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Biomedical subjects

M Bardou

Publications and source records attributed to M Bardou.

At least 19 recordsLinked to original sources
PubMed2006

Hospitalization for gastrointestinal bleeding associated with non-steroidal anti-inflammatory drugs among elderly patients using low-dose aspirin: a retrospective cohort study.

OBJECTIVES: Many elderly patients are prescribed both low-dose aspirin (ASA), for cardiovascular protection and non-steroidal anti-inflammatory drugs (NSAIDs) for pain control. Compared with non-selective NSAIDs (NS-NSAIDs), celecoxib has a superior gastrointestinal (GI) safety profile in general. It is unclear, however, whether this fact holds good among patients taking ASA. We compared GI hospitalization rates among elderly patients taking celecoxib, NS-NSAIDs, celecoxib and ASA or NS-NSAIDs and ASA. METHODS: This was a retrospective cohort study using Quebec government databases. All patients 65 yrs of age or older who filled a prescription for celecoxib or an NS-NSAID between April 1999 and December 2002 were included. Cox regression models were used to compare the GI hospitalization rates between the four exposure categories adjusting for potential confounders. RESULTS: A total of 332 491 patients were included. Among 1 522 307 celecoxib prescriptions, 430 214 were filled by patients concurrently receiving ASA (celecoxib and ASA); 195 369 of 863 646 NS-NSAID prescriptions were filled by patients receiving ASA (NS-NSAID and ASA). Celecoxib without ASA was less likely than NS-NSAID without ASA to be associated with GI hospitalization [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.33-0.50]; celecoxib and ASA was also less likely to be associated with GI hospitalization than NS-NSAID and ASA (HR 0.62, 95% CI 0.48-0.80); GI hospitalization rates were similar for celecoxib and ASA and NS-NSAID without ASA (HR 1.01, 95% CI 0.81-1.25). CONCLUSION: Among elderly patients receiving cardiovascular protection with ASA and pain control with anti-inflammatory drugs, celecoxib may be safer with regards to GI toxicity than NS-NSAIDs.

Aged↗
PubMed2005

Stimulation of the ADRB3 adrenergic receptor induces relaxation of human placental arteries: influence of preeclampsia.

Preeclampsia, which complicates 3-8% of pregnancies, is one of the leading causes of neonatal morbidity and mortality. Its pathophysiology remains unclear. The aim of the present study was to investigate the presence and the role of beta2- and beta2-adrenergic receptors (ADRB2 and ADRB3, respectively) in human placental arteries and to assess the influence of preeclampsia on ADRB responsiveness. SR 59119A, salbutamol, and isoproterenol (ADRB3, ADRB2, and nonselective ADRB agonists, respectively) induced a concentration-dependent relaxation of placental artery rings obtained from women with uncomplicated or preeclamptic pregnancies. SR 59119A-induced relaxation was unaffected by the blockade of ADRB1 and ADRB2 by 0.1 microM propranolol but was significantly decreased by the blockade of ADRB1, ADRB2, and ADRB3 by 10 microM propranolol. Both SR 59119A and salbutamol were associated with a significant increase in cAMP production that was significantly inhibited by pretreatment with 0.1 microM propranolol only for salbutamol. SR 59119A-induced relaxation (E(max) = 28% +/- 5% vs. 45% +/- 4%, respectively) and cAMP production (2.7 +/- 0.5 vs. 4.9 +/- 0.4 pmol/mg of protein, respectively; P < 0.01) were decreased in arteries obtained from preeclamptic compared to normotensive women. Both ADRB2 and ADRB3 transcripts were expressed at the same level between arteries from normotensive and preeclamptic women. Western blot analysis, however, revealed a decreased expression of the ADRB3 immunoreactive protein in arteries from preeclamptic compared to normotensive women. We suggest the presence of functional ADRB2 and ADRB3 in human placental arteries. Even if preeclampsia is associated with an impairment of the ADRB3 responsiveness, ADRB3 agonists may have future pharmaceutical implications in the management of pregnancy-related disorders.

