S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: III. Actions in models of potential antidepressive and anxiolytic activity in comparison with ropinirole

In forced-swim tests in mice and rats, the novel D(3)/D(2) receptor agonist S32504 [(+)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] dose-dependently (0.04-2.5 mg/kg) and stereospecifically suppressed immobility compared with its enantiomer S32601 [(-)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth-[1,2-b]-1,4-oxazine]. Ropinirole was less potent than S32504 in this procedure, and it was likewise less potent than S32504 (0.04-2.5 mg/kg) in attenuating motor-suppressant properties of the alpha(2)-adrenoceptor agonist S18616 [(S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(1',2',3',4'-tetrahydronaphthalene)]]. In a learned helplessness paradigm, S32504 (0.08-2.5 mg/kg) suppressed escape failures. Furthermore, in a chronic mild stress model of anhedonia, S32504 (0.16-2.5 mg/kg) rapidly restored the suppression of sucrose consumption. S32504 inhibited marble-burying behavior in mice (0.04-0.16 mg/kg) and aggressive behavior in isolated mice (0.04-2.5 mg/kg): only higher doses of ropinirole mimicked these actions of S32504. In tests of anxiolytic activity, S32504 was more potent (0.0025-0.16 mg/kg) than ropinirole in suppressing fear-induced ultrasonic vocalizations, and S32601 was inactive. Furthermore, in contrast to ropinirole, S32504 modestly enhanced punished responses in a Vogel conflict procedure and increased open-arm entries in a plus-maze. At doses active in the above-described procedures, S32504 did not elicit hyperlocomotion. In the forced-swim, marble-burying, and ultrasonic vocalization models, actions of S32504 were blocked by the D(2)/D(3) antagonists haloperidol and raclopride and by the D(2) antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol], but not by the D(3) receptor antagonist S33084 [(3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide. Finally, chronic administration of S32504 did not, in contrast to venlafaxine, modify corticolimbic levels of serotonin(2A) receptors or brain-derived neurotrophic factor. In conclusion, S32504 displays a broad and distinctive profile of activity in models of potential antidepressive and anxiolytic properties. Its actions are more pronounced than those of ropinirole and principally involve engagement of D(2) receptors.     

116 ectopic pregnancies observed in Bangui (Central African Republic)

Although ectopic pregnancy continues to endanger the life of patients in the Central African Republic, data on this pathology is drastically missing. This study is the result of an observation carried out over a period of 1 year taking all ectopic pregnancy cases into account with a view to identify the risk factors of this pathology and to draw the epidemiological profile of the patients concerned. Controls were used for the identification of the risk factors. The frequency of ectopic pregnancies was of 1 case against 61.8 deliveries. Ectopic pregnancies were more frequent among young women, with a peak in the 20-29 age group. Gonococcus infections and multiple partners were found to be correlated with the occurrence of ectopic pregnancies. If paraclinical tests had helped establish the diagnosis, the presence of clinical symptoms was decisive, thus explaining late diagnosis with tubal rupture followed by an hemorrhage. Those patients who were attended at an advanced stage had to undergo tubal resection, a treatment jeopardizing their obstetrical future. Clearly, African practitioners must imperatively learn to identify the clinical symptoms of this pathology.     

The Vogel conflict test: procedural aspects,gamma-aminobutyric acid,glutamate and monoamines

A multitude of mechanisms are involved in the control of emotion and in the response to stress. These incorporate mediators/targets as diverse as gamma-aminobutyric acid (GABA), excitatory amino acids, monoamines, hormones, neurotrophins and various neuropeptides. Behavioural models are indispensable for characterization of the neuronal substrates underlying their implication in the etiology of anxiety, and of their potential therapeutic pertinence to its management. Of considerable significance in this regard are conflict paradigms in which the influence of drugs upon conditioned (trained) behaviours is examined. For example, the Vogel conflict test, which was introduced some 30 years ago, measures the ability of drugs to release the drinking behaviour of water-deprived rats exposed to a mild aversive stimulus ("punishment"). This model, of which numerous procedural variants are discussed herein, has been widely used in the evaluation of potential anxiolytic agents. In particular, it has been exploited in the characterization of drugs interacting with GABAergic, glutamatergic and monoaminergic networks, the actions of which in the Vogel conflict test are summarized in this article. More recently, the effects of drugs acting at neuropeptide receptors have been examined with this model. It is concluded that the Vogel conflict test is of considerable utility for rapid exploration of the actions of anxiolytic (and anxiogenic) drugs. Indeed, in view of its clinical relevance, broader exploitation of the Vogel conflict test in the identification of novel classes of anxiolytic agents, and in the determination of their mechanisms of action, would prove instructive.     

Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents

This study characterized the influence of acute administration of diverse classes of antidepressant agent upon the spontaneous locomotor activity (LA) of mice in a novel, open-field environment. The selective serotonin (5-HT) reuptake inhibitors (SSRIs), citalopram, fluoxetine, paroxetine, fluvoxamine, litoxetine and zimelidine, dose-dependently enhanced LA. Their actions were mimicked by the mixed 5-HT/noradrenaline (NA) reuptake inhibitors (SNRIs), venlafaxine, duloxetine and S33005. In contrast, clomipramine only slightly elevated LA and two further tricyclics, imipramine and amitriptyline, were inactive. Further, the selective NA vs. 5-HT reuptake inhibitors (NARIs), reboxetine, desipramine, maprotiline, nisoxetine and nortriptyline all failed to increase LA. The "atypical antidepressants," mianserin and mirtazapine, neither of which modify 5-HT reuptake, as well as the mixed SSRI/5-HT(2) antagonists, nefazodone and trazodone, also failed to increase LA. Doses of SSRI and SNRI which increased LA did not modify motor performance in the rotarod test. Further, they did not enhance LA in rats, suggesting that this response is characteristic of mice. Finally, upon prehabituation of mice to the activity chamber, the SSRI, citalopram, and the SNRI, venlafaxine, failed to increase LA. In conclusion, in mice exposed to a novel environment, inhibition of 5-HT reuptake by SSRIs and SNRIs enhances spontaneous LA in the absence of a generalized influence upon motor function. This response provides a simple parameter for characterization of SSRIs and SNRIs, and differentiates them from other classes of antidepressant agent. Although an influence upon arousal and/or anxiety is likely related to the increase in LA, the functional significance of this response requires additional elucidation.     

Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra

Unilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra pars compacta (SNPC) neurons in rats induce behavioural hypersensitivity to dopaminergic agonists. However, the role of specific dopamine receptors is unclear, and potential alterations in their transduction mechanisms remain to be evaluated. The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [³⁵S]GTPγS binding) at cloned hD₂ (and hD₃) receptors. At rat striatal membranes, dopamine stimulated [³⁵S]GTPγS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D₂/D₃ receptor antagonist, raclopride, indicating the involvement of other receptor subtypes. In contrast, quinelorane-induced stimulation (48% of the effect of dopamine) was abolished by raclopride, and by the D₂ receptor antagonist, L741,626. Further, novel antagonists selective for D₃ and D₄ receptors, S33084 and S18126, respectively, blocked the actions of quinelorane at concentrations corresponding to their affinities for D₂ receptors. Quinelorane potently induced contralateral rotation in unilaterally 6-OHDA-lesioned rats, an effect abolished by raclopride and L741,626, but not by D₃ and D₄ receptor-selective doses of S33084 and S18126, respectively. In functional ([³⁵S]GTPγS) autoradiography experiments, quinelorane stimulated G-protein activation in caudate putamen and, to a lesser extent, in nucleus accumbens and cingulate cortex of naive rats. In unilaterally SNPC-lesioned rats, quinelorane-induced G-protein activation in the caudate putamen on the non-lesioned side was similar to that seen in naive animals (50% stimulation), but significantly greater on the lesioned side (80%). This increase was both pharmacologically and regionally specific since it was reversed by raclopride, and was not observed in nucleus accumbens or cingulate cortex. In conclusion, the present data indicate that, in rat striatum, the actions of quinelorane are mediated primarily by D₂ receptors, and suggest that behavioural hypersensitivity to this agonist, induced by unilateral SNPC lesions, is associated with an increase in D₂, but not D₃ or D₄, receptor-mediated G-protein activation.     

Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France

Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years.     

Peritoneal carcinomatosis and hepatic infiltration related to the dissemination of a micropapillary cell carcinoma of the bladder

Most cases of liver failure related to the infiltration of the liver by neoplastic cells are associated with hematological neoplasia or small cell carcinoma of the lung. We report case of liver failure related to a rare infiltration of the liver by a micropapillary bladder carcinoma. Micropapillary bladder cell carcinomas have recently been isolated among bladder tumors. They are characterized by life-threatening features as they spread rapidly to the interstitial stromal matrix leading to a highly aggressive course. The present case emphasizes the pathological features and poor prognosis of these neoplasia, as rapid submucosal spreading may prevent curative locoregional treatment.     

Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia

Graft-versus-host disease in its acute (aGvHD) or chronic form (cGvHD) remains the most important posttransplantation factor influencing outcome after allogeneic hematopoietic stem cell transplantation (HSCT). It increases transplantation-related mortality (TRM) but reduces risk of relapse. The net effect of these 2 discordant effects determines survival. In view of current interests to exploit graft-versus-leukemia (GVL) effects, we analyzed 4174 HLA-identical sibling transplantations for chronic myeloid leukemia in first chronic phase, depending on the presence or absence and severity of GvHD with a landmark analysis. During the first 100 days, only aGvHD grades III and IV had an impact on TRM. During the time period day 100 to 3 years increasing severity of aGvHD is associated with increased TRM and decreased relapse incidence (RI) with hazard ratios (HRs) for TRM as follows: grade 0, HR = 1.0; grade I, HR = 1.52 (1.19-1.96); grade II, HR = 2.48 (1.95-3.14); grade III, HR = 5.76 (4.44-7.48); grade IV, HR = 14.7 (10.9-19.9) and likewise for RI: grade I versus 0, HR = 0.94 (0.76-1.16); grade II, HR = 0.60 (0.46-0.77); grade III, HR = 0.48 (0.29-0.81); grade IV, HR = 0.14 (0.02-0.99). Beyond 3 years, TRM and RI are determined by cGvHD. Limited cGvHD reduces RI to the same extent as extensive cGvHD but has no impact on TRM and, hence, results in best survival with an HR = 0.48 (0.32-0.71). aGvHD grade I has the highest likelihood of subsequent limited cGvHD, which results in cumulative incidence estimates of survival at 10 years being best for patients with initial aGvHD grade I: survival at 10 years grade 0 = 59%, I = 63%, II = 56%, III = 26%, IV = not applicable. These data clarify the role of GvHD in posttransplantation outcome. Considerations for long-term outcome are essential when short-term data of interventions on GvHD are analyzed.     

Impact of chimaerism analysis and kinetics on allogeneic haematopoietic stem cell transplantation outcome after conventional and reduced-intensity conditioning regimens

This retrospective study aimed to analyse the impact on overall survival (OS) and event-free survival (EFS) of chimaerism status and kinetics following allogeneic conventional and reduced-intensity conditioning haematopoietic stem cell transplantation, and to compare this with the impact of other well-known factors. We investigated the chimaerism status of 187 patients [84 females, 103 males; median age 39.5 years (range, 17-62 years)]. After transplantation, 121 patients (65%) presented full donor chimaerism (FDC) and 63 (34%) mixed chimaerism (MC). For MC, we divided the population into patients who presented regressive mixed chimaerism (RMC) (21 patients: 11%), stable mixed chimaerism (SMC) (20 patients: 11%) and progressive mixed chimaerism (PMC) (22 patients: 12%). At last follow-up, 71 patients were alive and 116 had died (48% from disease progression and 52% from transplant-related causes). With a mean follow-up of 39.4 and 34.8 months, the 5-year probabilities of OS and EFS for the total group were, respectively, 55% and 43%: 69.5% and 61% for FDC, 35.4% and 25% for RMC, 42.6% and 28.6% for SMC, and 21% and 10.4% for PMC (P < 0.0001 and P < 0.0001). Multivariate analysis only showed a significant impact of chimaerism status on OS, as well as acute and chronic graft-versus-host disease on EFS, with a trend for conditioning regimen.