Imaging x-ray spectrometer at the high energy density instrument of the European x-ray free electron laser.

A multipurpose imaging x-ray crystal spectrometer is developed for the high energy density instrument of the European X-ray Free Electron Laser. The spectrometer is designed to measure x rays in the energy range of 4-10 keV, providing high-resolution, spatially resolved spectral measurements. A toroidally bent germanium (Ge) crystal is used, allowing x-ray diffraction from the crystal to image along a one-dimensional spatial profile while spectrally resolving along the other. A detailed geometrical analysis is performed to determine the curvature of the crystal. The theoretical performance of the spectrometer in various configurations is calculated by ray-tracing simulations. The key properties of the spectrometer, including the spectral and spatial resolution, are demonstrated experimentally on different platforms. Experimental results prove that this Ge spectrometer is a powerful tool for spatially resolved measurements of x-ray emission, scattering, or absorption spectra in high energy density physics.

Effects of the beta3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: relevance to its antidepressant/anxiolytic-like profile.

SR58611A is a selective beta(3)-adrenoceptor (Adrb3) agonist which has demonstrated antidepressant and anxiolytic properties in rodents. The present study confirmed the detection of Adrb3 mRNA transcript in rodent brain sub-regions and evaluated the effect of SR58611A on serotonergic and noradrenergic transmission in rats and mice in an attempt to elucidate the mechanism(s) underlying these properties. SR58611A (3 and 10 mg/kg, p.o.) increased the synthesis of 5-HT and tryptophan (Trp) levels in several rodent brain areas (cortex, hippocampus, hypothalamus, striatum). Moreover, SR58611A (10 mg/kg, p.o.) increased the release of 5-HT assessed by in vivo microdialysis in rat prefrontal cortex. Systemic (3 mg/kg, i.v.) or chronic administration of SR58611A (10 mg/kg, p.o.), in contrast to fluoxetine (15 mg/kg, p.o.), did not modify the activity of serotonergic neurons in the rat dorsal raphe nucleus. The increase in 5-HT synthesis induced by SR58611A was not observed in Adrb3s knockout mice, suggesting a selective involvement of Adrb3s in this effect. SR58611A (3 and 10 mg/kg, p.o.) did not modify norepinephrine synthesis and metabolism but increased its release in rat brain. Repeated administration of SR58611A (10 mg/kg, p.o.) did not modify basal norepinephrine release in rat prefrontal cortex whereas it prevented its tail-pinch stress-induced enhancement similarly to reboxetine (15 mg/kg, p.o.). Finally SR58611A increased the firing rate of noradrenergic neurons in the rat locus coeruleus following systemic (3 mg/kg, i.v.) or local (0.01 and 1 microM) but not chronic (10 mg/kg, p.o.) administration. These results suggest that the anxiolytic- and antidepressant-like activities of SR58611A involve an increase of brain serotonergic and noradrenergic neurotransmissions, triggered by activation of Adrb3s.

2-Chloro-N-[(S)-phenyl [(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide, monohydrochloride, an inhibitor of the glycine transporter type 1, increases evoked-dopamine release in the rat nucleus accumbens in vivo via an enhanced glutamatergic neurotransmission.

2-Chloro-N-S-phenyl 2S-piperidin-2-yl methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734) is a potent and selective inhibitor of the glycine transporter type 1, which increases central N-methyl-D aspartate glutamatergic tone. Since glutamate has been shown to play a role in the regulation of the dopaminergic system in dopamine-related disorders, such as schizophrenia, we investigated the possibility that SSR504734 may modify the basolateral amygdala-elicited stimulation of dopamine release in the nucleus accumbens via an augmentation of glutamate receptor-mediated neurotransmission. First, our data confirmed that SSR504734 is an inhibitor of GlytT1. In the nucleus accumbens of anesthetized rat, SSR504734 (10 mg/kg, i.p.) induced an increase of extracellular levels of glycine as measured by microdialysis coupled with capillary electrophoresis with laser-induced fluorescence detection. Second, the data demonstrated that SSR504734 (10 mg/kg, i.p.) enhanced the facilitatory influence of glutamatergic afferents on dopamine neurotransmission in the nucleus accumbens. Using an electrochemical technique, we measured dopamine release in the nucleus accumbens evoked by an electrical stimulation of the basolateral amygdala. SSR504734 facilitated dopamine release evoked by a 20 or a 40 Hz frequency basolateral amygdala stimulation. This facilitatory effect was dependent on glutamatergic tone, as intra-nucleus accumbens application of 6-7-dinitroquinoxaline-2,3-dione (10(-3) M) or DL-2-amino-5-phosphonopentanoic acid (10(-3) M), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D aspartate receptors antagonists, respectively, inhibited dopamine release evoked by basolateral amygdala stimulation. Furthermore DL-2-amino-5-phosphonopentanoic acid co-administrated with SSR504734 hampered the dopamine-evoked release facilitation. These data underline the in vivo implication of the glycine uptake mechanism in the control of subcortical glutamate/dopamine interactions.

