Electron-induced ionization and cationic fragmentations of the isolated molecule of 2,4-imidazolidinedione (hydantoin): a study of the relaxing path thresholds.

In this work, our new experimental setup has been used to study the ionization and fragmentation of a prebiotic molecule, hydantoin, by electron impact. Scanning of the incident electron energy allows the determination of the appearance thresholds of the cations. The vertical ionization potential was found to be in good agreement with previous data. Dissociation thresholds for the main fragmentation patterns were also measured. In parallel, thanks to quantum chemical calculations, reaction schemes compatible with the experimental results are given.

Measurement of the absolute gamma-ray emission intensities from the decay of 103Pd.

Palladium-103 decays through electron capture to excited levels of 103Rh, and especially to the 39.748-keV metastable state. A high activity palladium chloride solution was standardized by liquid scintillation, using the Triple-to-Double Coincidence Ratio method. The absolute photon emission intensities were determined by gamma-ray spectrometry using point sources prepared with the standard solution. Different detectors and measuring conditions were used to cross-reference the results. The most intense photon emission intensities are derived with about 1% relative combined standard uncertainty.

Improvement of the activity measurement method for solid dosimeters emitting X-rays.

Today, there is growing interest for neutrons in the intermediate energy range between 100keV and 1MeV, which are responsible for damaging materials in reactor. To improve this deficiency, we use rhodium and niobium which, through the inelastic neutron scattering reaction, leads to the formation of 103mRh and 93mNb low-energy X-emitters. This paper describes the improvements and validation made on this type of complex measurement by X spectrometry: self-attenuation, fluorescence correction, and emission intensity were poorly known previously.

Measurement of absolute K X-ray emission intensities in the decay of 103mRh.

A new experiment was designed to measure the photon emission intensities in the decay of 103mRh. The rhodium samples were activated in the ISIS experimental nuclear reactor at CEA Saclay. The procedure includes an absolute activity measurement by liquid scintillation counting using the Triple-to-Double Coincidence Ratio method, followed by X-ray spectrometry using a high-purity germanium detector to determine the photon emission intensities. The new result (IX = 0.0825 (17)) is derived with a significant reduction of the uncertainty.

Consistency of photon emission intensities for efficiency calibration of gamma-ray spectrometers in the energy range from 20keV to 80keV.

The efficiency calibration for different high-purity germanium detectors in the low-energy range was established by the conventional method, using standard radioactive sources. The peak shapes were carefully analysed taking account of natural linewidth, full-energy width at half maximum and scattering. Complementary information was obtained by Monte Carlo simulation using the PENELOPE code, after optimization of the geometrical parameters. This was used to measure photon emission intensities of some low-energy emitting radionuclides, including 133Ba, and compared to the tabulated values.

New design of the pulsed electro-acoustic upper electrode for space charge measurements during electronic irradiation.

The behaviour of space charges injected in irradiated dielectrics has been studied for many years for space industry applications. In our case, the pulsed electro-acoustic method is chosen in order to determine the spatial distribution of injected electrons. The feasibility of a ring-shaped electrode which will allow the measurements during irradiation is presented. In this paper, a computer simulation is made in order to determine the parameters to design the electrode and find its position above the sample. The obtained experimental results on polyethylene naphthalate samples realized during electronic irradiation and through relaxation under vacuum will be presented and discussed.

Phase II multicentre study of docetaxel plus 5-fluorouracil in patients with anthracycline-pretreated metastatic breast cancer.

The purpose of the study was to determine the efficacy and safety of docetaxel plus continuous infusion of 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracyclines. A total of 41 patients with histologically proven metastatic breast cancer and performance status 0-2, who had received at least one anthracycline-containing regimen, received docetaxel 85 mg m(-2) followed by continuous infusion of 5-FU 750 mg m(-2) day(-1) for 5 days every 3 weeks for up to eight cycles. All patients received corticosteroid premedication, but there was no prophylactic colony-stimulating factor support. The most frequent metastatic sites were the liver (61%), bone (29%), and lung (29%). All 41 patients were assessable for toxicity and 30 were eligible and assessable for efficacy. The objective response rate was 70.0% (95% CI: 53.6-86.4%) for the per protocol group and 53.7% (95% CI: 38.4-68.9%) for the intent-to-treat (ITT) population. For the ITT population, median duration of response was 8.4 months (95% CI: 6.7-12.2 months), median time to progression was 6.7 months (95% CI 5.5-8.6 months), and median survival was 17 months (95% CI: 12.3-not recorded months). Grade 3/4 neutropenia occurred in 54% of patients, with febrile neutropenia in 24% of patients and 5% of cycles, but infections were rare. Stomatitis was frequent, grade 3 in 24% of patients and grade 4 in one patient (2%), but manageable. Diarrhoea was rare, grade 3 in 7% of patients and 1% of cycles. Other grade 3/4 nonhaematological toxicities were infrequent. In conclusion, this docetaxel/5-FU regimen is highly active and well tolerated in patients with anthracycline-pretreated metastatic breast cancer. The efficacy is particularly promising, as one-third of patients were either second-line and/or anthracycline-resistant/refractory.