Adrenergic beta-2 Receptor Agonists↗
PubMed2005

Meta-analysis: proton-pump inhibition in high-risk patients with acute peptic ulcer bleeding.

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 H(2)RA. 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.

Administration, Oral↗
PubMed2004

Beta3-adrenoceptor is the predominant beta-adrenoceptor subtype in human myometrium and its expression is up-regulated in pregnancy.

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.

Adrenergic beta-Agonists↗
PubMed2004

The cost-effectiveness of high-dose oral proton pump inhibition after endoscopy in the acute treatment of peptic ulcer bleeding.

BACKGROUND: Recent data suggest a role for high-dose oral proton pump inhibition in ulcer bleeding. AIM: To compare the cost-effectiveness of oral high-dose proton pump inhibition to both high-dose intravenous proton pump inhibition and placebo administration. METHODS: The model adopted a 30-day time horizon, and focused on patients with ulcer haemorrhage initially treated endoscopically for high-risk stigmata. Re-bleeding rates were set a priori based on non-head-to-head data from the literature, and charges and lengths of stay from a national American database. Sensitivity analyses were carried across a broad range of clinically relevant assumptions. RESULTS: Re-bleeding rates for patients receiving intravenous, oral, or placebo therapies were 5.9%, 11.8%, and 27%, respectively. The mean lengths of stay and costs for admitted patients with and without re-bleeding were 4.7 and 3 days; $11,802, and $7993, respectively. High-dose intravenous proton pump inhibition was more effective and less costly (dominant) than high-dose oral proton pump inhibition with incremental savings of $136.40 per patient treated. The oral high-dose strategy in turn dominated placebo administration. Results remained robust according to one- and two-way sensitivity analyses. CONCLUSION: In patients undergoing endoscopic haemostasis, subsequent high-dose intravenous proton pump inhibition is more cost-effective than high-dose oral proton pump inhibition, which in turn dominates placebo. The results from this exploratory-type cost analysis require confirmation by head-to-head prospective trials performed in Western populations.

Cost-Benefit Analysis↗
PubMed2004

High-dose intravenous proton pump inhibition following endoscopic therapy in the acute management of patients with bleeding peptic ulcers in the USA and Canada: a cost-effectiveness analysis.

BACKGROUND: The efficacy of high-dose intravenous proton pump inhibition has recently been shown, yet its cost-effectiveness remains poorly studied. AIM: To assess the cost-effectiveness of this approach separately for American and Canadian health care settings. METHODS: A validated decision model included patients with bleeding ulcers after successful endoscopic haemostasis. Probabilities were determined from the literature, and charges and lengths of stay from national databases. A third-party payer perspective was adopted over a 30-day time horizon. RESULTS: Re-bleeding rates were 5.9% for patients who received high-dose intravenous proton pump inhibition and 22.9% for those who did not. Hospitalization costs for patients with and without re-bleeding were 11,802 US dollars and 7993 US dollars, and 5220 Canadian dollars and 2696 Canadian dollars, respectively. High-dose intravenous proton pump inhibition was more effective and less costly than the alternative of not administering it. The cost-effectiveness ratios for high-dose and no high-dose intravenous proton pump inhibition were 9112 US dollars and 11,819 US dollars (3293 dollars and 4284 dollars for the Canadian case), respectively. Sensitivity and threshold analyses showed that the results were robust across a wide range of clinically relevant assumptions. CONCLUSION: In the USA and Canada, administering high-dose intravenous proton pump inhibition for 3 days is both more effective and less costly than not doing so for patients with bleeding ulcers after successful endoscopic haemostasis.

Anti-Ulcer Agents↗
PubMed2004

The human near-term myometrial beta 3-adrenoceptor but not the beta 2-adrenoceptor is resistant to desensitisation after sustained agonist stimulation.

