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Conditions requiring inhibition of acid secretion, such as gastro-oesophageal reflux disease or peptic ulcers, are very common and their prevalence is expected to rise as they are seen predominantly in the elderly. The general basis of treatment with antisecretory agents is to maintain gastric pH >4 for a substantial proportion of the 24-hour cycle. Among the drugs available to inhibit acid secretion, proton pump inhibitors (PPIs) have been shown to have the best benefit-risk ratio and have been used widely. Intravenous administration of a PPI provides gastric acid suppression faster than oral administration does. Whereas some indications for the use of intravenous PPIs are widely known, mostly for acute management of peptic ulcer bleeding, there are some controversies surrounding their use in other conditions such as stress-induced mucosal damage. There is still a need to define the best schedule for intravenous PPI administration (i.e. bolus infusion or constant infusion), the optimal time to switch from intravenous to oral administration and the choice of which agent is best. In most of the clinical scenarios where PPIs are recommended, they can be administered via either oral or enteral routes, unless the patient is nil by mouth. Since there are no head-to-head comparisons of the different intravenous PPIs available worldwide (omeprazole, lansoprazole, pantoprazole and esomeprazole), the rule might be to choose the drug with the best proven efficacy in each specific condition. Indeed, the key difference between them, the ability to reach and to maintain a threshold gastric pH, might not necessarily translate into clinically significant differences.

Cancer remains the second leading cause of death, after cardiovascular diseases, in industrialized countries. The first goal to achieveis to prevent cancer occurrence or to diagnose it at an early and curable stage. Some screening strategies have been developed, with controversies across countries, for several cancer type; colorectal, breasts or prostate cancer for example.

Objective To assess the potential impact of new guidelines recommending routine antenatal prophylaxis at 28 weeks of pregnancy on incidence, consequences and cost of rhesus immunization. Study design All rhesus immunizations of 224,500 ongoing pregnancies in two neighbouring administrative areas in France between 2000 and 2006 were enrolled in this retrospective study. To determine the aetiology of immunization and to specify when sensitization occurred, we searched sensitizing events between the last negative and the first positive red-cell antibody test results. Perinatal consequences and costing were also analyzed. Results From 138 rhesus negative women bearing anti-D antibodies, none had received routine prophylaxis at 28 weeks. 37% were primary immunizations and 63% were reactivating former immunization. 63% sensitizations occurred after unprovoked foetal-maternal haemorrhage, mostly after 28 weeks (54%). Twenty-five (18.1%) sensitizations resulted from inappropriate management of existing prophylaxis. Immigrants with previously acquired antibodies accounted for 10% of cases. There was no foetal demise and none born before 28 weeks among our 140 babies. Only 25% required intensive care, mostly those born to mothers reactivating immunization, with an overall good perinatal outcome. Systematic 28-week prophylaxis would have cost about €2.5 million to reduce overall cost of immunizations by €0.6 million. Conclusions The incidence of rhesus immunization in our population was low at 0.41‰. Routine antenatal prophylaxis could have avoided 54% of these immunizations but expected perinatal benefits are low, as newborns with the worst issue were born to mothers with unavoidable immunizations. Therefore the cost-effectiveness of this strategy is doubtful.

Conditions requiring inhibition of acid secretion, such as gastro-oesophageal reflux disease (GORD), peptic ulcers, non-ulcer dyspepsia or the use of NSAIDs, are very common, and their prevalence is expecting to rise as they are seen predominantly amongst the elderly. Among the drugs available to inhibit acid secretion, proton pump inhibitors (PPI) have been shown to have the best efficacy-safety ratio and have been used widely.This paper was intended to provide an overall presentation of one of these PPIs, pantoprazole.This study was first intended to give an overview of pantoprazole, so a Medline search was conducted using pantoprazole as unique search term, without publication date restriction. We found 826 references for pantoprazole and selected some of the most relevant publications to conduct this review.Five different PPIs are commercially available: omeprazole, pantoprazole, rabeprazole, lansoprazole and esomeprazole. Pantoprazole differs from other PPIs by a selective binding to the ion transport pathway, a good stability at neutral pH values, and a relatively robust plasma concentration-time curve. These pharmacokinetic differences may not be fully converted into pharmacodynamic differences of pantoprazole versus other PPIs. Pantoprazole has been assessed in most of the clinical situations where acid suppression is required, and showed great efficacy and an excellent safety profile. Some safety concerns were raised with long-term use of PPIs, but they are well balanced by the benefit of PPIs for patients with conditions such as GORD or peptic ulcer.

