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 résultats études merck Losartan+ismn

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sffcc9296 (Sylvie)

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MessageSujet: résultats études merck Losartan+ismn   Jeu 30 Déc - 13:56

Je viens de trouver les résultats très intéressant d'une étude de Merck de 2006/2007 : http://clinicaltrials.gov/ct2/show/NCT00943852?term=losartan+ismn&rank=1

C'est tout chaud (nov 2010). Ils montrent que le donneur de NO (ISMN) a un impact considérable sur la pression artérielle centrale. Ce que MG appelait "une toute nouvelle façon de traiter l'hta".




J Am Soc Hypertens. 2010 Nov-Dec;4(6):311-8.
Single-dose effects of isosorbide mononitrate alone or in combination with losartan on central blood pressure.

Kaufman R, Nunes I, Bolognese JA, Miller DL, Salotti D, McCarthy JM, Smith WB, Herman GA, Feig PU.

Department of Experimental Medicine, Merck Research Laboratories, Merck Sharp & Dohme Corp., Rahway, New Jersey, USA.
Abstract

Antihypertensive drugs can have different effects on central and brachial blood pressures, which may affect outcomes. Nitric oxide donors have acute effects on central blood pressure but have not been assessed with renin-angiotensin system blockade. Thirteen patients with prehypertensive/Stage 1 hypertension were randomized to five single-dose treatments separated by ≤4 days using a double-blind, crossover study design: angiotensin receptor blocker (ARB) losartan 100 mg, isosorbide mononitrate (ISMN) 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo. Central and brachial blood pressures were measured throughout 10 hours. Mean placebo-subtracted decrease from baseline in augmentation index (AIx) approximately 1% for losartan 100 mg, 26% for ISMN 60 mg, 19% for losartan 100 mg + ISMN 15 mg, and 24% for losartan 100 mg + ISMN 60 mg. Administered with losartan 100 mg or alone, ISMN lowered AIx, demonstrating that acute effects of a nitrate donor are much larger than those of an ARB even when administered with an ARB. Differences from placebo were statistically significant except for losartan 100 mg. AIx is a good biomarker of acute hemodynamic effects of nitric oxide in prehypertensive/Stage 1 hypertension.
Copyright © 2010 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

PMID: 21130977 [PubMed - in process]



http://www.ncbi.nlm.nih.gov/pubmed/21130977?dopt=Abstract




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D@n (Daniel Beldio)

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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 14:10

Merci Sylvie,

Mais 13 patients c'est statistiquement significatif ?!?... scratch
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sffcc9296 (Sylvie)

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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 14:13

Oui bien sûr, ça peut l'être.
Si c'est significativement significatif sur un petit nombre de sujets, ça veut dire justement que le résultat est excellent, ie que la différence avec le comparateur est importante.

("statistiquement significatif", ça veut dire que les résultats obtenus ne peuvent pas être dus a hasard. Ca ne veut pas dire que l'échantillon est important)
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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 14:19

Hier en regardant les critères d'inclusion du MK8266, j'ai remarqué ce qui suit:
Participants, at screening, will have a positive Augmentation Index.
(http://clinicaltrials.gov/ct2/show/NCT01263314?term=MK+8266&rank=3=)

Or, dans l'étude que tu apportes:
AIx (augmentation index) is a good biomarker of acute hemodynamic effects of nitric oxide in prehypertensive/Stage 1 hypertension.

Je crois que la boucle est bouclée ... le 8266 est, je pense, un composé Nicox.

Merci Sylvie!
cheers
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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 14:21

Ca
+ 8266 qui commence ces essais le même jour que l'autre composé Nicox
+ les critères d'exclusions liés à des composés donneurs de No

je trouve que cela fait beaucoup... c'est un composé Nicox, je pense.
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sffcc9296 (Sylvie)

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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 14:23

Tu vas p-e un peu vite quand même. Si Merck a son propre composé et qu'ils visent aussi une diminution de la PA centrale, ils vont aussi mesurer l'AIx.
Maintenant cette étude semble indiquer que du point de vue de l'AIx, il est p-e inutile de comparer une molécule nicox à sa molécule de base. (cf 8266 sur clinical). Idea


Dernière édition par sffcc9296 (Sylvie) le Jeu 30 Déc - 15:43, édité 4 fois
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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 14:29

ca m'étonnerait qu'ils aient un composé en interne
- qui joue aussi sur le NO, sinon pourquoi des critères d'exclusion sur les composés donneurs de No
- qui soit si proche en terme de développement que le composé Nicox: entrés en essais cliniques le même jour Exclamation

...
Si ce n'était pas un composé Nicox, pourquoi avoir élargi l'accord en septembre dernier... Merck semble être très intéressé par le No, et je crois que personne ne peut dire que ce n'est pas vrai: longueur de leurs études = investissements importants, potentiellement un composé donneur de NO développé en interne ...