1. In order to compare the beta(2)- and beta(3)-adrenoceptor (beta-AR) desensitisation process in human near-term myometrium, we examined the influence of a pretreatment of myometrial strips with either a beta(2)- or a beta(3)-AR agonist (salbutamol or SR 59119A, respectively, both at 10 microm, for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP) production induced by these agonists. 2. To assess some of the mechanisms potentially implicated in the beta-AR desensitisation process, we studied the influence of such treatment on the number of beta(2)- and beta(3)-AR binding sites, the beta(2)- and beta(3)-AR transcripts expression and the phosphodiesterase 4 (PDE4) activity. 3. Salbutamol, but not SR 59119A, concentration-response curve (CRC) was shifted by a 15 h salbutamol preincubation, with a significant difference in -log EC(20) values (6.31+/-0.13 vs 5.58+/-0.24, for control and 15 h salbutamol pretreatment, respectively, P<0.05). Neither salbutamol nor SR 59119A CRCs were modified after a 15 h preincubation with SR 59119A. 4. A 15 h exposure of myometrial strips to salbutamol significantly reduced the salbutamol-induced (0.60+/-0.26 vs 1.54+/-0.24 pmol mg(-1) protein, P<0.05), but not the SR 59119A-induced, cAMP production. No decrease in cAMP production was observed after a 15 h SR 59119A exposure. 5. A 15 h salbutamol exposure of myometrial strips significantly reduced the beta(2)- but not the beta(3)-AR binding site density, whereas no decrease in the number of beta(2)- and beta(3)-AR binding sites was observed after a 15 h SR 59119A treatment. 6. Neither PDE4 activity nor the beta(2)- and beta(3)-AR mRNA expression levels were affected by salbutamol or SR 59119A treatments. 7. Our results indicate that beta(3)-AR, but not beta(2)-AR, are resistant to the agonist-induced desensitisation. In our model, beta(2)-AR desensitisation is mediated by a decreased number of beta(2)-AR that was not explained by transcriptional regulation of the receptor.

Adrenergic beta-2 Receptor Agonists↗
PubMed2002

Excessive alcohol consumption favours high risk polyp or colorectal cancer occurrence among patients with adenomas: a case control study.

BACKGROUND AND AIMS: Excessive alcohol consumption is a risk factor for developing colorectal adenomas. This study aimed to investigate the influence of excessive alcohol consumption on the occurrence of high risk polyps (adenoma > or = 10 mm, villous component, high grade dysplasia) or colorectal cancer among patients with at least one colonic adenoma. PATIENTS AND METHODS: Three groups of patients with at least one colorectal adenoma were included in a case control study: 401 heavy drinkers (group HD, mean daily alcohol intake 117 (SD 4) g/day for a mean duration of 22 (SD 0.6) years), aged 57 (0.5) years (78% men); 152 patients suffering from irritable bowel syndrome (IBS), aged 61 (0.9) years (57% male); and 108 patients with a family history (FH) of colorectal adenoma or cancer, aged 55 (1) years (64% male). Exclusion criteria were: anaemia, haematochezia, personal history of colorectal adenoma or cancer, and for groups HD and IBS a family history of colorectal adenoma and/or cancer. Relative risks were estimated by the odds ratio (OR) using a logistic regression model and were expressed with 95% confidence interval (CI). RESULTS: After age and sex adjustment, the likelihood of having an adenoma > or = 10 mm was higher in group HD than in the IBS group (OR 1.8, 95% CI (1.2-2.7)) and the likelihood of having high risk adenomas or cancer was higher in group HD compared with the IBS group (OR 1.6, 95% CI (1.2-2.1)) and the FH group although this was not significant (OR 1.6, 95% CI (0.97-2.6) (p=0.081); 90% CI (1.03-2.4)). After age and sex adjustment, the likelihood of having an adenoma with high grade dysplasia or cancer was higher in group HD than in the IBS group (OR 1.7, 95% CI (1.02-2.8)) or group FH, although this was not significant (OR 3.7, 95% CI (0.98-15) (p=0.076); 90% CI (1.10-12.47)). CONCLUSION: In patients with at least one colorectal adenoma, excessive alcohol consumption increases the likelihood of developing high risk adenomas or colorectal cancer.

