Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist.

BACKGROUND AND PURPOSE: Activation of post-synaptic 5-HT(1A) receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT(1A) receptor agonist. EXPERIMENTAL APPROACH: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. KEY RESULTS: F15599 was highly selective for 5-HT(1A) receptors in binding experiments and in [(35)S]-GTPgammaS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT(1A) receptors. In cell lines expressing h5-HT(1A) receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT(1A) receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [(35)S]-GTPgammaS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated G(alphai) than G(alphao) activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT(1A) receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT(1A) receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT(1A) receptors in vivo almost as potently as F13714. CONCLUSIONS AND IMPLICATIONS: F15599 showed a distinctive activation profiles for 5-HT(1A) receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT(1A) receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.

[Spontaneous splenic rupture: report of three new cases and review of the literature]. / Ruptures non traumatiques de la rate: trois nouveaux cas et revue de la littérature.

This study reports 3 new cases of spontaneous (or atraumatic) splenic rupture of the spleen, including two with massive hemoperitoneum and one with a secondary rupture of splenic infarct, and reviews the literature about this rare disease. These spontaneous ruptures are rare and potentially fatal. They result from infectious diseases (mainly mononucleosis and and paludism) and hematological diseases (mainly malignant hemopathies) in more than 50% of cases. Mortality is close to 20%, and includes some deaths occurring before diagnosis was established and postoperatives deaths, which can result from delayed management and bad general condition of the patients. Splenectomy is usually mandatory. Non-surgical treatment can be indicated only in young and stable patients.

5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential.

To examine further the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT1A receptors determines the magnitude of their psychotropic activity, we studied the relationship between the maximal receptor activation produced by various 5-HT1A receptor ligands and their antidepressant-like effects (i.e., decreased immobility in the forced swimming test in rats). Using three different in vitro assays suitable to measure differences among high, intermediate, and low efficacy 5-HT1A receptor agonists, ligands were identified with intrinsic activities ranging from low-negative (i.e., the inverse agonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane-carboxamide (WAY 100635)) to high-positive (i.e., 3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone (F 13714)). In addition, novel compounds with intermediate intrinsic activity, like buspirone, but with high selectivity for 5-HT1A receptors, unlike buspirone, were identified. The maximal effects of the 5-HT1A receptor ligands in the forced swimming test correlated positively (rS=0.91, P<0.005) with the rank order of their intrinsic activity at 5-HT1A receptors. This relationship constitutes evidence that the magnitude of the psychotropic activity of 5-HT1A receptor ligands is a positive function of their intrinsic activity at the receptor, and suggests that F 13714, which had maximal effects in the forced swimming test significantly larger than any of the other compounds examined here, did so because of its higher intrinsic activity at 5-HT1A receptors.

Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors.

The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1 -yl-metha none. Incorporation of a fluorine atom in the beta-position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and long-lasting 5-HT1A agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT1A receptors (versus dopaminergic D2 and adrenergic alpha1 receptors) and displayed more potent 5-HT1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-(H or CH3)-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-+ ++methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin- 2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT1A receptor agonist in vitro and in vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT1A receptor agonists with marked antidepressant potential.

Design and synthesis of a series of 6-substituted-2-pyridinylmethylamine derivatives as novel, high-affinity, selective agonists at 5-HT1A receptors.

A search for novel, selective agonists with high intrinsic activity at the 5-HT1A subtype of serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations led to the design of 6-substituted-2-pyridinylmethylamine as a potential 5-HT1A pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT1A, alpha1-adrenergic, and D2-dopaminergic receptors. Compounds with high affinity for 5-HT1A receptors (pKi >/= 8) were examined for agonist properties by measuring their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells permanently transfected with the h5-HT1A receptor gene and expressing the h5-HT1A receptor protein). Several compounds of the type aryl¿4-[(6-substituted-pyridin-2-ylmethylamino)methyl]piperidin -1-yl¿ methanone had nanomolar affinity for 5-HT1A binding sites and were more than 500-fold selective with respect to alpha1 and D2 sites. Importantly, their 5-HT1A agonist properties were demonstrated in HA7 cells where they behaved as potent inhibitors of cAMP accumulation. In particular, (3, 4-dichlorophenyl)¿4-[(6-oxazol-5-ylpyridin-2-ylmethylamin o)methyl]pip eridin-1-yl¿methanone (70) and (3, 4-dichlorophenyl)¿4-[(6-azetidinopyridin-2-ylmethylamino)met hyl]piper idin-1-yl¿methanone (36) appeared to be more potent than, and at least as efficacious as, the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. SAR studies revealed that the pyridine nitrogen atom and the nature and the position of the substituents on the pyridine ring were critically involved in the ability of the compounds to recognize and activate 5-HT1A receptors. Structural modifications of the nonpharmacophoric part of the molecule showed, however, that the entire structure was required for affinity at 5-HT1A binding sites.