Effects of NCX 4050, a new NO donor, in rabbit and human corpus cavernosum.

The effects of NCX 4050, a drug belonging to a new class of NO donors, was investigated in isolated preparations of human and rabbit corpus cavernosum (CC) and in human foetal corpora cavernosa (hfCC) smooth muscle cells. In strips of rabbit CC, NCX 4050 (0.001-100 microM) induced a concentration-dependent relaxation which was influenced neither by Nw-nitro-l-arginine-methyl-ester (l-NAME; 100 microm) nor by endothelium deprivation. The NCX 4050-induced relaxation was significantly reduced by the guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 microm) and enhanced by a specific phosphodiesterase 5 inhibitor, sildenafil (300 nm). Moreover, NCX 4050 (0.01-1 microm), induced a concentration-dependent potentiation of the relaxant response induced by electrical field stimulation (EFS) in rabbit preparations pre-treated with guanethidine and indomethacin. The relaxant effect of NCX 4050 was similar to that obtained by increasing concentrations (0.001-100 microm) of sodium nitroprusside (SNP) in either rabbit or human preparations. To further investigate the activity of NCX 4050 on human corpora cavernosa, we exposed cultured hfCC smooth muscle cells to increasing concentrations of NCX 4050 and SNP. We found that both compounds dose-dependently reduced cell proliferation. The antiproliferative effect of all the concentration tested of NCX 4050 was completely blocked by ODQ (1 microm). These results suggest that in rabbit and human corpora cavernosa NCX 4050 acts by activating guanylate cyclase activity, induces smooth muscle relaxation and quiescence. Our results provide a rationale for a possible future use of NCX 4050 in the pharmacotherapy of erectile dysfunction linked to an impaired release of NO from the endothelium.

Nitric-oxide releasing molecules: a new class of drugs with several major indications.

Nitric oxide (NO) deficiency has been implicated in many pathological and physiological processes within the mammalian body providing a plausible biologic basis for the use of NO replacement therapy in these conditions. Exogenous NO sources may hopefully constitute a powerful way to supplement NO when the body cannot generate enough for normal biological functions. This theory has opened up the possibility of designing new drugs that are capable of delivering NO into tissues and the bloodstream in a sustained and controlled manner. This objective has been reached by grafting an organic nitrate structure onto existing molecules with various spacers such as aliphatic or aromatic chain, with different degree of complexity. This approach has led to the synthesis of several new chemical entities in various pharmacological classes, whose profile seems to challenge the parent drug not only on the basis of new pharmacological properties but also on a better toxicological and safety profile. In this article, general aspects on NO and NO donors are reviewed. Major focus is placed upon recent developments of novel NO donors, NO releasing device(s) as well as innovative improvements to conventional NO donors. Several examples are given in some important therapeutic indications such as cardiovascular diseases (NO-aspirin), pain and inflammation (NO-paracetamol), osteoporosis and urinary incontinence (NO flurbiprofen with aliphatic spacer), Alzheimer s disease (NO-flurbiprofen with anti-oxidant spacer), respiratory disorders (NO-steroids).

Antiproliferative effect of Pygeum africanum extract on rat prostatic fibroblasts.

The effect of a Pygeum africanum extract (Tadenan) (Pa), used in the treatment of micturition disorders associated with BPH, has been examined on the proliferation of rat prostatic stromal cells stimulated by different growth factors. EGF, bFGF, and IGF-I but not KGF are mitogenic for prostatic fibroblasts in culture. Pygeum africanum inhibits both basal and stimulated growth with IC50 values of 4.5, 7.7 and 12.6 micrograms./ml. for EGF, IGF-I and bFGF, respectively, compared to 14.4 micrograms./ml. for untreated cells, the inhibition being stronger towards EGF. Pygeum africanum inhibited the proliferation induced by TPA or PDBu in a concentration-dependent manner with IC50 values of 12.4 and 8.1 micrograms./ml. respectively. The antiproliferative effects of Pa were not ascribed to cytotoxicity. These results show that Pygeum africanum is a potent inhibitor of rat prostatic fibroblast proliferation in response to direct activators of protein kinase C, the defined growth factors bFGF, EGF and IGF-I, and the complex mixture of mitogens in serum depending on the concentration used. PKC activation appears to be an important growth factor-mediated signal transduction for this agent. These data suggest that therapeutic effect of Pygeum africanum may be due at least in part to the inhibition of growth factors responsible for the prostatic overgrowth in man.

