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Biomedical subjects

Marc Thibonnier

Publications and source records attributed to Marc Thibonnier.

8 recordsLinked to original sources
PubMed2005

Mapping the binding site of six nonpeptide antagonists to the human V2-renal vasopressin receptor.

Whereas arginine vasopressin binds to its receptor subtypes V(1)R and V(2)R with equal affinity of approximately 2 nM, nonpeptide antagonists interact differently with vasopressin receptor subtypes. The V(2)R antagonist binding site was mapped by site-directed mutagenesis at six selected amino acid positions, K100D, A110W, M120V, L175Y, R202S, and F307I, predicted to be involved in antagonist binding differences between V(2) R and V(1)R. These mutations did not alter the affinity for arginine vasopressin. However, the affinity for six nonpeptide receptor antagonists SR121463B [1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]-5-ethoxy-3-spiro-[4[(2 morpholinoethoxy)cy-clohexane]indoline-2-one, phosphate monohydrate cis-isomer], SR49059 [(2S)1-[(2R3S)-(5-chloro-3-(2 chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide], SSR149415 [(2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2pyrrolidine carboxamide, isomer(-)], OPC21268 [1-[1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl]-3,4-dihydro-2(1H)-quinolinone], OPC41061 [(+/-)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-o-tolu-m-toluidide], and OPC31260, [(+/-)-5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-1,2, 3,4,5-tetrahydro-1H-benzazepine monohydrochloride], was altered to varying degrees, resulting in differences up to 6000-fold. Replacement of the small alanine for the bulky tryptophan in position 110 resulted in a reduced affinity for all six antagonists. In contrast, replacement of the large methionine for the smaller valine in position 120 caused a dramatic increase in affinity, up to a K(i) of 7 fM for OPC31260. Molecular modeling revealed that the binding sites for arginine vasopressin and the nonpeptide antagonists are partially overlapping. Whereas arginine vasopressin binds on the extracellular surface of V(2) R, the nonpeptide antagonists penetrate deeper into the transmembrane region of the receptor, in particular OPC21268. The mutagenesis data point to significant differences in the shape of the V(1)R and V(2)R antagonist binding pockets. The most important factor determining the specificity of nonpeptide antagonists seems to be the shape of the binding pocket on the receptor.

Amino Acid Sequence↗
PubMed2005

Vardenafil improved patient satisfaction with erectile hardness, orgasmic function and sexual experience in men with erectile dysfunction following nerve sparing radical prostatectomy.

PURPOSE: Nerve sparing radical retropubic prostatectomy (NS-RRP) results in erectile dysfunction in a significant number of patients. Vardenafil, a potent and selective phosphodiesterase type 5 inhibitor, is generally safe. It improves International Index of Erectile Function erectile function domain scores, and penetration and erection maintenance success rates in patients who have undergone NS-RRP. We report additional parameters important to patient perceptions regarding erection quality and satisfaction with sexual experience following NS-RRP. MATERIALS AND METHODS: A total of 440 men at 58 centers throughout the United States and Canada participated in this randomized, placebo controlled, double-blind trial with 3 phases, namely baseline (4-week untreated period), treatment (12 weeks) and followup (7 days). Participants received placebo (145), 10 mg vardenafil (146) or 20 mg vardenafil (149) at home on demand but no more than once per calendar day. Efficacy and satisfaction with erection quality and sexual experience were determined during the trial. RESULTS: The 10 and 20 mg vardenafil doses were significantly superior to placebo for the International Index of Erectile Function domains for intercourse satisfaction, orgasmic function and overall satisfaction with sexual experience (vs placebo p <0.0009). Significant improvement in the satisfaction rate with erection hardness were demonstrated for each vardenafil dose compared with placebo (p <0.0001). Vardenafil was generally well tolerated. Common adverse events were headache, vasodilatation and rhinitis. CONCLUSIONS: In this difficult to treat population of men with erectile dysfunction subsequent to NS-RRP on demand treatment with vardenafil during a 3-month period significantly improved key aspects of the sexual experience important to patient quality of life.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Genetics of vasopressin receptors.

Membrane receptors that couple to guanine nucleotide binding protein (GPCRs) represent one of the largest families of proteins in the genome. Because of their universal distribution and multiple actions, genetic variations of GPCRs are associated with various human diseases. For instance, the clinical phenotype of congenital nephrogenic diabetes insipidus has been linked to more than 155 loss-of-function putative mutations of the arginine vasopressin (AVP) V(2) receptor, which span each and every segment of this seven-transmembrane domain receptor. These mutant receptors, which are mostly trapped in the endoplasmic reticulum, can be rescued by membrane-permeant nonpeptidic AVP receptor antagonists. An overexpression of V(1)-vascular and V(3)-pituitary AVP receptors has been observed in some endocrine tumors. The single nucleotide polymorphism of AVP receptors in the context of complex genetic traits is currently being investigated, and preliminary findings have been reported in arterial hypertension and autism.

Animals↗
PubMed2004

Erection quality scale: initial scale development and validation.

