Biomedical subjects

Christian Richard

Publications and source records attributed to Christian Richard.

42 records · Page 3Linked to original sources

PubMed2002

SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist.

Experiments were performed to characterize the pharmacology of SCH 206272 [(R,R)-1'[5-[(3,5-dichlorobenzoyl)methylamino]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]-N-methyl-2-oxo-[1,4'bipiperidine]-3-acetamide] as a potent and selective antagonist of tachykinin (NK) NK(1), NK(2), and NK(3) receptors. SCH 206272 inhibited binding at human tachykinin NK(1), NK(2), and NK(3) receptors (K(i) = 1.3, 0.4, and 0.3 nM, respectively) and antagonized [Ca(2+)](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK(1), NK(2), or NK(3) receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 +/- 0.3) induced by the tachykinin NK(1) receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b = 8.2 +/- 0.3) induced by the tachykinin NK(2) receptor agonist, neurokinin A. In isolated guinea pig tissues, SCH 206272 inhibited substance P-induced enhancement of electrical field stimulated contractions of the vas deferens, (pK(b = 7.6 +/- 0.2), NKA-induced contraction of the bronchus (pK(b) = 7.7 +/- 0.2), and senktide-induced contraction of the ileum. In vivo, oral SCH 206272 (0.1-10 mg/kg, p.o.) inhibited substance P-induced airway microvascular leakage and neurokinin A-induced bronchospasm in the guinea pig. In a canine in vivo model, SCH 206272 (0.1-3 mg/kg, p.o.) inhibited NK(1) and NK(2) activities induced by exogenous substance P and neurokinin A. Furthermore, in guinea pig models involving endogenously released tachykinins, SCH 206272 inhibited hyperventilation-induced bronchospasm, capsaicin-induced cough, and airway microvascular leakage induced by nebulized hypertonic saline. These data demonstrate that SCH 206272 is a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. This compound may have beneficial effects in diseases thought to be mediated by tachykinins, such as cough, asthma, and chronic obstructive pulmonary disease.

Acetamides↗

PubMed2002

Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor.

We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.

Animals↗

PubMed2002

Truncated hemoglobin HbN protects Mycobacterium bovis from nitric oxide.

Mycobacterium tuberculosis, the causative agent of human tuberculosis, and Mycobacterium bovis each express two genes, glbN and glbO, encoding distantly related truncated hemoglobins (trHbs), trHbN and trHbO, respectively. Here we report that disruption of M. bovis bacillus Calmette-Guérin glbN caused a dramatic reduction in the NO-consuming activity of stationary phase cells, and that activity could be restored fully by complementing knockout cells with glbN. Aerobic respiration of knockout cells was inhibited markedly by NO in comparison to that of wild-type cells, indicating a protective function for trHbN. TyrB10, which is highly conserved in trHbs and interacts with the bound oxygen, was found essential for NO consumption. Titration of oxygenated trHbN (trHbN.O(2)) with NO resulted in stoichiometric oxidation of the protein with nitrate as the major product of the reaction. The second-order rate constant for the reaction between trHbN.O(2) and NO at 23 degrees C was 745 microM(-1).s(-1), demonstrating that trHbN detoxifies NO 20-fold more rapidly than myoglobin. These results establish a role for a trHb and demonstrate an NO-metabolizing activity in M. tuberculosis or M. bovis. trHbN thus might play an important role in persistence of mycobacterial infection by virtue of trHbN's ability to detoxify NO.

Bacterial Proteins↗

PubMed2002

Combination of venoarterial PCO2 difference with arteriovenous O2 content difference to detect anaerobic metabolism in patients.