The pathophysiology underlying preterm labor triggered by inflammatory conditions such as chorioamnionitis remains largely unclear. It has already been suggested that beta-3 adrenergic (ADRB3) agonists might be of interest in the pharmacological management of preterm labor. Although there is evidence implicating ADRB receptors in the control of inflammation, there are minimal data relating specifically to ADRB3. To explore the cellular consequences of chorioamnionitis and detect apoptosis, we first performed immunostaining and Western blot experiments on human myometrial samples obtained from women with confirmed chorioamnionitis. We then developed an in vitro model of chorioamnionitis by incubating the myometrial samples obtained from uncomplicated pregnancies with Escherichia coli lipopolysaccharide (LPS). We observed that chorioamnionitis was associated with a significant increase in cleaved CASP3 protein expression, as well as chromatin condensation, which were reproduced experimentally by LPS stimulation (10 microg/ml, 48 h). Lipopolysaccharide stimulation of normal human myometrium also induced CASP3 transcripts, increased the proapoptotic marker BAX, and decreased the antiapoptotic marker BCL2. Lipopolysaccharide-induced apoptosis was antagonized by neutralization of secreted tumor necrosis factor by a specific antibody. Furthermore, LPS stimulation increased medium culture levels of proinflammatory cytokines interleukin 6 (IL6) and IL8. Lipopolysaccharide-induced apoptosis and cytokine production were prevented by the new and potent ADRB3 agonist SAR150640 in a concentration-dependent manner. SAR150640 by itself did not exhibit any effect on apoptosis or cytokine production in control tissues. This study shows that chorioamnionitis is associated with apoptosis of human myometrial cells. It emphasizes the potential therapeutic interest of ADRB3 agonists in the field of preterm labor and other inflammatory conditions.

International audience; The management of premature birth still remains unsatisfactory. Since the relative lack of efficiency and/or safety of current tocolytic agents have been highlighted, it is necessary to develop new uterorelaxant drugs deprived of important maternal and foetal side effects. Our work reported in this review focuses on a potential new target for tocolytic drugs, the beta3-adrenoceptor (ADRB3). This third type of ADRB is shown to be present and functional in human myometrium. We demonstrated that ADRB3 agonists are able to inhibit in-vitro spontaneous contractions of myometrial strips, via a cyclic AMP-mediated pathway. Furthermore, we established that ADRB3 is the predominant subtype over the ADRB2 in human myometrium and that its expression is increased in near-term myometrium, compared to non-pregnant myometrium. Finally, we reported that contrary to ADRB2, the human myometrial ADRB3 is resistant to long-term agonist-induced desensitisation. These compelling data confirm the clinical potential interest of ADRB3 agonists in the pharmacological management of preterm labour.

Liver or lung metastases usually relapse under chemotherapy. Such life-threatening condition urgently needs new, systemic anticancer compounds, with original and efficient mechanisms of action. In B16 melanoma mice treated with cyclophosphamide, D'Agostini et al. [D'Agostini, C., Pica, F., Febbraro, G., Grelli, S., Chiavaroli, C., Garaci, E., 2005. Antitumour effect of OM-174 and Cyclophosphamide on murine B16 melanoma in different experimental conditions. Int. Immunopharmacol. 5, 1205-1212.] recently found that OM-174, a chemically defined Toll-like receptor(TLR)2/4 agonist, reduces tumor progression and prolongs survival. Here we review 149 articles concerning molecular mechanisms of TLR2/4 agonists, alone or in combination with chemotherapy. It appears that TLR2/4 agonists induce a well controlled tumor necrosis factor-alpha (TNF-alpha) secretion, at plasma levels known to permeabilize neoangiogenic tumor vessels to the passage of cytotoxic drugs. Moreover, TLR2/4 agonists induce inducible nitric oxide synthase (iNOS) expression, and nitric oxide is able to induce apoptosis of chemotherapy-resistant tumor cell clones. Finally, TLR2/4-stimulation activates dendritic cell traffic and its associated tumor-specific, cytotoxic T-cell responses. Therefore, parenteral TLR2/4 agonists seem promising molecules to prolong survival in cancer patients who relapse under chemotherapy.

HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by N(omega)-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080+/-27 vs 12189+/-761 arbitrary density units [ADU] for MC and control groups respectively, P

Summary Background: Recent data suggest that profound acid suppression may improve outcomes of patients in peptic ulcer bleeding. Aim: To better characterize the role of different pharmacological therapies in this population. Methods: MEDLINE was used to identify randomized trials (01/1990–04/2003) that assessed the efficacy of pharmacological treatments for patients with bleeding peptic ulcers exhibiting high-risk stigmata (Forrest Ia–IIb). Three groups of treatment were assessed: proton-pump inhibitors given as high-dose bolus followed by intravenous constant infusion (40–80 mg and at least 6 mg/h), high-dose oral proton-pump inhibitors (at least twice the standard dosage), non-high-dose proton-pump inhibitors (other proton-pump inhibitors dosing schedules). Mixed-effect models were used to determine rate differences between treatment and control groups. Results: Eighteen studies (1855 patients) were included. High-dose intravenous proton-pump inhibitors significantly reduced rebleeding (−14.6%), surgery (−5.4%) and mortality (−2.7%) compared with placebo, and rebleeding (−20.6%) compared with H2RA. Compared with placebo, high-dose oral proton-pump inhibitors significantly reduced only rebleeding (−11.8%), while non-high-dose proton-pump inhibitor treatment significantly improved all three outcomes. Conclusions: High-dose intravenous proton-pump inhibitor significantly decreases ulcer rebleeding, surgery and mortality. Early data on high-dose oral proton-pump inhibitor suggest improved rebleeding. The non-high-dose proton-pump inhibitor regimens, including a broad range of dosing, also improved outcomes, suggesting that doses inferior to those in the high-dose intravenous proton-pump inhibitor may be effective.

