of structural analogues of MDMA.

Blockade of noradrenaline transport abolishes 4-methylthioamphetamine-induced contraction of the rat aorta in vitro.

The aim of this study was to characterize the effects of 4-methylthioamphetamine (4-MTA) on contractility and noradrenaline (NA) transport and release in the isolated rat aorta. Descending thoracic aortic rings were isolated from male Wistar rats (220-240 g) and the effect of 4-MTA on contractility was measured by isometric force displacement. 4-MTA (0.1 microm-1 mm) induced a concentration-dependent contraction of aortic rings, with a pD(2) of 4.40 +/- 0.38, and an E(max) of 0.80 +/- 0.05 g tension. The alpha(1)-adrenoceptor antagonist, prazosin (1 microm) and alpha(2) antagonist, yohimbine (1 microm) inhibited maximal contraction to 100 microm 4-MTA by 45.0 +/- 6.7% and 53.5 +/- 7.1% of control values respectively, whereas the 5-hydroxytryptamine (5-HT) antagonist, ketanserin (100 nm) had no effect on the 4-MTA-mediated contraction. The specific NA transport inhibitor, nisoxetine (1 microm) abolished contraction of the aorta by 4-MTA. 4 Nisoxetine-sensitive [(3)H]-NA transport in aortic rings was measured over a concentration range of 0-5 microm [(3)H]-NA, and had a maximal rate of transport (V(max)) of 0.77 +/- 0.07 pmol [(3)H]-NA min(-1) mg(-1) protein and a Michaelis affinity constant (K(M)) of 2.3 +/- 0.5 microm. 4-MTA inhibited nisoxetine-sensitive [(3)H]-NA transport with a pIC(50) of 6.16 +/- 0.18 and the pIC(50) for inhibition of nisoxetine-sensitive [(3)H]-NA transport by 3,4-methylenedioxymethamphetamine (MDMA) was 6.83 +/- 0.13. 4-MTA (1-100 microm) significantly stimulated release of pre-loaded [(3)H]-NA from aortic rings and 4-MTA-induced [(3)H]-NA release was inhibited by 1 microm nisoxetine. These data suggest that 4-MTA causes contraction of the rat aorta in vitro by a mechanism that is consistent with an ability to cause release of NA at the level of the NA transporter. It is concluded that 4-MTA has the potential to increase the extracellular concentration of NA peripherally as well as centrally, and that this may cause adverse cardiovascular effects in its users.

In vitro neuronal and vascular responses to 5-HT in rats chronically exposed to MDMA.

1. This study examined the effects of chronic exposure of rats to 3,4-methylenedioxymethamphetamine (MDMA) on [(3)H]5-hydroxytryptamine ([(3)H]5-HT) re-uptake into purified rat brain synaptosomes, 5-HT-induced isometric contraction of aortic rings and [(3)H]5-HT re-uptake into rat aorta. 2. Rats were administered MDMA (20 mg kg(-1) i.p.) twice daily over 4 days. One, 7, 14 or 21 days post treatment, whole brain synaptosomes and descending thoracic aortic rings were prepared for investigation. 3. Chronic MDMA treatment significantly reduced the maximum rate (V(max)) of specific high-affinity [(3)H]5-HT re-uptake 1 day after treatment and for up to 21 days post-final administration of MDMA. Direct application of MDMA (100 microM) abolished synaptosomal re-uptake of [(3)H]5-HT in vitro. 4. Chronic MDMA administration significantly reduced the maximum contraction (E(max)) to 5-HT at 1 and 7 days after treatment, but not at 14 or 21 days. 5. Chronic MDMA administration had no effect on sodium-dependent [(3)H]5-HT re-uptake into aorta 1 day after treatment, nor did 100 microM MDMA have any direct effect on [(3)H]5-HT uptake into aortic rings in vitro. 6. These results show, for the first time, an altered responsiveness of vascular tissue to MDMA after chronic administration. In addition, they demonstrate a difference in the sensitivity of central and peripheral 5-HT uptake systems to chronic MDMA exposure, and suggest that the action of MDMA in the cardiovascular system does not arise from a direct effect of MDMA on peripheral 5-HT transport.

[Prevention of recurrent hemorrhage caused by the rupture of esophageal varices in cirrhotic patients. A controlled study of propranolol and clip ligation of the esophagus]. / Prévention de la récidive hémorragique par rupture de varices oesophagiennes chez le cirrhotique. Etude contrôlée comparant le propranolol et la ligature de l'oesophage sur clip.

Among the various treatments of ruptured oesophageal varices two seem to be effective: oral propranolol therapy and ligation of the oesophagus on clip. In this controlled study these two methods were compared in a series of 55 patients hospitalized for ruptured oesophageal varices. After haemodynamic stability was obtained, the patients were allocated at random to either propranolol therapy (n = 28) or surgery (n = 27). Twenty-one per cent of these patients belonged to group C of Child's classification and 54 per cent to group A. The parameters studied were similar in both groups. Five patients were excluded from the study: 2 in the medical group when it appeared that propranolol was contra-indicated and 3 in the surgical group who died before the operation; however, these 5 patients were taken into account in a second statistical evaluation. Nineteen out the 26 patients under propranolol (73 per cent) had rebleeding (within the first 10 days in 3 cases). In the surgical group recurrent bleeding was observed in 4 out of the 24 patients (17 per cent), and 4 other patients died post-operatively. The difference in favour of the surgical group was highly significant (P less than 0.001), and it remained significant (P less than 0.05) when the 5 patients who could not be treated were included into the calculations. Cox's multivariate analysis showed that patients in Child's C group had a poorer prognosis.

[Pseudotumoral hepatic tuberculosis. Ultrasonics and x-ray computed tomography apropos of a case]. / Tuberculose hépatique pseudo-tumorale. Aspects échographiques et scanographiques à propos d'un cas.

Results of CT scan and ultrasound exploration were discordant in a patient with the pseudotumoral form of hepatic tuberculosis. Although rare, this localization should not be unrecognized because of the curable nature of the affection. Tissular characterization of lesion was not possible by medical imaging alone and liver puncture-biopsy examination was necessary.

[Calcifying muscular metastases of colonic origin. Apropos of a case localized in the psoas muscle]. / Les métastases calcifiantes musculaires d'origine colique. A propos d'un cas localisé au psoas.

A case is reported of calcifying metastases of colon origin localized to psoas muscle. Emphasis is placed on the effectiveness of CT scan and MR imaging and the rarity of this localization. The presence of intra-lesional calcifications as described in hepatic metastases raises the question of the etiopathogenic mechanism and the predictive value of the detection of a calcified mass during the course of colon adenocarcinoma.