Ca demande à encore être creusé, mais je pense fortement qu'il s'agit d'un composé Nicox.

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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 14:32

j'ai rajouté une ligne à mon message précédent. Wink

Si c'est bien le cas, au vu des résultats de l'étude (cf premier post), phase 2 quasi certaine ama mi 2011. Very Happy
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bob



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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 15:33

En sept Sujet: Re: Rechercher les composés Nicox - Merck Dim 19 Sep -
je m'interrogeais sur la nécessité qu'avait MERCK
d'effectuer des études en rapport avec le NO.


Je pense avoir trouvé 3 études en rapport
avec NICOX .


Aucune référence de nouvelles moles est communiqué mais,

http://clinicaltrials.gov/ct2/results?term=merck+AND+nitric+oxide


le Losartan est étudié :on sait que NICOX a breveté un dérivé
(nitrooxyderivate von losartan)

NICOX et MERCK travaillent sur les intéractions rénales ??
l'ISMN,(l'isosorbide mononitrate) est un composé à propriétés diurétiques
et on le retrouve sur les 3 études.

Sur la troisième étude (L'AMLODIPIDE) est un composé sur lequel le docteur
J. DJIAN du staff NICOX a particulièrement travaillé CHEZ NOVARTIS.


SYLVIE RAY Vous avez une meilleur lecture que moi
Je commence peut-être à y voir plus clair
Very Happy
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Seb

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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 16:26

Merci à tous pour les infos et les commentaires cheers

Nous avons la preuve que nous pouvons savoir les phases non divulgués de Merck tongue
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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 16:41

je ne comprends pas ce que tu dis, bob
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sffcc9296 (Sylvie)

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MessageSujet: Re: résultats études merck Losartan+ismn   Jeu 30 Déc - 16:59

Raymond a écrit:


Ca demande à encore être creusé, mais je pense fortement qu'il s'agit d'un composé Nicox.



C'est vrai que quand on voit 4 études de pharmacocinétique en 1 an, on a bien envie de faire un lien avec une certaine "nouvelle méthode de libération du NO".
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Philippe Vaillantpvailla8



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MessageSujet: Re: résultats études merck Losartan+ismn   Sam 1 Jan - 13:15

ISMN15mg+ Losartan diminution de l'index de 19%
ISMN 60mg diminution de l'index 26%
Comme dit plus haut l'association de ISMN au Losartan n'apporte rien au niveau de la mesure de l’index Aortique. On pourrait donc comparer les résultats de ISMN 60mg à celui de l'ISMN15g (sous réserve que son association au Losartan n'apporte rien à ce dosage non plus).
L’augmentation de 200% de la dose l’ISMN améliore de 30% l’amélioration de l’index aortique mesuré.
Cette augmentation de la concentration est-elle nécessaire pour un résultat thérapeutique supérieur ou simplement pour que les résultats soient significatifs sur une petite série de 13 patients ?
On peut penser que la nouvelle thérapeutique vise à se rapprocher des 30% d’amélioration de l’index aortique. Mais l’intérêt de cette amélioration des résultats (mesure de l’index améliorée de 26% par rapport aux 19%) sera à pondérer par l’augmentation de 200% des doses thérapeutiques et de ses effets secondaires éventuels. L’association au Losartan ne pourra améliorer l’index Aortique mais pourrait améliorer la pression artérielle mesurée au bras par d’autre voie de contrôle. L’association au Losartan ne modifie la pression artérielle aortique ce qui en permettrait l’association.
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bob



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MessageSujet: Re: résultats études merck Losartan+ismn   Sam 1 Jan - 20:10

Raymond a écrit:
je ne comprends pas ce que tu dis, bob

Tu n'est pas le seul RAY
je ne me comprend pas moi même, parfois Very Happy

J'ai perdu la traçabilité des recherches de l'époque

Toutefois ce qui m'interpelle
1: c'est ces études à répétition sur l'ismr
2:l'option des combinaisons de divers moles
3:surtout le fait que le brevet MERCK NICOX

http://fr.espacenet.com/publicationDetails/biblio?KC=A1&date=20100211&NR=2010015447A1&DB=fr.espacenet.com&locale=fr_FR&CC=WO&FT=D

utise un dérivé des sartans



Il en est dit: en fin de description du brevet (pris ça et la)

Par rapport au composé A (composé de référence), les composés de l'invention, à condition abaissement BP, avec effet de pointe étendue et la durée d'action (voir tableau de données 2).