International audience; To assess whether pregnancy might influence the functionality and expression of human myometrial beta(2)- and beta(3)-adrenoceptors (beta(2)- and beta(3)-AR), we performed functional, binding, Western blot, and molecular biology experiments in human nonpregnant and near-term pregnant myometrium. Inhibition of spontaneous contractions induced by a beta(3)-AR agonist, SR 59119A, was significantly greater in pregnant, compared with nonpregnant, myometrial strips (E'(max) = 61 +/- 5% vs. 44 +/- 5% for pregnant and nonpregnant myometrium, respectively), whereas salbutamol, a beta(2)-AR agonist, was significantly less efficient in pregnant, compared with nonpregnant, myometrium (E(max) = 29 +/- 4 vs. 54 +/- 8%). Although two populations of binding sites corresponding to beta(2)- and beta(3)-AR were identified in both nonpregnant and pregnant myometrium, we found a clear predominance of the beta(3)-AR subtype. Moreover, beta(3)-AR binding sites were up-regulated 2-fold in myometrium at the end of pregnancy. Both beta(2)- and beta(3)-AR mRNA were expressed in human nonpregnant and pregnant myometrium. Contrary to beta(2)-AR, the expression of the beta(3)-AR transcripts and immunoreactive proteins was increased in pregnant, compared with nonpregnant, myometrium. Such compelling data suggest a predominant role for beta(3)-AR in the regulation of human myometrium contractility, especially at the end of pregnancy, which might have important consequences for the clinical management of preterm labor.

Bleeding from stress-related mucosal disease (SRMD) in critically ill patients remains an important clinical management issue. Although only a small proportion (2% to 6%) of patients admitted to an ICU setting will bleed (1), a significant proportion exhibit the clinical risk factors, mainly mechanical ventilation for more than 48 hrs and the presence of a coagulpathy (2), that predict a higher risk of bleeding; furthermore, upper gastrointestinal mucosal lesions can be found in 75% to 100% of ICU patients (3). Although uncommon, stress-ulcer bleeding (SUB) is a severe complication as it is estimated that up to 50% patients will die, mostly from decompensation of an underlying condition or multiorgan failure (4). The use of SUB prophylaxis remains a matter of concern, its efficacy has been questioned with, in addition, some concerns about the risk of adverse events such as nosocomial pneumonia and clostridium difficile infection (5). Several medications have been assessed, including sucralfate, histamine-2 receptor antagonists (H2RAs), and protonpump inhibitors (PPIs). As H2RAs were shown to be superior to sucralfate (6), use of prophylactic pharmacotherapy comes down to opting for H2RAs or PPIs—a choice that has remained controversial as the underlying pathophysiology of SRMD differs from that of bleeding peptic ulcers, relating less on acid secretion and more on decreased mucosal blood flow, local ischemia, hypoperfusion, and reperfusion injury (3). In this issue of Critical Care Medicine, Dr. Alhazzani et al (7), report a systematic review and meta-analysis on the use of H2RAs or PPIs for stress ulcer prophylaxis in critically ill patients. The authors conclude that PPIs compared with H2RAs are more effective at reducing clinically important upper gastrointestinal bleeding (relative risk [RR] 0.36; 95% CI 0.19, 0.68) and overt upper gastrointestinal bleeding (RR 0.35; 95% CI 0.21, 0.59), without significantly increasing the risk of nosocomial pneumonia (RR 1.06; 95% CI 0.73, 1.52; p = 0.76). PPIs, however, appear to reduce neither ICU mortality nor length of stay, confirming and expanding findings of our meta-analysis published earlier this year (8). The major strength of this study