Beneficial effects of Tadenan therapy after two weeks of partial obstruction in the rabbit.

Tadenan (Debat Laboratories, France) is a plant extract used in Europe for the treatment of micturition disorders associated with benign prostatic hypertrophy (BPH). Prior studies demonstrated that pretreatment of rabbits with Tadenan significantly reduced the contractile dysfunction observed after 2 weeks of partial outlet obstruction. The specific aim of the present study was to determine the effect of Tadenan therapy following the creation of partial outlet obstruction. Two sets of experiments were performed: one with mild and the other with severe outlet obstruction. For both sets of experiments, male New Zealand rabbits (3-5 kg) were separated into 3 groups of 5 rabbits each. Each rabbit in groups 1 and 2 was obstructed using standard methodology. Rabbits in group 3 served as controls and did not receive any surgery. After 2 weeks, each rabbit in group 1 received Tadenan orally at 100 mg/kg/day for 3 weeks; each rabbit in group 2 received vehicle (peanut oil). After 3 weeks of treatment (5 weeks after partial outlet obstruction), rabbits were anesthetized and cystometries were performed. Immediately after cystometry, the rabbits were euthanized, the bladder rapidly removed, and 4 longitudinal strips prepared and mounted in individual baths for contractile studies. The contractile responses to field stimulation, carbachol, adenosine-5'-triphosphate (ATP), and potassium chloride (KCl) were determined, as follows: (1) Bladder mass approximately doubled in the mildly obstructed groups. Bladder mass increased significantly (3-5-fold) in the severely obstructed groups. (2) Cystometrograms from the mildly obstructed rabbits treated with peanut oil showed low compliance, whereas those of the mildly obstructed rabbits treated with Tadenan showed normal compliance. The cystometrograms of all severely obstructed rabbits showed low compliance. (3) Mild obstruction caused small but significant decreases in the contractile response to field stimulation that were reversed by Tadenan treatment. No changes were noted in response to bethanechol, ATP, and KCl stimulation. (4) Severe obstruction caused significant decreases in the response of bladder strips to field stimulation and bethanechol. Following Tadenan therapy, there was a significant improvement in the response to high-frequency field stimulation and a substantial improvement in the response to bethanechol (response equal to control). No changes were noted in response to ATP and KCl stimulation. In conclusion, Tadenan treatment reversed the bladder dysfunctions induced by mild partial outlet obstruction, and resulted in improved bladder function in the severe model of outlet obstruction. These studies are consistent with previous studies showing that Tadenan pretreatment protects the bladder against the development of contractile dysfunctions.

Effects of tadenan pretreatment on bladder physiology and biochemistry following partial outlet obstruction.

PURPOSE: Tadenan is a pharmaceutical agent used in the treatment of BPH. Prior studies demonstrated that pretreatment of rabbits with Tadenan significantly reduced the contractile dysfunction following two weeks of partial outlet obstruction. The specific aim of the present study was to determine the effect of Tadenan pretreatment on the time course of the response to partial outlet obstruction and correlate the effect of Tadenan on the contractile responses to field stimulation, bethanechol, and KCl with both mitochondrial enzyme activity (citrate synthase) and sarcoplasmic reticular function (calcium-ATP'ase activity). MATERIALS AND METHODS: Sixty male New Zealands white rabbit (3 to 5 kg.) were separated into 12 groups of 5 rabbits each. Each rabbit in groups 1-6 received Tadenan orally at 100 mg./kg./day for three weeks; each rabbit in groups 7-12 received vehicle (peanut oil). Each rabbit in groups 2-6 and 8-12 received a partial outlet obstruction as described below. One group of Tadenan treated and one group of vehicle-treated rabbits were euthanized at 1, 3, 5, 7, and 14 days following partial outlet obstruction. The non-obstructed groups were studied after 4 weeks of drug or vehicle treatment. Each bladder was rapidly removed and weighed, and 3 longitudinal strips prepared and mounted in individual baths for contractile studies. The remainder of the bladder was frozen for biochemical analysis. The contractile responses to field stimulation, bethanechol, and KCl were determined; and the enzyme activities of citrate synthase (marker for mitochondrial function) and calcium-ATP'ase (marker for sarcoplasmic reticulum) were determined. RESULTS: 1) Tadenan did not reduce the effect of partial outlet obstruction on bladder mass. 2) Although the contractile responses to forms of stimulation were reduced at 1 day following partial outlet obstruction, Tadenan pretreatment resulted in a significant protective effect on the contractile responses to field stimulation, bethanechol, and KCl at 3, 5, 7, and 14 days of obstruction. 3) The activities of both citrate synthase and calcium ATP'ase were reduced significantly at 1 day following obstruction for both Tadenan treated and vehicle treated groups. The activities of both enzymes returned to near normal levels at 7 and 14 days for the Tadenan groups whereas the activities of both enzymes remained significantly reduced in the vehicle treated groups. CONCLUSIONS: These results clearly demonstrate that Tadenan pretreatment protected the bladder from both the contractile and metabolic dysfunctions induced by partial outlet obstruction.