Effects of the vasopressin (V1b) receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, on FG 7142-induced increase in acetylcholine and norepinephrine release in the rat.

Arginine vasopressin and corticotropin-releasing factor are two neuroactive peptides that regulate hypothalamic-pituitary-axis and associated stress response. While the potential antidepressant and anxiolytic profiles of corticotropin-releasing factor 1 antagonists have been well studied, the concept of blockade of vasopressin system as another approach for the treatment of emotional processes has only been made available recently by the synthesis of the first non-peptide antagonist at the V1b receptor, SSR149415. In the present study SSR149415 has been compared with the corticotropin-releasing factor 1 antagonist SSR125543 and with anxiolytic and antidepressant drugs on the response of hippocampal cholinergic and cortical noradrenergic systems to the anxiogenic benzodiazepine receptor inverse agonist FG 7142. Acute (0.3-10 mg/kg, i.p.) and long-term administration (10 mg/kg, i.p., 21 days) of SSR149415 and SSR125543 reduced the FG 7142-induced increase in extracellular concentrations of acetylcholine in the hippocampus of anesthetized rats measured by microdialysis. By contrast acute and long-term administration of SSR149415 failed to reduce the FG 7142-induced increase in the release of norepinephrine in the cortex of freely moving rats. The present results demonstrate that the two compounds have similar profiles in a model of activation by an anxiogenic drug of the hippocampal cholinergic system and they suggest that SSR149415 and SSR125543 may have anti-stress anxiolytic and antidepressant effects via a mechanism of action different from classical benzodiazepine ligands and noradrenergic antidepressants.

SR 120819A, an orally-active and selective neuropeptide Y Y1 receptor antagonist.

An orally-active antagonist of neuropeptide Y (NPY) Y1 receptors, SR 120819A, has been characterized. This compound displays highly selective and competitive affinity for rat, guinea-pig and human (Ki = 15 nM) NPY Y1 receptors. In vitro, SR 120819A blocks the inhibitory effect of NPY on adenylyl cyclase activity in human SK-N-MC cells and that of the selective Y1 agonist, [Leu31,Pro34]NPY, on rabbit vas deferens contraction (pA2 = 7.20 +/- 0.07). In vivo, by intravenous route, this compound acts as an antagonist in anesthetized guinea-pigs and, notably, after oral administration, SR 120819A counteracts the pressor response of [Leu31,Pro34]NPY (5 micrograms/kg i.v.) with a long duration of action (> 4 h at 5 mg/kg p.o.). Thus, SR 120819A is the first orally-effective NPY Y1 receptor antagonist yet described. It could be a useful tool for exploring the role of NPY and the therapeutic relevance of an antagonist at NPY Y1 receptors.

Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent--a pilot study in the setting of coronary angioplasty.

AIM OF THE STUDY: To assess the antithrombotic properties of SR90107/ORG31540. a sulfated pentasaccharide, which enhances specifically antithrombin III mediated inactivation of factor-Xa, in a clinical setting known to promote arterial thrombosis, i.e. coronary angioplasty. METHODS AND RESULTS: Percutaneous transluminal coronary angioplasty (PTCA) was carried out with conventional balloons with a single 5 min intravenous infusion of 12 mg pentasaccharide, and 500 mg intravenous aspirin. Heparin was not allowed before, during PTCA, and within 24 h after PTCA. The primary end point was the rate of abrupt vessel closure during and within 24 h after the procedure. The sample size was set at 60 evaluable patients, in order to be able to conclude with a good level of confidence (>95%) that the abrupt vessel closure rate was less than 10%, if less than 3 abrupt vessel closures were observed. Seventy-one patients were included in the study, of whom 10 needed elective stenting, and were not considered as evaluable for efficacy. Two out of the 61 remaining evaluable patients experienced acute vessel closure during the study period [3.28%, 95% confidence interval (0.4%; 11.4%)]. No major bleeding occurred. The drug plasma concentrations reached 1.91+/-0.39 mg/], 10 min after pentasaccharide injection, and decreased on average to 1. 18+/-0.27 mg/l at 2 h, and to 0.36+/-0.11 mg/l at 23 h after administration of pentasaccharide. Activated clotting time (ACT) and activated partial thromboplastin (aPTT) time remained within normal range. Thrombin-antithrombin complex levels fell from 22+/-17.1 to 4.5+/-3.4 microg/ml, prothrombin fragment 1+2 levels decreased from 2.15+/-1.01 to 1.73+/-0.87, and activated factor VII levels decreased from 43.4+/-16.8 mU/ml to 18.9+/-7.3 mU/ml respectively from baseline to 2 h following injection of the tested drug. CONCLUSIONS: Administration of pentasaccharide led to the inhibition of thrombin generation without modification of aPTT and ACT. The rate of abrupt vessel closure was within range of rates reported in historical series. Thus we conclude that the anti-thrombotic activity of pentasaccharide, as shown in this pilot trial in the setting of coronary angioplasty, deserves further investigation.