The widespread use of nonselective NSAIDs and cyclo-oxygenase (COX)-2 inhibitors has a substantial impact on healthcare budgets worldwide. The cost of their gastrointestinal (GI) adverse effects is a major component of their direct cost and has received much attention in the literature. Published studies have often differed in their methodologies and results. It is important for decision makers to understand the reasons for these differences in order to make informed decisions. We conducted a literature review to summarise data that evaluate the direct costs of NSAID-related GI adverse effects worldwide. This resulted in 789 articles from which 29 studies met the inclusion criteria and were fully reviewed. Of these 29, the 9 studies that assessed the cost of COX-2 inhibitors were all based on decision economic models, compared with only 7 of the remaining 20 studies, which assessed the cost of nonselective NSAIDs. In most studies, the perspective was that of the healthcare payer and the costs assessed were reimbursement costs. Costs of GI events almost doubled between regular users and non-users of nonselective NSAIDs and were much higher in high-dose versus low-dose users. The ratio of the total cost of nonselective NSAIDs to their acquisition cost reported in all studies varied from 1.36 to 2.12. Both of these numbers were reported in one single study assessing several different NSAIDs in France. Thus, the GI adverse events attributable to nonselective NSAIDs are substantial, and their costs often exceed the cost of the nonselective NSAID itself.The acquisition cost of the COX-2 inhibitors was the main driver of their total cost. The GI adverse effects with the COX-2 inhibitors added 10-20% to their acquisition cost in North America, while this increase was about 50% in some European countries. Decision analysis models showed that the direct costs of COX-2 inhibitors were lower than those of nonselective NSAIDs in patients at risk of NSAID gastropathy but higher in patients at no to low risk of gastropathy. Thus, from an economic perspective, the healthcare system would benefit from treating patients at risk of NSAID gastropathy with COX-2 inhibitors, but not those at no to low risk.

We aimed to investigate the role of K(+) channels and nitric oxide (NO) on the relaxant effects of arachidonic acid in the human intralobar pulmonary arteries. Arachidonic acid produced a concentration-dependent relaxation (E(max)=93+/-3% of maximal relaxation induced by papaverine 0.1 mM;-log EC(30)=7.03+/-0.09) that was antagonized by the cyclooxygenase inhibitor indomethacin (1 microM), by the combination of cyclooxygenase blockade and cytochrome P450 (CYP) blockade with 17-octadecynoic acid (17-ODYA, 10 microM), by the combination of cyclooxygenase inhibition and NO synthase (NOS) inhibition with N(omega)-nitro-l-arginine (l-NOARG, 100 microM), by the simultaneous inhibition of CYP and NOS and by the simultaneous blockade of cyclooxygenase, CYP and NOS. Arachidonic acid-induced relaxation was significantly inhibited by glibenclamide (1 microM, ATP-dependent K(+) channel (K(ATP)) blocker), apamin and charybdotoxin (0.3 microM small (SK(Ca)) and 0.1 microM big (BK(Ca)) conductance Ca(2+)-sensitive K(+) channel blocker, respectively), and 4-aminopyridine (1 mM, voltage-dependent K(+) channel (K(V)) blocker). Indomethacin and ketoconazole suppressed the antagonistic effects of glibenclamide and apamin and 17-ODYA those of all the K(+) channel blockers tested. l-NOARG suppressed only the antagonistic effect of glibenclamide. We suggest that K(ATP), SK(Ca), BK(Ca) and K(V) are involved in the arachidonic acid-induced relaxation of human pulmonary arteries. Cyclooxygenase metabolites are the main relaxing agents of arachidonic acid, involving K(ATP) and SK(Ca) channels. CYP-dependent metabolites modulate arachidonic acid-induced relaxation through a pathway involving K(+) channels. K(ATP) channels are involved through a NOS-dependent pathway.

1. Gastro-oesophageal acid reflux may cause airway responses such as cough, bronchoconstriction and inflammation in asthmatic patients. Our previous results suggest that microvascular leakage induced, in the guinea-pig airways, by intra-oesophageal hydrochloric acid (HCl) infusion was mainly dependent on the release of tachykinins. Nociceptin, an endogenous ligand of the opioid receptor NOP, has been shown to inhibit bronchoconstriction and cough in guinea-pig or cat by inhibiting tachykinin release. 2. The purpose of this study was to investigate the effects of nociceptin on the intra-oesophageal HCl-induced airway microvascular leakage evaluated by Evans blue dye extravasation measurement in anaesthetised guinea-pigs pretreated with propranolol, atropine and phosphoramidon. 3. Infusion of intra-oesophageal HCl led to a significant increase in plasma extravasation in the main bronchi and trachea. This increase was abolished when animals underwent a bilateral vagotomy. 4. Airway microvascular leakage was inhibited by nociceptin (3-30 microg x kg(-1) i.v.) in a dose-dependent manner (maximal inhibition at the dose of 30 microg x kg(-1): 19.76+/-1.13 vs 90.92+/-14.00 ng x mg(-1) tissue for nociceptin and HCl infusion, respectively, in the main bronchi, P0.01). The NOP receptor agonist [Arg(14),Lys(15)]N/OFQ mimicked the inhibitory effect of nociceptin, but at a 10-fold lower dose (3 microg x kg(-1) i.v). The NOP receptor antagonist J-113397 had no effect on plasma protein extravasation by itself, but was able to block the inhibitory effect of nociceptin. 5. Morphine (1 mg x kg(-1)) had a similar inhibitory effect as that of nociceptin. Naloxone pretreatment abolished the effect of morphine, but was enable to block the inhibitory effect of nociceptin. 6. Under similar conditions, nociceptin, in the previous range of concentration, was unable to counteract the airway microvascular leakage induced by substance P (SP). 7. These results suggest that airway plasma extravasation induced by intra-oesophageal HCl instillation might be inhibited by specific stimulation of the NOP receptor with nociceptin. Nociceptin is likely to act at a pre-junctional level, by inhibiting tachykinin release, since it was unable to prevent SP-induced airway plasma extravasation.