L'ARBs mentionné ci-dessus de l'invention sont utiles également en combination avec d'autres pharmacologiquement substances actives comprenant l'angiotensine convertissant des inhibiteurs d'enzyme, des antagonistes de récepteurs d'endothelin, vasodilatateurs, bloqueurs de canal calcique (amlodipine),des diurétiques(hydrochlorothiazide) .......... ect
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vinsse

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MessageSujet: pour ceux(ou celles)qui sont interessé(e)s   Lun 3 Jan - 11:20

texte complet de l'abstract...je vous fais grace des tableaux associés
l

Introduction


Blood pressure (BP) is conventionally measured in the brachial artery, but recent noninvasive technologies have made it possible to measure central BP,1 a parameter potentially highly sensitive to the effect of nitric oxide (NO).[1], [2] and [3] Thus, central BP parameters have been proposed to be independent or better predictors of cardiovascular outcomes than brachial BP.[1], [4], [5] and [6] This is supported by observational longitudinal, population-based studies,7 special population studies,[8], [9] and [10] and results from an intervention study.11

Inhibition of the renin-angiotensin system (RAS) is an effective mechanism for treatment of hypertension but has limited efficacy in subpopulations in which systolic hypertension is particularly prevalent, such as the elderly.12 It is recognized that patient subpopulations have impaired endothelial function, with lower levels of bioavailable NO.[13] and 14 S. Taddei, A. Virdis, L. Ghiadoni, A. Magagna and A. Salvetti, Vitamin C improves endothelium-dependent vasodilatation by restoring nitric oxide activity in essential hypertension, Circulation 97 (1998), pp. 2222–2229. View Record in Scopus | Cited By in Scopus (444)[14] NO-donating agents, such as isosorbide mononitrate (ISMN), counteract endothelial dysfunction and have been shown to be effective in elderly patients with otherwise difficult-to-treat systolic hypertension.[3], [15] and [16] In addition, nitrates have been shown to have substantial effects on central BP.[1], [2] and [3]

Nitrates have the potential to act synergistically with RAS inhibition due to downregulation of angiotensin type 1 (AT1) receptors.17 Thus, it is important to evaluate the antihypertensive effect of NO in the setting of RAS inhibition, such as with angiotensin receptor blocker (ARB) therapy. Therefore, the central and brachial BP effects of the ARB losartan and the NO donor ISMN were measured in this study for 10 hours after single doses were administered alone or in combination to patients with prehypertensive/Stage 1 hypertension in a double-blind, randomized, placebo-controlled, five-period crossover study.
Methods

The study was sponsored by Merck Sharp & Dohme Corp. as Protocol 0954-317 and is registered at www.clinicaltrials.gov as NCT00943852. The study protocol was approved by the Institutional Review Board of the New Orleans Center for Clinical Research, Knoxville, Tennessee; all subjects gave written informed consent.
Patient Population

The study randomized 13 men and postmenopausal women 45–70 years of age with prehypertensive/Stage 1 (systolic BP 130–160 mm Hg and diastolic BP 85–100 mm Hg). Twelve patients who completed two or more periods of the study were included for analysis. Removal of one patient because he completed only one study period did not substantially change baseline characteristics of the analysis population. Patients were eligible if they had a positive augmentation index (AIx), body mass index >18 and ≤35 kg/m2, and serum creatinine ≤2.0 mg/100 mL or creatinine clearance ≥60 mL/min. Patients treated with short-acting beta-blockers were excluded. Therapy with angiotensin-converting enzyme (ACE) inhibitors and/or ARBs was discontinued at least 1 week before the run-in period. Any other hypertension medication was required to be stable (no new or discontinued medications for hypertension) for at least 4 weeks before the prestudy visit and throughout the study.
Treatment