[Laparoscopy-assisted colonic polypectomy or how to be helped by laparoscopy to prevent colectomy in benign colonic polyps considered to be unresectable by colonoscopy]. / La polypectomie colique coelio-assistée, ou comment s'aider de la coelioscopie pour éviter une colectomie pour les polypes coliques bénins jugés inextirpables en coloscopie?

The aim of this study was to prospectively evaluate the role of laparoscopic surgery in all patients presenting with colonic polyps. From April 1994 to April 1996, 16 consecutive patients were treated. The laparoscopy starts the procedure, then a colonoscopy easily and rapidly locates the colonic lesion. Under laparoscopic supervision a new snare polypectomy is often possible. If polypectomy remains impossible, a mini-laparotomy is performed above the polyp and allows polypectomy by extra-peritoneal colotomy. In one case, the polyp was not found on colonoscopy. Colonoscopic polypectomy was possible in 6 cases (40%), and 9 mini-laparotomies were necessary (60%). No colectomy was performed. The final histologic result showed two Dukes A carcinomas justifying secondary wide colectomy. Laparoscopy-assisted polypectomy is a safe and efficient procedure, allows complete excision of polyps and may avoid a colonic resection.

Immune-complex glomerulonephritis associated with Staphylococcus aureus infection of a totally implantable venous device.

We report a previously unrecognized complication of totally implanted subcutaneous ports. A patient with a totally implantable central venous device developed a septic syndrome. Blood and injection-reservoir cultures grew Staphylococcus aureus. There was no evidence of endocarditis. The port was removed but acute oliguric renal failure developed. A percutaneous renal biopsy showed acute diffuse proliferative glomerulonephritis. There was no extracapillary crescent. On immunofluorescence study, capillary wall granular deposits stained brightly for IgG and C3. These findings were thought to be consistent with infection-associated immune-complex glomerulonephritis.

Curative resection for left colonic carcinoma: hemicolectomy vs. segmental colectomy. A prospective, controlled, multicenter trial. French Association for Surgical Research.

PURPOSE: This study was developed to compare median and actuarial survival after left hemicolectomy vs. left segmental colectomy. METHODS: Between January 1980 and January 1985, 270 consecutive patients (133 males and 137 females; mean age, 64 +/- 12 (range, 18-91) years with left colonic carcinoma located between the left third of the transverse colon and (but not, including) the colorectal juncture were randomly allotted to undergo either left hemicolectomy or left segmental colectomy. Left hemicolectomy removed the entire left colon along with the origin of the inferior mesenteric artery and the dependent lymphatic territory. Left segmental colectomy removed a more restricted segment of the colon and left the origin of the inferior mesenteric artery unmolested. RESULTS: After elimination of 10 patients for protocol violation, 131 patients with left hemicolectomy and 129 with left segmental colectomy were analyzed. Both groups were similar with regard to preoperative risk factors (age, sex, obesity, weight loss, anemia, diabetes, cirrhosis, kidney failure, steroid therapy or radiation therapy performed for any cause other than cancer), pathology findings (size, degree of differentiation, Dukes stage, invasion of lymph nodes at the origin of the inferior mesenteric artery), and associated lesions. Only the length of tumor-free margins of colon removed was significantly longer in left hemicolectomy. The number of early postoperative abdominal and extra-abdominal complications was similar in both groups. Overall, early postoperative mortality was 4 percent higher, but not significantly in left hemicolectomy (eight deaths, 6 percent) than in left segmental colectomy (three deaths, 2 percent). Median survival was 10 years and nearly equivalent in both groups. The two actuarial survival curves were similar. Bowel movement frequency was significantly increased after left hemicolectomy during the first postoperative year. Our results suggest that survival after left segmental colectomy is equivalent to that of left hemicolectomy. Notwithstanding the observation of other carcinologic rules, left segmental colectomy rather than left hemicolectomy may theoretically be performed under laparoscopy without compromising the carcinologic outcome.

[Colorectal preparation for excision surgery. Development after 4 randomized multicenter studies]. / Préparation colo-rectale à la chirurgie d'exérèse. Evolution après 4 études multicentriques randomisées.