4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide, hydrochloride (SSR126768A), a new potent and selective, orally active oxytocin (OT) receptor antagonist was characterized in several biochemical and pharmacological models. In binding studies, SSR126768A showed nanomolar affinity for rat and human recombinant and native OT receptors (K(i) = 0.44 nM) and exhibited much lower affinity for V(1a), V(1b), and V(2) receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 microM). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I(125)]d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8) (125)I-Tyr-NH(2)(9)]VT in situ labeling to OT receptors highly expressed in these tissues. In functional studies, SSR126768A behaved as a full antagonist and potently antagonized OT-induced intracellular Ca(2+) increase (K(i) = 0.50 nM) and prostaglandin release (K(i) = 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA(2) = 8.47). Similarly, in human pregnant myometrial strips, SSR126768A inhibited the contractile uterine response to OT. In conscious telemetrated rats, oral administration of SSR126768A (1-10 mg/kg) produced a competitive inhibition of the dose response to OT on uterine contractions up to 24 h at 3 mg/kg p.o.; no tachyphylaxis was observed after 4-day repeated treatment. Finally, SSR126768A (30 mg/kg p.o.) significantly delayed parturition in pregnant rats in labor similar to ritodrine (10 mg/kg p.o.). Thus, SSR126768A is a potent, highly selective, orally active OT receptor antagonist with a long duration of action. This molecule could find therapeutic application as a tocolytic agent for acute and chronic oral management of preterm labor.

To examine whether the risk of some selected adverse effects increases with the number of systemic non-steroidal anti-inflammatory (NSAID) drugs. The French Pharmacovigilance database was examined for an association between drug reaction reports and the exposure to one and two or more NSAIDs using a case/non-case study design. In the analysis, 54,583 spontaneous reports of adverse drug reactions were included, consisting of 2270 reports of hepatic injury, 994 reports of acute renal failure, 194 reports of gastrointestinal bleeding and 525 reports of angioedema, among others. Use of NSAIDs significantly increased the risk of hepatic injury, gastrointestinal bleeding, acute renal failure and angioedema. The odds ratios tended to increase with the number of NSAIDs for hepatic injury, gastrointestinal bleeding and acute renal failure but not for angioedema. In comparison with reports that did not mention any use of NSAIDs, the odds ratios associated with the use of a single NSAID and two or more NSAIDs were respectively 1.2 (95%CI: 0.9–1.5) and 2.2 (95%CI: 1.3–3.8) for hepatic injury, 7.3 (95%CI: 4.9–10.9) and 10.7 (95%CI: 2.9–40.2) for gastrointestinal bleeding, 3.2 (95%CI: 2.5–4.1) and 4.8 (95%CI: 2.6–8.8) for acute renal failure. For angioedema, the odds ratios were roughly similar when a single NSAID (OR=2.7; 95% CI: 2.2–3.4) or two or more NSAIDs (OR=2.0; 95%CI: 0.7–6.0) were used. The risk of severe ADRs (hepatic injury and acute renal failure) was six- to sevenfold higher in reports mentioning concomitant use of two NSAIDs or more than in those that did not. This study shows that concomitant use of two or more NSAIDs was associated with an excess risk of adverse effects such as hepatic injury, acute renal failure and gastrointestinal bleeding. Although simultaneous use of several systemic NSAIDs has no pharmacological justification, this may raise a serious public health problem with the increasing use of over-the-counter non-steroidal anti-inflammatory agents.