The study plan provided for sequences of five single, blinded, oral treatments (losartan 100 mg, ISMN 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo) administered as overencapsulated tablets of losartan potassium 100 mg (1 × 100-mg tablet), extended-release ISMN 60 mg (2 × 30-mg tablets), losartan potassium 100 mg (1 × 100-mg tablet) + extended-release ISMN 15 mg (1/2 × 30-mg tablet), losartan potassium 100 mg (1 × 100-mg tablet) + extended-release ISMN 60 mg (2 × 30-mg tablets), and placebo (1 tablet), administered double dummy in each period. All doses were administered with not, vert, similar240 mL water approximately 2 hours after a light breakfast, with a light lunch consumed at approximately 5 hours after study drug administration. Patients were randomized to sequences of balanced crossover design with ≥4-day washout periods between each single dose.
Measurements

Triplicate observations of heart rate and brachial cuff BP with a validated, semiautomated, oscillometric device (Welch Allyn 6200 Series, New York, NY) and duplicate central BP assessments (SphygmoCor Pulse Wave Analysis System™, AtCor Medical Pty Ltd, Sydney, Australia) were obtained on the same arm throughout the study, at predose (baseline) and 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, and 10 hours postdose in each treatment period. The SphygmoCor Pulse Wave Analysis System™ uses radial applanation tonometry to provide the following measurements and calculations: central aortic systolic, diastolic, and pulse (systolic minus diastolic) pressures; heights of central pulses P1 (determined by the incident wave) and P2 (peak systolic pressure, augmented by the reflected wave); the augmentation pressure (difference P2 minus P1); the augmentation index AIx (the ratio of augmentation pressure to pulse pressure reported as %); and T1 and T2 (in milliseconds) as times from onset of ventricular ejection to P1 and P2 (round-trip travel time of the forward wave from the ascending aorta to the major reflecting site and back).

Patients remained in a sitting or semi-recumbent position during the observation periods. Between measurements, patients engaged in sedentary activities in an environment with controlled room temperature. Patients did not sleep or nap from start of the predose procedures through completion of the 10-hour postdose procedures.

Safety was assessed by physical examinations, vital sign measurements, 12-lead electrocardiogram, laboratory safety tests (hematology, blood chemistry, and urinalysis), and assessment of clinical adverse experiences (AEs).
Statistical Methods

The primary hypotheses was that a single dose of losartan 100 mg + ISMN 60 mg would be associated with a greater mean decrease in AIx over a 10-hour post-dose period as compared with a single dose of losartan 100 mg or placebo. The prespecified primary end point was AIx. A difference of ≥15 percentage points was expected in AIx between losartan 100 mg + ISMN 60 mg versus losartan 100 mg or placebo. The study was designed with 80% power (alpha = 0.05, one-sided) to detect an effect size (difference/standard deviation) of 0.9, because 0.9 was the smallest effect size for key endpoints reported by Stokes et al.[3] and [16] Balance of treatment and period effects was addressed by isolating two treatments (ISMN 60 mg and placebo) in Periods 1 and 2, and the other three treatments in Periods 3, 4, and 5, which achieved balance within Periods 1 and 2 and within Periods 3, 4, and 5. For the post-hoc analyses, relationships among central and brachial BP measurements were evaluated analytically by computation of Pearson correlation coefficients.

Although designed for enrollment of 18 patients, because of lower than expected baseline BPs in individual patients, the study was stopped and analyzed after 13 patients were randomized and 11 patients had completed at least three study periods (5 patients completed all five study periods and 6 patients completed three or four of the study periods). Of the two remaining randomized patients, one had completed two periods and was included in the analysis, whereas the other had completed only one period and was excluded. The primary hypothesis was addressed by those interim results, even in consideration of multiplicity related to the interim nature of the analysis (see Results).

Comparison of AIx among treatments was made using difference in absolute percentage points rather than relative reduction because prior information from literature[3] and [16] has been computed using difference in absolute percentage points. Because heart rate affects Aix,[18] and [19] heart-rate-corrected AIx was used for all analyses of AIx.