Adenoma↗
PubMed2002

Relaxation of proximal and distal isolated human bronchi by halothane, isoflurane and desflurane.

Volatile anaesthetics relax airway smooth muscle in vitro. The amount of relaxation might depend on the type and concentration of volatile anaesthetics, the calibre and precontraction level of the bronchi, and also on the species considered. These effects were investigated on isolated human bronchi. Isometric relaxations produced by halothane, isoflurane and desflurane bubbled on human bronchial rings precontracted with carbachol were recorded and compared with time controls. Volatile anaesthetics induced a concentration-dependent relaxation at 0.66, 1.33 and 2 minimum alveolar concentration (MAC). The relaxation was greater in mildly (carbachol 3x10(-7) M) than in highly (carbachol 2x10(-6) M) precontracted bronchi. Halothane was more potent in relaxing distal as compared to proximal bronchi; this differential effect was less pronounced with isoflurane and not observed with desflurane. While the three volatile anaesthetics induced similar relaxation on proximal bronchi, halothane was significantly more potent than desflurane on distal bronchi, with isoflurane being intermediate. The relaxation induced by 1.33 MAC of halothane, isoflurane and desflurane on moderately precontracted distal bronchi (carbachol 1x10(-6) M) was attenuated by pretreatment with glibenclamide 1x10(-5) M. In conclusion, halothane, isoflurane and desflurane exert direct but differential relaxant effects on human isolated bronchial smooth muscle. This may provide supplemental bronchodilation during anaesthesia. Although adenosine triphosphate-sensitive K+ channels are involved in these relaxant effects, they are unlikely to explain the observed differences between the three volatile anaesthetics.

Anesthetics, Inhalation↗
PubMed2001

Effects of phosphodiesterase inhibitors on hypoxic pulmonary vasoconstriction. Influence of K(+) channels and nitric oxide.

We studied the relaxant effects of the cyclic nucleotide phosphodiesterase inhibitors theophylline (non-selective), rolipram (type IV, 3',5'-cyclic monophosphate (cAMP)-specific) and zaprinast (type V, 3',5'-cyclic monophosphate (cGMP)-specific) on the hypoxic vasoconstriction in the isolated perfused rat lung and the involvement of K(+) channels and nitric oxide (NO) in these effects. K(+) channels were inhibited by glibenclamide, charybdotoxin, apamin and 4-aminopyridine and nitric oxide synthase by L-N(G)-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response. L-NAME and 4-aminopyridine increased this response. Rolipram, zaprinast and theophylline shared the ability to oppose the hypoxic pulmonary vasoconstriction. The order of potency was zaprinast>rolipram>theophylline. Glibenclamide partially inhibited the relaxant effects of rolipram and theophylline. Charybdotoxin inhibited the dilator response to rolipram. Apamin inhibited partially the vasodilation induced by rolipram and zaprinast. 4-Aminopyridine inhibited partially the relaxant effects of theophylline. L-NAME failed to block the effects of the three compounds. These data illustrate different pharmacological profiles according to the phosphodiesterase inhibitors and support the potential interest of selective inhibitors as relaxant agents in pulmonary vessels.

4-Aminopyridine↗
PubMed2001

Non-steroidal anti-inflammatory and cytoprotective drug co-prescription in general practice. A general practitioner-based survey in France.