The effects of neurokinins and neurokinin receptor selective agonists have been investigated on human intralobar pulmonary vessels. Substance P (SP) and [Sar 9 Met(O 2 ) 11 ]SP, a selective NK 1 receptor agonist, induced concentration-dependent relaxation of pulmonary vessels precontracted with phenylephrine. The mean negative log (M) EC 50 values for SP and [Sar 9 Met(O 2 ) 11 ]SP were 8.6 and 8.9, respectively, on arterial preparations and 8.9 and 8.6, respectively, on venous preparations. Relaxations to [Sar 9 Met(O 2 ) 11 ]SP were abolished by the NK 1 receptor antagonist SR140333. The relaxations to a second application of [Sar 9 Met(O 2 ) 11 ]SP were markedly reduced, suggesting a rapid desensitization of the NK 1 receptor. Such desensitization was not observed with acetylcholine. The selective NK 2 receptor agonist, [Nle 10 ]NKA, and the selective NK 3 receptor agonist, [MePhe 7 ]NKB, caused neither contractions nor relaxations of pulmonary vessels. The NK 1 receptor-mediated relaxations were abolished by removing the endothelium or by a combination of N G -nitro-L-arginine and indomethacin, whereas each compound exerted a partial inhibitory effect. Similar results were observed with acetylcholine. Positive immunostaining for NK 1 receptors was only found in the endothelium. Reverse transcription-polymerase chain reaction detected messenger RNA for NK 1 receptors without any detection of messenger RNA for NK 2 or NK 3 receptors. In conclusion, human pulmonary arteries and veins express endothelial NK 1 receptors that mediate relaxation through a combination of cyclooxygenase and nitric oxide activities and are subjected to rapid tachyphylaxis.

We examined the influence of K+ channel antagonists on the vasorelaxation induced by theophylline (non selective PDEI), siguazodan (PDE3I), rolipram (PDE4I) and zaprinast (PDE5I) in human intralobar pulmonary arteries. All PDEI tested induced a concentration-dependent relaxation with theophylline being significantly (p < 0.05) more efficient and rolipram more potent than PDE5I and PDE3I (Emax values, expressed as a percentage of maximal relaxation by papaverine 10(-4)M, were 92% +/- 2%, 84% +/- 8%, 90% +/- 4% and 99% +/- 1%, and pD2 values were 7.30 +/- 0.35, 6.14 +/- 0.25, 5.86 +/- 0.17, and 4.85 +/- 0.47 for rolipram, siguazodan, zaprinast and theophylline, respectively). 4-Aminopyridine (4-AP, Kv, voltage dependent channel blocker, 1 mM) induced a significant increase (+17% p < 0.05) of U46619-induced vasoconstriction whereas the other K+-channels blockers, glibenclamide (KATP channels, 1 microM) charybdotoxin (predominant BKCa, large conductance Ca2+-sensitive K+ channels, 0.1 microM) and apamine (SKCa, small conductance, 0.3 microM) were without effect. The concentration response curves (CRC) for rolipram were significantly shifted to the right by glibenclamide (1 microM), charybdotoxin (0.1 microM) and 4-AP (1 mM). The CRC for siguazodan was significantly displaced to the right by 4-AP. None of the potassium channel blockers displaced the CRC for zaprinast and theophylline. Apamine was without effect on the CRC for all the PDEI used in this study. (1) PDE3, 4 and 5 are functionally present in human intralobar pulmonary arteries; (2) the vasoconstriction induced by U46619 is downregulated by 4-aminopyridine sensitive-K+ channels; (3) the relaxant effects of rolipram (PDE4I) are partly mediated through KATP, BKCa, and Kv potassium channels and those of siguazodan (PDE3I) by Kv potassium channels.

Purpose In order to assess biases occurring in primary care prescription studies, we compared non-steroidal anti-inflammatory drug (NSAID) prescribing patterns reported by general practitioners directly (GP-based survey) and from a pharmacy-based survey of general practitioner prescribing (pharmacy-based survey). Methods Volunteer GPs of the administrative area of Cote d'Or (France) returned a mailed questionnaire on NSAID prescribing patterns for consecutive patients seen during a 2-month period. In order to obtain a reference basis, pharmacies of the same administrative area provided all prescriptions that included NSAIDs during a 1-week period originating in general practice. Results The rate of participation was 25% for the GPs and 40% for the pharmacies. Participant GPs were representative of GPs of the area with regard to sex, year of graduation and practice area but pharmacies from rural areas were over-represented. The GP-based survey and the pharmacy-based survey provided respectively 770 and 1050 prescriptions. There were no differences between either survey in the type of NSAIDs prescribed and in the most frequently associated drugs. GPs who volunteered in the GP survey prescribed NSAIDs more frequently orally and at higher doses than GPs involved in the pharmacy-based survey. They also prescribed more gastroprotective drugs, especially in the elderly. None of these results could be explained by differences in patient characteristics and GP practice areas. Conclusion GPs who actively participate in prescription surveys exhibit prescribing patterns that fit better with official recommendations than the average. Although selection biases cannot be ruled out, it is suggested that some changes in GP prescription habits may have been induced by the survey itself. Copyright © 2001 John Wiley & Sons, Ltd.