1,265 patients having elective surgery with colectomy for cancer or sigmoiditis have been included in four successive randomized multidepartmental studies in order to define the most effective preparation, reducing the rate of postoperative infections, and the shortest one. The first study included 202 patients divided up into 2 groups, and compared a three-day conventional preparation (CP) (low-residue diet, laxatives and enemas) with a total digestive irrigation (TDI) (9 liters in 6 h) with Mannitol. Both preparations were associated with a three-day preoperative antibiotic therapy with Neomycin and Tetracyclin. Intolerance to TDI (50% of cases) and the greater number of fistulae with this method lead to preferring CP. The second study (326 patients in 4 groups) compared on one hand, a CP with the single absorption of a sachet of Sennosides or 2 liters of 10% Mannitol, and on the other hand, the preoperative antibiotic treatment utilizing Neomycin or Tetracyclin over three days with a 24-hour treatment with Metronidazole. Its conclusions are that the absorption of Sennosides is better tolerated than Mannitol and significantly more effective than the CP. There is no significant difference between the antibiotic therapy over three days and that over 24 h. The third study (335 patients in 4 groups) compared on one hand, lukewarm water enemas to enemas with iodinated polyvidone diluted to 5%, and on the other hand an antibiotic therapy utilizing Metronidazole on the day before, the same day and the three following surgery with a 24-hour antibiotic therapy utilizing Metronidazole (1.5 g) and/or Cefotaxime (4 g) on the same day as the operation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Surgical resection of hepatocellular carcinoma. Retrospective study of 42 cases]. / Résection chirurgicale des carcinomes hépato-cellulaires. Etude rétrospective de 42 observations.

We studied the results 42 liver resections performed for hepatocellular carcinoma. Thirty-three patients underwent major liver resections. Hepatocellular carcinomas were associated with cirrhosis in 30.9 p. 100 of cases. The overall operative mortality was 24.3 p. 100: 60 p. 100 in patients with cirrhosis who underwent major liver resections and 12.5 p. 100 in patients with cirrhosis undergoing limited resections. The overall 5-year survival rate was 14.8 p. 100; the 5-year survival rate in patients with hepatocellular carcinoma without cirrhosis was 20 p. 100 whereas no patient with associated cirrhosis of the liver survived at 3 years. We conclude that surgical resection of hepatocellular carcinoma must be performed whenever possible: a limited resection should be done if the tumor is small, especially in patients with cirrhosis; a major liver resection must be proposed when the tumor is large and if the remaining liver parenchyma is normal.

Hemodynamic and biochemical monitoring during major liver resection with use of hepatic vascular exclusion.

Twenty-four resections under hepatic vascular exclusion (HVE) have been performed in patients with massive liver tumors. The procedure of HVE was used to minimize blood loss and the chance of gas embolism; it included clamping of the portal triad and occlusion of the inferior vena cava above and below the liver. In 12 of these patients the HVE was associated with clamping of the abdominal aorta above the celiac axis (AoC). During the "anhepatic" phase, which lasted 24 to 65 minutes (mean 39 minutes), neither venous shunt nor refrigeration was used. When HVE was associated with AoC, the circulation to the lower part of the body was completely excluded so that the systemic circulation was reduced to a small upper compartment in which the mean arterial pressure increased by 33% while the cardiac index decreased by 40%. The diastolic pulmonary arterial pressure remained unchanged. When HVE was not associated with AoC, the body was divided into an upper vascular compartment with normal venous resistance and a lower vascular compartment with increased resistance to the venous return and increased blood volume. The cardiac index, which was distributed to these two compartments, decreased by 40% to 50% but the mean arterial pressure decreased by only 14%. The good hemodynamic tolerance to HVE without AoC that was observed in these patients confirms the efficiency of collateral venous channels in the circumstances reported. AoC appears to be unnecessary in most patients if accurate fluid volume loading has been achieved before HVE. The study of acid-base balance demonstrates the ability of the human body to correct spontaneously the acidosis that follows the release of the clamps, provided a stable hemodynamic state is maintained. Only minor disorders of coagulation, without abnormal bleeding, were observed, and no prophylactic treatment was necessary. There were no deaths during operation, but a 25% postoperative mortality rate was observed mainly related to the underlying disease and the status of the remnant liver parenchyma. Despite its apparent sophistication, HVE is a simple and safe procedure for performing otherwise hazardous liver resections for tumors of large size or that are located close to the inferior vena cava and the suprahepatic veins. Its hemodynamic and metabolic consequences appear to be moderate.

[Resection of a retrohepatic inferior vena cava during hepatectomy for cancer. Favorable evolution without venous reconstruction]. / Résection de la veine cave inférieure rétro-hépatique au cours d'une hépatectomie pour tumeur. Evolution favorable sans reconstruction veineuse.

A primary malignant tumor of the liver in a 48-year-old woman was resected by right hepatectomy extending to the medial segment of the left lobe, along with the retrohepatic inferior vena cava. The caval interruption was not followed by a venous reconstruction or an associated right nephrectomy. The favorable outcome suggests that resection of the suprarenal portion of the inferior vena cava can be considered in some exceptional cases, even if venous collateral circulation has not developed.