BACKGROUND AND AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most frequently prescribed drugs. Gastrointestinal damage, the most common side effect of NSAIDs. can be limited by the prescription of cytoprotective agents. In order to assess determinants of NSAID-associated cytoprotective agent prescriptions in primary care practice, we performed a general practitioner (GP)-based study. METHODS: After a 2-month intensive information campaign, the participation of all GPs of the Côte d'Or (France) administrative area was requested. During a 2-month period, GPs had to return a mailed questionnaire on NSAID prescription for up to ten consecutive patients aged over 18 years who required NSAIDs. This 30-item questionnaire included questions about the patient, the type of NSAID and the GP. RESULTS: GP participation rate was 24%, and 791 prescriptions were provided. GPs who participated in the study were representative of GPs of the area in terms of sex, time elapsed since graduation and GP practice area. Around 80% of the patients included in the study were under the age of 65 years. The proportion of prescriptions combining NSAIDs and gastroprotective agents was 29.5%. Omeprazole accounted for 58% of the coprescriptions and misoprostol for 29%. Independent determinants associated with the co-prescription of a cytoprotective agent were age [odds ratio (OR) 4.1; confidence interval (CI) 95% 2.3 7.4], previous history of poor NSAID tolerance (OR 10.4; CI 95% 5.8-18.6), previous history of moderate to severe digestive disorders (OR 13.4; CI 95% 5.1 35.4) and indication for chronic illness (OR 1.8, CI 95% 1.1-3.1). Prescriptions of cytoprotective drugs were in conformity with official guidelines for 78.3% of the patients. Although around 60% of the patients with risk factors for poor tolerance received a gastroprotective drug, 50% of the patients over 65 years did not receive it. Conversely, nearly 12% of the patients with no risk factors were prescribed cytoprotective agents. Patient history was the main reason put forward by GPs for prescribing cytoprotective drugs. CONCLUSION: Although a large majority of GP prescriptions were in accordance with official recommendations, inadequate NSAID prescription practices remain relatively frequent especially with regard to the elderly.

Adult↗
PubMed2001

Hypoxic vasoconstriction of rat main pulmonary artery: role of endogenous nitric oxide, potassium channels, and phosphodiesterase inhibition.

This study investigated the influence of NO, potassium (K+) channel blockade, and the phosphodiesterase inhibitors (PDEIs) theophylline (non-selective PDEI), siguazodan (PDE3I), rolipram (PDE4I), and zaprinast (PDE5I) on rat isolated main pulmonary artery hypoxic (95% N2 and 5% CO2) vasoconstriction. Hypoxic vasoconstriction increased by 27% (p < 0.01) in the presence of the NO synthase inhibitor L-NAME (10(-4) M), and by 15% (p < 0.05) in the presence of the K(ATP) channel blocker glibenclamide (10(-6) M), without potentiation by the combination of these two drugs. Hypoxic vasoconstriction decreased by 28% (p < 0.01) in presence of the Kv,-voltage-dependent channel blocker 4-aminopyridine (10(-3) M), whereas the other K+ channel blockers, charybdotoxin (BKCa, large-conductance Ca2+-sensitive K+ channels) and apamin (SKCa, small-conductance Ca2+-sensitive K+ channels) had no effect. The nonselective PDEI theophylline induced a concentration-dependent relaxation (pD2 = 4.05, Emax = 90% [expressed as a percentage of maximal relaxation induced by papaverine 10(-4) M]). Among the selective PDEIs, siguazodan was significantly (p < 0.01) more efficient than rolipram and zaprinast (Emax values were 84%, 67%, and 58%, respectively) and significantly (p < 0.05) more potent than zaprinast (pD2 values were 6.48, 6.34, and 6.16 for siguazodan, rolipram, and zaprinast). Glibenclamide and L-NAME significantly (p < 0.05) shifted the concentration-response curve (CRC) for zaprinast to the right, and L-NAME shifted the CRC significantly to the right for siguazodan. In the presence of L-NAME, glibenclamide had no effect on the CRC of zaprinast. We conclude that (a) NO exerts a permanent inhibitory effect against hypoxic vasoconstriction that might be mediated in part by an activation of K(ATP) channels; (b) a 4-aminopyridine-sensitive K+ channel is involved in vasoconstriction under hypoxic conditions; (c) PDEs 3 and 5 are the predominant PDE isoforms in rat pulmonary artery relaxation; and (d) NO and K(ATP), but neither BK(Ca), SK(Ca), nor Kv channels, are involved in the relaxant effect of PDEIs.

Animals↗
PubMed2000

Inhibition by SR 59119A of isoprenaline-, forskolin- and VIP-induced relaxation of human isolated bronchi.