A pharmacodynamic study of SR 47436, a selective AT1 receptor antagonist, on blood pressure in conscious cynomolgus monkeys.

1. Conscious normotensive cynomolgus monkeys were chronically instrumented for the measurement of arterial blood pressure and heart rate to investigate the relationships between the plasma concentration, suppression of the pressor response to angiotensin II (AII), compensatory increase in plasma AII, and hypotensive effect obtained after a single oral dose of SR 47436, a potent and specific nonpeptide AT1 receptor antagonist. As blood sampling could influence the hypotensive effect of SR 47436 through activation of the renin angiotensin system (RAS), drug effects were studied in groups of animals with or without blood samplings. 2. SR 47436 at 10 mg kg-1 induced a hypotensive effect which was not greater following a second dose of 30 mg kg-1, indicating that a maximal hypotensive effect had already been obtained. 3. A single oral dose of SR 47436 (10 mg kg-1) caused a sustained hypotension and a marked inhibition of the AII-induced pressor response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bioavailability and a slow elimination of the drug (t 1/2 approximately 20 h), and were accompanied by a sustained increase in plasma AII concentration. Taken together, both the hypotensive response and the compensatory increase in AII indicated that vascular and juxtaglomerular AII receptors were blocked. 4. Although a fair correlation between individual plasma drug concentrations and inhibition of AII-induced pressor response was observed, neither the hypotensive effect nor the compensatory increase in AII correlated with the plasma drug levels. 5. Basal arterial pressure and AII-induced pressor response were not affected by blood samplings. 6. These results suggest that SR 47436 is an effective and long lasting AT1 receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys. It may be an efficacious blocker of the RAS in man and suitable for once-a-day dosing.

Characterization of the effect of SR48692 on inositol monophosphate, cyclic GMP and cyclic AMP responses linked to neurotensin receptor activation in neuronal and non-neuronal cells.

1. Neurotensin stimulated inositol monophosphate (IP1) formation in both human colonic carcinoma HT29 cells and in mouse neuroblastoma N1E115 cells with EC50 values of 3.5 +/- 0.5 nM (n = 4) and 0.46 +/- 0.02 nM (n = 3), respectively. Neurotensin also stimulated cyclic GMP production with an EC50 of 0.47 +/- 1.2 nM and inhibited cyclic AMP accumulation induced by forskolin (0.5 microM) with an IC50 of 1.33 +/- 1.5 nM (n = 3) on the N1E115 cell line. 2. The competitive antagonism by the non-peptide neurotensin receptor antagonist, SR48692 of neurotensin-induced IP1 formation revealed pA2 values of 8.7 +/- 0.2 (n = 3) for HT29 and 10.1 +/- 0.2 (n = 3) for N1E115 cells. SR48692 also antagonized the cyclic GMP and cyclic AMP responses induced by neurotensin in the N1E115 cell line with pA2 values of 10.7 +/- 0.7 (n = 3) and 9.8 +/- 0.3 (n = 3), respectively. 3. In CHO cells transfected with the rat neurotensin receptor, neurotensin stimulated IP1 and cyclic AMP formation with EC50 values of 3.0 +/- 0.5 nM (n = 3) and 72.2 +/- 20.7 nM (n = 3), respectively. Both effects were antagonized by SR48692, giving pA2 values of 8.4 +/- 0.1 (n = 3) for IP1 and 7.2 +/- 0.4 (n = 3) for cyclic AMP responses. 4. Radioligand binding experiments, performed with [125I]-neurotensin (0.2 nM), yielded IC50 values of 15.3 nM (n = 2) and 20.4 nM (n = 2) for SR48692 versus neurotensin receptor binding sites labelled in HT29 and N1E115 cells, respectively. 5 In conclusion, SR48692 appears to be a potent, species-independent antagonist of the signal transduction events triggered by neurotensin receptor activation in both neuronal and non-neuronal cell systems.