To study the influence of pregnancy and labor on the proportion and level of activation of monocyte subpopulations in human pregnancy.Peripheral blood samples were obtained from healthy nonpregnant women (n = 6); women in the third-trimester of healthy pregnancies (n = 18) and women with preterm premature rupture of membranes (n = 46), just before delivery for the last 2 groups. Monocyte subpopulations were characterized by flow cytometry using CD14, CD16, and activation level using macrophage chemoattractant protein-1 (MCP-1) and CCR2 antibodies.The relative proportion of each monocyte subset in nonpregnant women was similar to that in women with healthy or complicated pregnancies. However, pregnancy was associated with a significant decrease in MCP-1 expressing monocytes (79.5% ± 19.8% vs 9.3% ± 6.8% and 11.9% ± 8.3% for nonpregnant, healthy pregnancy, and preterm premature rupture of membranes (respectively, P.05). Spontaneous labor was associated with a return to nonpregnant values for the proportion of MCP-1 expressing monocytes in both normal (74.4% ± 16.9) and preterm premature rupture of membranes pregnancy (68.4% ± 35.6), irrespective of the mode of delivery (vaginal or cesarean section). This was not observed in women who delivered without spontaneous labor onset. CCR-2 (MCP-1 receptor) expression was not modified in monocytes at the time of labor, but was significantly increased in granulocytes (3646 ± 1080 vs 7338 ± 2718 for nonlaboring and laboring preterm premature rupture of membranes, respectively, P.05) CONCLUSION: In light of previous reports of a role for MCP-1 in labor, our results suggest the downregulation of activation levels of monocytes, via MCP-1 expression might be involved in maternofetal immune tolerance. Monocyte reactivation might be associated with labor.

Background. This study was undertaken to assess the place for surgery in patients with iatrogenic hemobilia. Methods. Nineteen patients were treated for hemobilia caused by percutaneous liver biopsy (n = 11), percutaneous transhepatic cholangiography (PTC, n = 5), or percutaneous biliary drainage (PBD, n = 3). Selective embolization was attempted in all patients who bled after percutaneous liver biopsy or PTC but one, whereas irrigation via the external catheter was tried first in patients bleeding after PBD. Results. Selective embolization was successful in 13 cases (87%) of 15. Technical impossibility of selective embolization (n = 2) and absence of recognizable vascular lesion (n = 1) were the reasons for surgery in three actively bleeding patients. Indications for delayed surgery included hemocholecystitis (n = 3) and inadvertent embolization of the gallbladder (n = 1). Biliary decompression was only required after PTC and was achieved by endoscopic sphincterotomy (n = 3), percutaneous transtumoral intubation (n = 1), or surgery (n = 1) after failure of percutaneous biliary dilatation. After PBD, repeat irrigation and tube replacement were used to stop the bleeding and to decompress the biliary tract without embolization or surgery. None of the 19 patients died, and none experienced recurrent bleeding. Conclusion. Surgical indications for iatrogenic hemobilia are limited and include failure or complication of arterial embolization, hemocholecystitis, and failed attempt at endoscopic or percutaneous biliary decompression in case of obstructive jaundice.

It is unclear whether global experts with financial conflicts of interest (FCOIs) should be included in, be excluded from, or have a limited role in developing international clinical practice guidelines (CPGs). Optimal management of FCOIs to ensure independent, expert CPGs remains ethically contested.To manage FCOIs and examine whether an ethics framework with discussion recusal by experts with FCOIs affects deliberations and voting on a CPG.Development of an ethics framework grounded on transparency and proportional management of COIs, including self-recusal, evaluation of the effect on COIs and CPG process by quantification of voting on recommendations, and qualitative assessment of experts' ethics dialogue.International consensus meeting to formulate a CPG in gastroenterology.34 experts from 15 countries.Counting the votes of experts with and without declared FCOIs and qualitative assessment of ethics discussions.62% of experts reported at least 1 FCOI. Eight out of 21 recommendations presented potential FCOIs. Experts with conflicts recused themselves from discussing 6 of the 8 recommendations, leaving a majority of nonconflicted discussants (median, 22; range, 19 to 26) for the 6 recommendations. Recusals did not affect voting outcomes but may have diluted the richness of the discussions. Ethics dialogue revealed accord on transparency but underscored challenges to proportional management of COIs beyond basic disclosure. Concerns about bias, COI definitions, expertise, and integrity express important international ethics questions.Small participant numbers and application of the framework to only 1 meeting of 1 CPG.An ethics framework may help to identify and manage COIs and catalyze both ethics dialogue and innovative COI standards that seek to balance impartiality and expertise for trusted CPGs. Optimal balancing remains contested. Recommendations include frameworks, interdisciplinary analysis, and international policy initiatives to better manage COIs in the CPG process.Canadian Association of Gastroenterology; European Association for Gastroenterology and Endoscopy; Asian Pacific Society of Digestive Endoscopy; and Institute of Diabetes, Metabolism, and Nutrition of the Canadian Institutes of Health Research.