In the human isolated bronchus (HIB) it has been shown that beta(3)-adrenoceptor stimulation fails to induce relaxation of airway smooth muscle. It has however been reported in human ventricular endomyocardial biopsies that beta(3)-adrenoceptor stimulation induced a marked negative inotropic effect which could be linked to Gi protein activation. The aims of this study were: (1) to determine in HIB (internal diameter 1-2 mm) whether the selective beta(3)-adrenoceptor agonist SR 59119A (N[7-methoxy-1,2,3, 4-tetrahydronaphthalen-(2R)methyl]-(2R)-2-hydroxy-2-(3-chloroph eny l)e thanamine hydrochloride) was able to inhibit adenylate-cyclase-mediated airway smooth muscle relaxation induced by isoprenaline, forskolin or vasoactive intestinal peptide (VIP) and (2) to investigate the role of the Gi protein in this interaction. SR 59119A (0.1 microM and 1 microM) induced a shift to the right of concentration response curve for isoprenaline (-0. 15+/-0.06 and -0.54+/-0.21 log unit, P<0.05 and P<0.01 respectively), forskolin (-0.12+/-0.02 and -0.30+/-0.05 log unit, P<0.001), and VIP (-0.42+/-0.12 log unit, P<0.01 with SR59119A 10(-6)M). The inhibitory effect of SR 59119A was (1) abolished by an incubation of HIB with pertussis toxin (1 microg/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to inactivate the Gi protein and (2) increased after an incubation of HIB with the pro-inflammatory cytokine IL-1beta (10 ng/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to up-regulate Gi protein expression. Our results suggest that the selective beta(3)-adrenoceptor agonist SR59119A might inhibit the cAMP-dependent relaxation of human isolated bronchus through Gi protein-mediated inhibition of adenylate cyclase.

Adenosine Monophosphate↗
PubMed2000

Functional, biochemical and molecular biological evidence for a possible beta(3)-adrenoceptor in human near-term myometrium.

The possible existence of a beta(3)-adrenoceptor (beta(3)-AR) in human near-term myometrium was investigated by in vitro functional and biochemical studies and analysis of mRNA expression. SR 59119A and SR 59104A and CGP 12177 (two selective agonists and a partial agonist, respectively, of the beta(3)-AR), salbutamol and terbutaline (beta(2)-AR agonists) each produced a concentration-dependent relaxation of the myometrial spontaneous contractions. There were no differences in pD(2) values for the relaxing potencies of terbutaline, salbutamol, CGP 12177 and SR 59119A. The rank order for their relaxing efficacies was SR 59119A>SR 59104A>terbutaline approximately salbutamol approximately CGP 12177 (E(max)=52+/-7%, 42+/-12% and approximately 30% respectively). Propranolol, a beta(1)- and beta(2)-AR antagonist, and ICI 118551, a beta(2)-AR antagonist (both at 0.1 microM), did not affect the SR 59119A-induced relaxation whereas SR 59230A, a selective beta(3)-AR antagonist (1 microM), significantly reduced the maximal relaxing effect of SR 59119A. SR 59119A and salbutamol induced a significant increase in cyclic AMP levels that was antagonized by SR 59230A but not by propranolol for SR 59119A, and by propranolol but not by SR 59230A for salbutamol. The beta(3)-AR mRNA was positively expressed in myometrium preparations in a reverse transcription polymerase chain assay. The results presented provide the first evidence for the existence of the beta(3)-AR subtype in human near-term myometrium and suggest that the effects of SR 59119A might be mediated through an increase in cyclic AMP level.

Adrenergic beta-Agonists↗
PubMed1999

Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium.