OBJECTIVES: The Erection Quality Scale (EQS) is a new, self-report measure for assessing the quality of penile erections. It is intended to complement existing diagnostic and outcome measures (eg, International Index of Erectile Function, Sexual Encounter Profile) in both clinical practice and outcomes research in erectile dysfunction (ED). METHODS: The initial phases of development and psychometric validation of the EQS are described. Specifically, qualitative research in patients and healthy men was used to generate relevant constructs. On the basis of the findings from these phases, and recommendations from an expert panel, seven constructs were selected for inclusion. Multiple items with different formats were drafted to measure each of the key constructs. An iterative process of cognitive testing, item revision, and item reduction was used to identify the 15 most appropriate items and their optimal response scales. This version of the scale was tested in a 200-subject discriminant validity study designed to gather data for a psychometric evaluation. Participants were classified into ED-untreated, ED-treated, and healthy control groups to evaluate the discriminant validity of the measure in men with different levels of erectile function. RESULTS: The study results supported a robust single-factor structure, indicating that the EQS provides an overall index of erection quality. An intraclass correlation coefficient of 0.85 denotes adequate test-retest reliability. Furthermore, the EQS correlated well with existing measures and differentiated patients from the three ED classifications, a preliminary indication of discriminant validity. CONCLUSIONS: The findings presented provide evidence of the scale's potential utility for measuring erection quality in future studies.

Adult↗
PubMed2004

Vardenafil provides reliable efficacy over time in men with erectile dysfunction.

OBJECTIVES: To evaluate the reliability of vardenafil efficacy and tolerability within 12 weeks in a broad population of men with erectile dysfunction (ED). METHODS: In a retrospective analysis of two pivotal, Phase III, randomized, double-blind, placebo-controlled trials conducted in 107 centers, 1650 men aged 18 years or older with ED received vardenafil 5 mg, 10 mg, or 20 mg on demand for 12 to 26 weeks. Outcome measures included the first-time and subsequent overall success rate until week 12 for diary entries regarding vaginal penetration (Sexual Encounter Profile [SEP]-2), erection maintenance (SEP-3), satisfaction with erection hardness, and overall satisfaction with the sexual experience. Mean efficacy was calculated for each patient during 12 weeks and then averaged for all patients within each treatment group. RESULTS: At baseline, the intention-to-treat population had moderate ED (International Index of Erectile Function-Erectile Function domain score of 13). For SEP-2 (penetration), the first-attempt and subsequent success rate was 44% and 74% for placebo, 71% and 81% for vardenafil 5 mg, 76% and 86% for vardenafil 10 mg, and 76% and 91% for vardenafil 20 mg, respectively. For SEP-3 (maintenance), first-attempt and subsequent success rate was 25% and 56% for placebo, 51% and 76% for vardenafil 5 mg, 65% and 76% for vardenafil 10 mg, and 59% and 84% for vardenafil 20 mg, respectively. For overall satisfaction with the sexual experience, the first-attempt and subsequent success rate was 19% and 48% for placebo, 48% and 68% for vardenafil 5 mg, 57% and 72% for vardenafil 10 mg, and 56% and 79% for vardenafil 20 mg, respectively. The reliability of vardenafil was similar or slightly greater in sildenafil-naive subjects compared with prior sildenafil responders. The most common adverse events were mild-to-moderate headache, flushing, and rhinitis. CONCLUSIONS: Vardenafil provides reliable efficacy for key erectile function parameters important to patients when continuing oral treatment for ED.

Clinical Trials, Phase III as Topic↗
PubMed2003

Vasopressin receptor antagonists in heart failure.

There is ample evidence that arginine vasopressin (AVP) is a component of the neurohormonal response to congestive heart failure (CHF). Furthermore, AVP might play a role in the development, progression and worsening of CHF. Because of the need for further improvement in the treatment of CHF, randomized clinical trials were conducted to assess the efficacy and safety of non-peptide AVP receptor antagonists in patients with CHF. In pivotal trials of three non-peptide AVP receptor antagonists, these compounds improved the fluid status, osmotic balance and hemodynamics of patients with CHF. These studies support the approval of this class of agents for the symptomatic treatment of CHF, but long-term studies are required to demonstrate their role in the outcome and quality of life of these patients.

Animals↗
PubMed2003

Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial.

The durability of key efficacy response parameters and safety of vardenafil was evaluated in a pivotal trial conducted in a broad population of men with erectile dysfunction (ED) in North America. In this randomized, double-blind, placebo-controlled, multicenter, fixed-dose, parallel-group, 6-month comparison study, men >18 years of age with ED for >6 months received 5-mg, 10-mg, and 20-mg doses of vardenafil as needed for up to 26 weeks. The primary efficacy variables were the International Index of Erectile Function (IIEF)-Erectile Function (EF) domain scores, and the Sexual Encounter Profile (SEP) mean per-patient success rates for penetration (SEP question 2) and maintenance of erections (SEP question 3). Safety data were also collected over time. Improvement in all primary efficacy variables was observed in all vardenafil groups versus placebo. These improvements occurred early and were either sustained or increased through week 26. Vardenafil in 10-mg and 20-mg doses was significantly superior to placebo at all time points for all efficacy variables (P <0.01), and all doses were superior to placebo at endpoint (P <0.001). Most treatment-emergent adverse events (headache, flushing, dyspepsia, and rhinitis) were mild or moderate in intensity, and incidence generally decreased over time. All 3 doses of vardenafil were superior to placebo across all primary efficacy variables and all study time points in a broad range of patients with ED, regardless of etiology or severity. Vardenafil was well tolerated. These results demonstrate that vardenafil provides sustained efficacy with reduced incidence of nuisance side effects over time. High resolution video, medium resolution video, low resolution video.

Aged↗