83% of patients had heartburn ≥2 days last week. Based on GerdQ scores 29% had high impact, 49% had medium impact and 22% low probability of GERD. In the OCP arm 81% had reflux esophagitis, 3% Barrett's esophagus and 5% had abnormal pH-metry. 147 patients (87%) in the NSP and 133 patients (80%) in the OCP arm were responders to therapy. NSP was found non-inferior to OCP, but superiority was not established (p=0.14). A costminimization analysis was conducted: the average direct medical cost in the NSP arm was 71 USD per patient compared with 542 USD in the OCP arm. CONCLUSION A symptombased approach using GerdQ, after excluding patients with alarm symptoms, reduces direct medical costs without loss in efficacy. GerdQ may provide physicians with a tool for more structured care of patients.

Dexlansoprazole MR is a modified release formulation of the R-enantiomer of lansoprazole, which employs a novel Dual Delayed Release (DDR) technology. Pharmacokinetic studies have shown that the DDR technology provides a two peaks drug release, accuring 1–2 hours and 4–5 hours after dosing, leading to an extended duration of therapeutic plasma drug concentrations compared with conventional delayed release lansoprazole. Dexlansoprazole MR 30 and 60 mg provided superior intragastric pH control compared to that obtained with lansoprazole 15 mg and 30 mg once daily dosing. Dexlansoprazole can be taken without regard to food. The drug has been shown to be as efficacious as lansoprazole in healing, and superior to placebo in maintaining healing, of erosive esophagitis. Dexlansoprazole appears to be well tolerated with a comparable safety profile to lansoprazole. Overall, dexlansoprazole DR has an interesting pharmacokinetic profile and is effective and well tolerated in the healing and maintenance of erosive esophagitis and in the treatment of GERD. Nevertheless in the absence of head-to-head comparison there is no mean to recommend its use preferentially to other PPIs.

G A A b st ra ct s data emanating from randomized clinical trials (RCTs) and epidemiological studies. We gathered summary data in a meta-analysis designed to better assess the effect of statins on the risk of developing CRC using epidemiological study data. Methods: Systematic searches were carried querying EMBASE, MEDLINE, CENTRAL, and ISI Web of knowledge. We selected epidemiological studies (non RCTs) published fully or presented in abstract form at major GI meetings. If needed, authors were contacted for additional information. The primary outcome was the occurrence of CRC, or a digestive cancer, depending on available information. Heterogeneity was sought and its presence or absence guided analytical model selection. Results are expressed as adjusted risk ratios (aRR) with their 95% confidence intervals (95%CI). Adapted sensitivity analyses were performed. Analyses were completed using SAS version 9.1 and RevMan 5. Results: 13 case-control (82,1416 patients) and 8 cohort studies (784,818 patients) were included. Statistical heterogeneity was noted in the cohort studies, which is why we adopted random effect models for this analysis; it was not the case for the case-control studies that we analyzed using fixed-effect models. Analysis of the case-control studies suggest a significant beneficial effect attributable to the statins compared to controls (aRR=0.92 [0.90-0.94] ; only a trend to a decrease was noted using cohort (RR=0.89 [0.75-1.05]. When all the studies were analyzed together, a significant but modest decrease was noted in the statin users (RR=0.92 [0.87, 0.98]). Conclusions: This meta-analysis suggests that prolonged statin use may provide a small but significant beneficial effect at decreasing the risk of CRC occurrence. The heterogeneity of the included studies limits any conclusions that can be drawn. The magnitude of the protective effect does not support promulgation of statins in the chemoprevention of CRC, at least in an average risk population.

In this issue, Sung and colleagues attempt to address an important clinical quandary: In patients who develop peptic ulcer bleeding while receiving antiplatelet therapy, should antiplatelet therapy...

need for transfusion, endoscopy or surgical haemostasis) ; there was no difference in the proportion of patients receiving PPI therapy before the GIB (34.5%, 33.9% and 39% in Gr. I, II and III). The mortality rate due to GIB did not differ between the 3 groups (4.2%, 4.6% and 4.9% in Gr. I, II and III). The proportion of patients whose APT was not discontinued, either temporarily or permanently, was 20.0%, 27.7% and 31.7% in Gr. I, II and III; Gr. I vs Gr. II comparison, p = 0.007). Analysis of the causes of GIB showed a greater proportion of erosive gastritis-related GIB in Gr. I (6.3%) and III (7.3%) than in Gr. II (0%) (Gr. I vs II, p = 0.04; Gr. III vs II, p = 0.055) and numerical trends towards a greater proportion of gastric ulcer in Gr. III (24.4%) as compared to Gr. I (13.6%, p=0.09) and Gr. II (12.3%, p = 0.011), and of diverticulosis-related GIB in patients receiving LDA [Gr. I (20.4%), Gr. III (17.1%), Gr. II (10.8%) (Gr. I vs II, p = 0.09)]. Conclusion:We have shown for the first time that GI bleeds associated with LDA, clopidogrel or the combination of both were very similar in their presentation and their prognosis. Apart from a trend towards more frequent bleeding due to erosive gastritis or diverticulosis with LDA, and due to gastric ulcer in those receiving dual therapy, the causes of GIB do not differ according to the type of APT received.