This study was aimed at evaluating the in vitro effects of phosphodiesterase inhibitors and beta2-adrenoceptor agonists on spontaneous contractions of human term myometrium. Rolipram, RP 73401 (3-cyclopentyloxy-N-(3,5(-dichloro-4-pyridil)-4-methoxybenzamide) and Ro 20-1724 (1-4-(3-butoxy-4-methoxybenzyl)-2-imidozolidinone) (phosphodiesterase 4 inhibitors) inhibited spontaneous myometrial contractions (Emax approximately 100%; pD2 of 6.80+/-0.28, 6.84+/-0.32 and 6.31+/-0.03, respectively). Salbutamol and formoterol were less effective (Emax=40+/-6% and 35+/-12%, respectively) than phosphodiesterase 4 inhibitors to reduce myometrial contractility. Inhibitors of phosphodiesterase 3 (milrinone and siguazodan) and 5 (zaprinast) were marginally effective. Rolipram (10-30 nM) and siguazodan (0.1 microM) potentiated the response to salbutamol (Emax=75+/-12%, 88+/-8% and 73+/-12% and pD2=6.51+/-0.20, 6.93+/-0.29 and 6.48+/-0.16, respectively). Sodium nitroprusside (pD2=6.76+/-0.29) and theophylline (pD2=5.15+/-0.22) were effective inhibitors of myometrial contractions. Chromatographic separation of phosphodiesterase isoenzymes demonstrated that phosphodiesterase 4 is predominant but other phosphodiesterase isoenzymes were also identified. In conclusion, phosphodiesterase 4 inhibitors alone or combined with beta2-adrenoceptor agonists have potential interest as tocolytic agents.

Adrenergic beta-Agonists↗
PubMed1999

[Functional colonic diseases: from physiopathology to pharmacology].

INTRODUCTION: Irritable bowel syndrome is a very frequent cause for consulting. The clinical entity is ill-defined and diagnosis is based on clinical features (Rome criteria), as no specific feature helps guide the diagnosis. Since its pathophysiology is currently being better described, this study was aimed at reviewing recent data. CURRENT KNOWLEDGE AND KEY POINTS: After involvement of the motor system had been suggested, more recent pathophysiological studies have focused on diffuse abnormalities of visceral perception with decrease in pain thresholds. Involvement of other physiopathological factors, particularly of psychological disturbances, has been suggested. FUTURE PROSPECT AND PROJECTS: Management of patients suffering from irritable bowel syndrome is still disappointing as pharmacological agent acting on gut motility are only partly efficacious. Better understanding of its physiopathology will open new avenues for the development of therapeutical agents truly efficacious on visceral hypersensitivity.

Animals↗
PubMed1999

Hypoxic pulmonary vasoconstriction.

Hypoxic vasoconstriction is unique to pulmonary circulation. The pulmonary response is part of a self-regulatory mechanism by which pulmonary capillary blood flow is automatically adjusted to alveolar ventilation for maintaining the optimal balance of ventilation and perfusion. In pathological conditions, hypoxic pulmonary vasoconstriction may occur as an acute episode or as a sustained response with pulmonary hypertension and vascular remodeling. Vasoactive substances produced from the endothelial cells (prostanoids, nitric oxide, or endothelin) or other mediators such as 5 hydroxytryptamine have been examined as possible mediators of hypoxic vasoconstriction. These appear more likely to be modulators than mediators of the vasoconstrictor response to hypoxia. Recent hypotheses have emerged indicating that O2 levels per se can regulate ion channel activity. The modulation of both K+ and Ca2+ channels differs according to the conduit or resistance pulmonary vessel type, tending to extend the former and contract the latter, thereby opposing the ventilation to perfusion mismatching. In the absence of drugs that act selectively on pulmonary circulation, inhaled therapy is an alternative in the treatment of pulmonary hypertension. According to its short half-life and to its potential cytotoxicity, nitric oxide is only of value in the management of patients with acute respiratory disease. Aerosolized prostacyclin and iloprost result in a sustained efficacy of the inhaled vasodilator regimen in patients with severe pulmonary hypertension and offer a new strategy for treatment of this disease. At the moment, therapy aimed at reversing the structural remodeling and matrix deposition in pulmonary arteries remains experimental. New drugs such as potassium channel openers or endothelin receptor antagonists warrant further investigations as possible therapeutic candidates in the treatment of pulmonary hypertension.

Animals↗