Means were derived as least squares means from the standard crossover model that included terms for patient, period, and treatment. Multiple readings of an individual end point at each time point were represented by their mean at each time point. Individual patient average values at each time point from 1 to 10 hours were summarized for each patient for each period by further averaging across the 1- to-10-hour time period. The same computations were made for change from baseline (hour 0) at the 1- to-10-hour time points. The primary metric for combining the observations of each endpoint across the time points was time-weighted average across the 0–10 hour observation period.
Interim Analysis

Originally, no interim analysis was planned for this study; thus, decision-making on the conduct of the trial based on these interim results would affect the overall alpha-level (prespecified as 0.05, one-tailed) for the overall analysis of the trial data. However, because P values for the primary hypotheses (losartan 100 mg + ISMN 60 mg versus losartan 100 mg and versus placebo) were <.0005, any decisions on stopping the trial prematurely for efficacy had little impact on overall precision of conclusions.
Results
Patient Accounting and Characteristics

Patient characteristics are presented in Table 1; patient disposition is presented in Figure 1. Removal of the patient who completed only one study period did not substantially change the baseline characteristics of the analysis population. On average, randomized patients were middle aged (58.0 years), with an average body mass index of 30.1 kg/m2, and Stage 1 hypertension (BP 143.5/91.2 mm Hg). Three patients required withdrawal of excluded concomitant medications in order to qualify for the study.

Heart Rate

There was a marginal but significant effect of ISMN 60 mg on heart rate (Table 2). Correcting AIx for heart rate did not affect the statistical significance observed for any of the treatments.

Hemodynamics

Both doses of ISMN with losartan 100 mg yielded statistically significantly lower average AIx compared with losartan 100 mg alone (Table 3). Losartan 100 mg + ISMN 60 mg was associated with a greater mean decrease in AIx in comparison with losartan 100 mg or placebo; a decrease of approximately 23% was observed for losartan 100 mg + ISMN 60 mg compared with losartan 100 mg and 24% compared with placebo. After placebo subtracting, AIx decreased by 26% for ISMN 60 mg alone but by only about 1% for losartan 100 mg alone. When ISMN was added to losartan 100 mg, compared with losartan alone, ISMN 15 mg and 60 mg decreased AIx by 18% and 23%, respectively when compared with losartan alone. Thus, both doses of ISMN when administered with losartan 100 mg yielded a significant decrease in AIx. Although the difference between coadministered ISMN 15 mg and 60 mg is small, it was statistically significant, suggesting a small dose-response for ISMN 60 mg versus 15 mg. When compared with placebo, all AIx decreases were marked and statistically significant except for AIx changes associated with losartan 100 mg alone, indicating that short-term RAS blockade has no effect on AIx as compared with the marked effect of the NO donor. Moreover, AIx afforded substantially greater precision for the additive effect of ISMN to losartan than brachial or other central BP parameters (Table 3).

These results are further illustrated for AIx (Figure 2) and central (Figure 3) and brachial (Figure 4) systolic and diastolic BPs. Time courses for decreases in AIx and BPs with ISMN were similar, whether given alone or in combination with losartan. Decreases in central and brachial BPs with losartan were not significant compared with ISMN (alone or with losartan). Decreases in AIx and BPs were substantially greater for the other treatments in the following ascending order of efficacy: losartan 100 mg + ISMN 15 mg, ISMN 60 mg, and losartan 100 mg + ISMN 60 mg. Losartan 100 mg + ISMN 60 mg was associated with slight but significantly lower AIx than losartan 100 mg + ISMN 15 mg, suggesting a minor dose response with ISMN 15 mg versus 60 mg.

Safety

Nineteen clinical AEs were reported. All were mild to moderate in intensity. The most common AEs were headache in 3 of 12 patients receiving high dose ISMN and hypotension in 3 of 11 patients receiving losartan + high-dose ISMN. There were no serious AEs reported.
Discussion

The current study assessed comparisons of AIx when losartan, ISMN, and placebo were administered alone or in combination to patients with prehypertensive/Stage 1 hypertension. In post-hoc analyses, correlations between AIx and other central BP measurements with brachial BP were assessed. This study adds to our prior understanding about central BP effects of antihypertensive therapies. The results are consistent with previously reported short-term effects of ARBs (single dose to 1 week of dosing), where AIx ranged from nonsignificant to a 7% decrease, whereas single doses of nitrates decreased AIx in the range of 10%–20%. Stokes et al studied the central BP effects of single doses of a nitrate (ISMN 60 mg), an ARB (eprosartan 600 mg), an ACE inhibitor (captopril 25 mg), and placebo in elderly patients with poorly controlled hypertension.3 AIx decreased about 20% after a single dose of ISMN, whereas the RAS agent did not significantly affect AIx. Other studies have investigated the dose-response relationship of nitrates on central BP parameters. In particular, robust and dose-dependent effects on central BP parameters (10–20 % decreases in AIx) were reported for single doses of sublingual or patch nitroglycerin preparations administered to healthy subjects and/or patients.2 Effects of ARBs on central BP parameters have also been examined in short- and long-term studies in young (mean age, 27 years) hypertensive men. When the ARB valsartan 80 mg or 160 mg were administered daily for 2–4 weeks to hypertensive men (mean age, 49 years), AIx decreased approximately 4% and 5%, respectively.20 In a 4-month crossover study of losartan versus atenolol in patients with hypertension and left ventricular hypertrophy, AIx after treatment with losartan was not significantly lowered when heart rate was included as a covariate.21 These results are consistent with the current study demonstrating a substantial, acute central BP effect of ISMN alone or on top of an ARB but a negligible effect of the ARB alone. The large magnitude and the small intraindividual variability of ISMN on AIx demonstrate that AIx is a robust hemodynamic biomarker of NO pharmacodynamic effects on the vasculature.