Protective effect of Tadenan on bladder function secondary to partial outlet obstruction.

PURPOSE: Tadenan (DEBAT, Paris, France) is a pharmaceutical agent used in the treatment of benign prostatic hyperplasia (BPH). The specific aim of this study was to determine if pretreatment of rabbits with Tadenan reduced either the hypertrophic response of the bladder to partial outlet obstruction or the accompanying contractile dysfunction. MATERIALS AND METHODS: Twenty-five male New Zealand rabbits (3 to 5 kg.) were separated into 5 groups of 5 rabbits each. Each rabbit in groups 1,2, and 3 received Tadenan orally at 1, 10 and 100 mg./kg./day for 3 weeks. Group 4 received vehicle only (peanut oil); Group 5 were controls. The bladders were evaluated (in vitro studies) after 2 weeks of obstruction. RESULTS: 1) Tadenan did not reduce the effect of partial outlet obstruction on bladder mass. 2) Tadenan pretreatment resulted in a significant protective effect on the contractile responses to field stimulation, bethanechol and KCl. CONCLUSIONS: These results clearly demonstrate that Tadenan pretreatment protected the bladder from the contractile dysfunctions induced by partial outlet obstruction.

Evidence for non-adrenergic binding sites for [3H]idazoxan in the smooth muscle of rabbit urethra.

The binding characteristics of [3H]idazoxan and [3H]rauwolscine, two potent alpha 2-adrenoceptor antagonists, were compared in the rabbit urethral smooth muscle. The maximal binding capacity was 6 times higher for [3H]idazoxan than for [3H]rauwolscine in male rabbits. No difference was observed for these radioligands in female rabbits. There were marked differences in the ability of alpha 2-adrenergic compounds to inhibit [3H]idazoxan and [3H]rauwolscine binding. These results were consistent with the existence of non-alpha 2-adrenoceptor sites for [3H]idazoxan in the rabbit urethral smooth muscle.

Effects of five alpha-blockers on the hypogastric nerve stimulation of the canine lower urinary tract.

Electrical stimulation of the hypogastric nerve increased both urethral and bladder pressures of anaesthetized male dogs, without affecting cardiovascular parameters. Intravenous injections of prazosin, phentolamine, thymoxamine, phenoxybenzamine and yohimbine inhibited the urethral pressure increase in a dose-dependent manner, but the increase in bladder pressure was not modified by these alpha-blockers.

Alpha 1- and alpha 2-adrenoceptors in the smooth muscle of male and female rabbit urethra.

[3H]Prazosin and [3H]rauwolscine, specific alpha 1- and alpha 2-antagonists respectively, were used to label alpha-adrenoceptors in membranes from male and female rabbit urethra. In the male rabbit, [3H]prazosin bound with high affinity (Kd = 0.56 nM) to a single population of sites with a capacity of 73 fmol/mg protein. [3H]Rauwolscine bound with a lower affinity (Kd = 2.24 nM) to another single class of sites with a capacity of 41 fmol/mg protein. The order of potencies of various adrenergic compounds in inhibiting radioligand binding suggested that [3H]prazosin and [3H]rauwolscine interacted in the urethra with sites having the characteristics of alpha 1- and alpha 2-adrenoceptors, respectively. In addition, studies on the female rabbit urethra showed that alpha 2-adrenoceptor density and affinity were respectively 6 times higher and 2 times lower than in the male. No significant sex difference was observed for urethral alpha 1-adrenoceptors.

[Effects of an extract of the bark of Pygeum africanum (V.1326) on prostatic secretions in the rat and in man]. / Effets d'un extrait d'écorce de Pygeum africanum (V.1326) sur les sécrétions prostatiques du rat et de l'homme.

Treatment with V.1326 in the rat induces an increase in prostatic secretion. In men with insufficient prostatic secretion, this treatment also induces an increased secretion.