SR 46559A: a novel and potent muscarinic compound with no cholinergic syndrome.

The cholinergic activities of SR 46559A, 3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki = 112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6-7 times lower. SR 46559A did not interact with brain nicotinic receptors and high affinity choline uptake sites nor did it inhibit brain acetylcholinesterase activity. In contrast to reference muscarinic agonists, SR 46559A (1 mM) did not inhibit the forskolin-induced activation of cAMP synthesis nor did it stimulate phosphoinositides breakdown in various brain preparations. However, this compound enhanced (+67% at 1 mM) diacylglycerol formation in rat striatal miniprisms, an effect fully reversed by atropine. As shown with reference agonists, SR 46559A inhibited (IC50 = 10 microM) the K(+)-evoked release of [3H]GABA from rat striatal slices and reduced at 0.5 and 1 microM, the population spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffer's collateral commissural pathway in rat hippocampal slices. In mice, SR 46559A at a near lethal dose (200 mg/kg PO) did not induce the typical cholinergic syndrome nor did it modify at 30 mg/kg PO the oxotremorine-induced hypothermia. Like muscarinic agonists, SR 46559A (1 mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50 = 0.12 mg/kg PO) rotations induced in mice by intrastriatal injection of pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and effect of ticlopidine on platelet aggregation in subjects with normal and impaired renal function.

The pharmacokinetics and the effect of ticlopidine on platelet aggregation were determined in patients with chronic renal failure (n = 6), who were not on dialysis and had glomerular filtration of 16.9 +/- 4.4 mL/min, and were matched with the pharmacokinetics and effects in healthy volunteers (n = 7). Participants were studied after acute oral administration of ticlopidine at the beginning of the study and after 36 days of treatment with 250 mg twice daily. For unchanged ticlopidine there were no significant differences between the concentration profiles for the two study groups. By day 36 the minimum concentrations in plasma were identical (0.35 +/- 0.22 mg/L and 0.36 +/- 0.21 mg/L, respectively). Using 14C-labeled ticlopidine, the concentration profiles of radioactivity on day 1 were similar to those on day 36 for both groups. However, maximum concentrations and area under the concentration-time curve at 72 hours were both higher in patients with renal failure than in healthy volunteers. Treatment with ticlopidine progressively decreased sensitivity to adenosine diphosphate-induced platelet aggregation. At day 36, the concentration of adenosine diphosphate required to achieve 50% platelet aggregation was approximately 2.5 times greater than before treatment. Both patients and healthy volunteers exhibited closely comparable changes. The response to collagen-induced platelet aggregation was not changed in patients by treatment with ticlopidine. In contrast, volunteers required a three- to fourfold increase in collagen concentration to achieve 50% platelet aggregation after 36 days of therapy. Although some differences in both pharmacokinetics and pharmacodynamics of ticlopidine have been demonstrated between patients and and healthy volunteers, results in this study demonstrated that a change of dosage is not required in renal failure.

Up-regulation of 5-HT2 receptors in the rat brain by repeated administration of SR 46349B, a selective 5-HT2 receptor antagonist.

Chronic administration (twice a day for three days and on the morning of the fourth day) of SR 46349B (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3-(2-fluoroph enyl)propen-1- yl]phenol hemifumarate) (10 mg/kg, orally), a selective 5-HT2 receptor antagonist, caused 24 h later a marked increase (+42%) of the maximum binding capacity of [3H]ketanserin in rat brain cortical membranes without change in its affinity constant. Further, administration of the 5-HT2 receptor agonist, (+/-)-DOI((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (1 mg/kg, i.p.), produced in chronic SR 46349B treated rats a significant increase in the amount of [3H]-inositol phosphate compared to corresponding controls. In addition, subacute administration of SR 46349B caused a 2-fold increase in the head-twitch response to (+/-)-DOI (0.5 mg/kg, i.p.). This enhanced response was blocked by an acute administration of ritanserin (6-(2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-7- methyl-5H-thiazolo[3,2-a]pyrimidin-5-one) (10 mg/kg). Finally, a significant enhancement (+29%) of 5-HT2 receptor mRNA levels was observed in the cortex. Taken together, these data showed that an up-regulation of 5-HT2 receptors occurred in rats following repeated treatment with a selective 5-HT2 receptor antagonist. The effects of SR 46349B on 5-HT2 receptors might implicate pre-translational regulation.