OBJECTIVE: Under conditions of tissue hypoxia total CO2 production (VCO2) should be less reduced than O2 consumption (VO2) since an anaerobic CO2 production should occur. Thus the VCO(2)/VO(2) ratio, and hence the venoarterial CO2 tension difference/arteriovenous O2 content difference ratio (DeltaPCO2/C(a-v)O2), should increase. We tested the value of the DeltaPCO2/C(a-v)O2 ratio in detecting the presence of global anaerobic metabolism as defined by an increase in arterial lactate level above 2 mmol/l (Lac+). DESIGN AND SETTING: Retrospective study over a 17-month period in medical intensive care unit of a university hospital. PATIENTS: We obtained 148 sets of measurements in 89 critically ill patients monitored by a pulmonary artery catheter. RESULTS: The DeltaPCO2/C(a-v)O2 ratio was higher in those with increased ( n=73) than in the normolactatemic group (2.0+/-0.9 vs. 1.1+/-0.6, p<0.0001). Among all the O2- and CO2-derived parameters the DeltaPCO2/C(a-v)O2 ratio had the highest correlation with the arterial lactate level ( r=0.57). Moreover, for a threshold value of 1.4 the DeltaPCO2/C(a-v)O2 ratio predicted significantly better than the other parameters (receiver operating characteristic curves) the presence of hyperlactatemia (positive and negative predictive values of 86% and 80%, respectively). The overall survival estimate at 1 month was greater when the DeltaPCO2/C(a-v)O2 ratio was less than 1.4 on the first set of measurements (38+/-10% vs. 20+/-8%, p<0.01). CONCLUSION: The DeltaPCO2/C(a-v)O2 ratio seems a reliable marker of global anaerobic metabolism. Its calculation would be helpful for a better interpretation of pulmonary artery catheter data.

Bacteria, Anaerobic↗

PubMed2002

Androgens modulate the balance between VEGF and angiopoietin expression in prostate epithelial and smooth muscle cells.

BACKGROUND: The vasculature of the prostate responds to androgens. Androgens most likely affect the vasculature indirectly by modulating the expression of angiogenic factors in the cells of the prostate. Most studies to date have examined the production of angiogenic factors by the prostate luminal epithelium. Here we examine the effects of androgen on production of three angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin-1, and angiopoietin-2, by the three major cell types in the prostate. METHODS: The ability of androgen to modulate VEGF, angiopoietin-1, and angiopoietin-2 production in cultured mouse prostate luminal epithelial, basal epithelial, and smooth muscle cells (SMCs) was assessed by Western blot and RT-PCR. RESULTS: The production of VEGF was modulated by androgens in both luminal epithelial and prostate SMCs but not in basal epithelial cells. However, in prostate luminal epithelial cell cultures, VEGF was predominately secreted apically, suggesting that in vivo most of the epithelium-derived VEGF is unavailable to the underlying blood vessels. In addition, prostate luminal epithelial cells produced angiopoietin-2, an angiogenesis inhibitor. In contrast, prostate SMCs produced angiopoietin-1, a positive modulator of angiogenesis. Synthesis of the angiopoietins did not respond to androgen treatment. CONCLUSIONS: Prostate smooth muscle may play an important role in regulating vascular responses to androgen.

Androgens↗

PubMed2002

Changes in BP induced by passive leg raising predict response to fluid loading in critically ill patients.

OBJECTIVE: To test the hypothesis that passive leg raising (PLR) induces changes in arterial pulse pressure that can help to predict the response to rapid fluid loading (RFL) in patients with acute circulatory failure who are receiving mechanical ventilation. DESIGN: Prospective clinical study. SETTING: Two medical ICUs in university hospitals. PATIENTS: Thirty-nine patients with acute circulatory failure who were receiving mechanical ventilation and had a pulmonary artery catheter in place. INTERVENTIONS: PLR for > 4 min and a subsequent 300-mL RFL for > 20 min. MEASUREMENTS AND MAIN RESULTS: Radial artery pulse pressure (PPrad), heart rate, right atrial pressure, pulmonary artery occlusion pressure (PAOP), and cardiac output were measured invasively in a population of 15 patients at each phase of the study procedure (i.e., before and during PLR, and then before and after RFL). PPrad, PAOP, and stroke volume (SV) significantly increased in patients performing PLR. These changes were rapidly reversible when the patients' legs were lowered. Changes in PPrad during PLR were significantly correlated with changes in SV during PLR (r = 0.77; p < 0.001). Changes in SV induced by PLR and by RFL were significantly correlated (r = 0.89; p < 0.001). Finally, PLR-induced changes in PPrad were significantly correlated to RFL-induced changes in SV (r = 0.84; p < 0.001). In a second population of 24 patients, we found the same relationship between PLR-induced changes in PPrad and RFL-induced changes in SV (r = 0.73; p < 0.001). CONCLUSION: The response to RFL could be predicted noninvasively by a simple observation of changes in pulse pressure during PLR in patients with acute circulatory failure who were receiving mechanical ventilation.

Adult↗