Neurotensin is an antagonist of the human neurotensin NT2 receptor expressed in Chinese hamster ovary cells.

The human levocabastine-sensitive neurotensin NT2 receptor was cloned from a cortex cDNA library and stably expressed in Chinese hamster ovary (CHO) cells in order to study its binding and signalling characteristics. The receptor binds neurotensin as well as several other ligands already described for neurotensin NT1 receptor. It also binds levocabastine, a histamine H1 receptor antagonist that is not recognised by neurotensin NT1 receptor. Neurotensin binding to recombinant neurotensin NT2 receptor expressed in CHO cells does not elicit a biological response as determined by second messenger measurements. Levocabastine, and the peptides neuromedin N and xenin were also ineffective on neurotensin NT2 receptor activation. Experiments with the neurotensin NT1 receptor antagonists SR48692 and SR142948A, resulted in the unanticipated discovery that both molecules are potent agonists on neurotensin NT2 receptor. Both compounds, following binding to neurotensin NT2 receptor, enhance inositol phosphates (IP) formation with a subsequent [Ca2+]i mobilisation; induce arachidonic acid release; and stimulate mitogen-activated protein kinase (MAPK) activity. Interestingly, these activities are antagonised by neurotensin and levocabastine in a concentration-dependent manner. These activities suggest that the human neurotensin NT2 receptor may be of physiological importance and that a natural agonist for the receptor may exist.

Expression of tachykinin NK2 receptor mRNA in human brain.

Tachykinin NK2 receptors have been suggested to play an important role in the central nervous system. This study, using reverse transcription-polymerase chain reaction revealed a detectable expression of NK2 receptor mRNA in various human brain regions, including the caudate nucleus, the putamen, the hippocampus, the substantia nigra and the cerebral cortex. The distribution of NK2 receptor expression in the cortex revealed a major expression in frontal and temporal cortex compared to occipital and parietal areas. These results provide a molecular basis for considering a role of NK2 receptors in human pathophysiology.

Pharmacokinetic study of three synthetic AT-binding pentasaccharides in various animal species-extrapolation to humans.

The 'synthetic pentasaccharide', SR 90107A/Org 31540 (SP) representing the minimal AT-binding sequence of heparin is a catalyst of factor Xa inhibition. Affinity of SP, Sanorg 32701 (32701) and SR 80027 (80027), two close analogues of SP for rat, rabbit, baboon and human AT has been evaluated. The dissociation constants (Kd) for AT of the three species were in the range of 41-132, 1.4-6.2 and 2.8-4.6 nM for SP, 80027 and 32701, respectively. Comparative pharmacokinetics (PK) of their anti-factor Xa activities were determined in rats, rabbits and baboons. An apparent correlation could be demonstrated between half-lives of elimination and the corresponding Kd for AT in rats and rabbits whereas in baboons, such a correlation was not found. These results showed that despite Kd values ten times lower for 32701 than for SP, both compounds showed close PK parameters in baboons whereas the very low Kd value for 80027 was associated with an extended terminal half-life in this species. The predicted human PK parameters were determined using an allometric model: an empirical approach based on the integration of data obtained in various animal species which allows the extrapolation to humans. The values obtained for the terminal half-lives of SP, 80027 and 32701 were 14.1, 88 and 6.5 h, respectively. For SP, calculation by allometry correlated well with the values observed in man. Since knowledge of duration of activity is pivotal for appropriate design of phase I clinical studies of anti-Xa oligosaccharides, allometry appears to be an interesting tool to predict the duration of action of such compounds in man.

Safety, tolerability, and pharmacokinetics of SR 49059, a V1a vasopressin receptor antagonist, after repeated oral administration in healthy volunteers.

UNLABELLED: The conventional evaluation of safety and tolerability during Phase I may not be sufficient for new exploratory non-peptide receptor antagonists as selective vasopressin (AVP) receptor antagonists. Previous research and validation of surrogate markers considerably enhance the understanding of phase I, and may even contribute with high accuracy to an early approach of dose finding. SR 49059 is a new potent and selective non peptide AVP-antagonist, with high affinity, selectivity and efficacy towards both animal and human AVP-V1a receptors. The aim of this study was to assess its tolerability and to determine both its pharmacokinetic and pharmacodynamic profiles. The safety and tolerability of SR 49059 was assessed in an ascending repeated dose tolerability trial, double-blind for each dose. 50 healthy subjects non smoker males, divided into 5 groups (doses) of 10 were included, (8 treated/2 placebo per group) and received oral doses of either 1, 10, 100, 300 or 600 mg of SR 49059 o.d. for 7 days. Clinical tolerability and biological safety was excellent for all subjects up to the highest dose of 600 mg SR 49059 appeared to have no action on AVP plasma level, hemostasis parameters, nor on blood pressure, heart rate, ECG, diuresis or plasma/urine osmolality. Two previously validated surrogate markers using exogenous vasopressin were sufficient to provide evidence of the V1a antagonistic effects of SR 49059 after the first single oral administration, and during the 7 days of treatment: Ex-vivo AVP induced platelet aggregation inhibition: SR 49059 has shown potent antagonistic properties in inhibiting AVP-induced human platelet aggregation in vitro (IC50 = 3.7 nM). Using this ex vivo qualitative test, a dose and time proportional activity was observed at doses as low as 10 mg, and an almost complete inhibition was demonstrated from 100 mg and above, from Day 1 with a steady state level of inhibition from Day 4 up to Day 7. AVP induced blanching skin area inhibition: Intradermic administration of AVP 0.1 ml (25 ng) produced a measurable vasoconstriction (computer analysis of blanching area), which was also dose dependently antagonised by the oral administration of SR 49059 with the same profile as for platelet-aggregation inhibition. Steady state SR 49059 levels were achieved on days 4-5 with moderate (1.8-2.4 fold) accumulation (t1/2: 32 hrs). Cmax values were in the range 0.8-30 ng/ml. The IC50 of AVP (50 nM) -induced platelet aggregation and cutaneous blanching effect were 2.1 +/- 0.7 nM (1.3 ng/mL) and 4.6 +/- 2.5 nM (2.8 ng/mL), respectively. CONCLUSIONS: During early phase I, in addition to the conventional safety profile, validated surrogate markers may provide evidence of activity for selective vasopressin receptor antagonists. The results confirmed that SR 49059 is in human a specific V1a-antagonist without activity at V2 receptors, with a good safety profile.

Pain as a mutual experience for patients, nurses and families: a perspective from Valencia, Spain.

The Spanish data collection was consistent with the overall study design and drew from three groups: laboring women, children and elderly patients. The Valencia data was amongst the most detailed, specific and complete in this international study. This is most likely due to the experienced nature of the Spanish research team. The study results revealed more commonalities than differences in all age groups with regard to pain identification and pain alleviation. Across age groups, pain was identified by study participants through observation and listening.

[Xerostomia]. / La xerostomía.

A great many conditions may lead to dry mouth; indeed, xerostomy is a very frequent clinical finding that occasionally does not receive the attention deserved. A review of this condition is carried out, providing a practical perspective for the general stomatologist regarding the physiopatological mechanisms involved, the clinical manifestations, diagnostic procedures and current therapeutic approaches.

[Sialoadenosis of the parotid glands: diagnostic considerations]. / Sialoadenosis de las glándulas parótidas: consideraciones diagnósticas.

We present 3 cases of Sialoadenosis of the parotid glands, one male and two females, who presented associated systemic pathology (liver cirrhosis and diabetes mellitus), detected following clinically suspect syaloadenosis (the patients were unaware of their systemic disease). In all three cases definitive diagnosis was established by needle aspiration of the gland. Which revealed great acinar dilatation. Finally, differential diagnosis was established between sialoadenosis and those conditions with clinical presentations similar to those described for sialoadenosis.

Compound odontoma erupting in the mouth: 4-year follow-up of a clinical case.

A case of a compound odontoma erupting in the oral cavity is presented: a follow-up study of 4 yr has been performed evaluating the possible relationship with a previous dental trauma. A discussion is presented concerning the etiologic aspects, clinical signs, diagnostic aids and therapeutic approaches to this type of lesion.

[Sjögren's syndrome]. / El sindrome de Sjögren.

We carry out an updated review of Sjögren's syndrome on occasion of the presentation of three new clinical cases whose oral manifestations led the patients to first seek help. Each patient was subjected to clinical exploration, together with complementary evaluations, aimed at establishing an early and precise diagnosis of the syndrome. We consider it important to adopt a series of standardized diagnostic criteria and revise treatment to maintain the orodental conditions as favorable as possible.