Recent research has been directed toward development of antihypertensive agents that are NO donors or that modulate NO bioactivity aimed at increasing antihypertensive efficacy, promoting vascular and end-organ protection, and improving outcomes.22 Administration of nitrates, alone or in combination with other antihypertensive therapy, has been limited by potential side effects, such as hypotension, as well as by potential development of nitrate tolerance.22

Results of the Anglo-Scandinavian Cardiac Outcomes Trial-Conduit Artery Functional Endpoint study showed that the two treatment arms had different effects on central pressures, even though brachial pressures were the same in the two groups, suggesting that the substantially different observed effects on outcomes may be related to differences in central BP despite similar brachial BP.11 Current technology, such as tonometric methodology used in this study, provides validated, noninvasive, and convenient measurements of central BP parameters from radial pulse wave forms. The magnitude and timing of the pulse wave that reflects toward the proximal aorta can augment central BP and change with age and conditions that make blood vessels less compliant.6 Nitrates, which have been used to treat difficult-to-control systolic hypertension[3] and [16] and, to a lesser degree, other vasodilators, decrease pressure wave amplification and, therefore, decrease central BP and pulse pressure more than other classes, such as beta-blockers, for equivalent effect on brachial BP.23 Differences between central and brachial BP among antihypertensive agents have been demonstrated in several studies, such as the demonstration that calcium channel blockers and diuretics have greater effect on AIx and augmentation pressure compared with ACE inhibitors and, particularly, beta-blockers.24 T. Morgan, J. Lauri, D. Bertram and A. Anderson, Effect of different antihypertensive drug classes on central aortic pressure, Am J Hypertens 17 (2004), pp. 118–123. Abstract | View Record in Scopus | Cited By in Scopus (134)24 Therefore, central BP effects may need to be considered, in addition to brachial BP, when evaluating beneficial effects of an antihypertensive. In the longitudinal Strong Heart Study, central pulse pressure was 50% more sensitive than brachial pressure in predicting cardiovascular events.7 A study of end-stage renal disease showed that central BP, but not brachial BP, predicted all-cause mortality.8 The Dicomano study demonstrated the central, but not brachial, pressure independently predicted cardiovascular events in elderly patients.9 Aortic augmentation pressure was shown to predict adverse outcomes independent of brachial pressure in patients with established coronary artery disease.5 These numerous studies have resulted in a consensus document proposing central BP parameters to be more closely correlated with cardiovascular risk than brachial BP.4

There are several limitations to this study. The analysis was planned for 18 patients and the study was stopped after 11 of 13 randomized patients had completed at least three periods of the study, a stop point when the twelfth patient had completed two periods and was also included in the analysis. However, the highly significant P value for the primary objective of the study shows the reliability of the results despite a small sample size because of the early termination of the study. Similarly, despite the highly significant P values, the single-dose design provided for the evaluation of acute effects but does not address longer term treatment effects on central BP. Evaluation of persistence of the effect would require studies with longer dosing. Moreover, detecting any interaction between NO and angiotensin type I receptors (AT1) resulting from a downregulation of AT1 induced by NO may require chronic dosing.17

This study confirms that NO substantially decreases AIx, and other central systolic BP parameters either as monotherapy or when administered with an ARB. The study also supports the use of AIx as a noninvasive functional biomarker to measure the acute effect of NO agents. The large magnitudes of response to the NO donor ISMN in conjunction with the low attached variability observed in this study should be helpful in designing and powering future clinical trials.
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sffcc9296 (Sylvie)

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MessageSujet: Re: résultats études merck Losartan+ismn   Lun 3 Jan - 12:24

Merci Vinsse. On peut donc retenir, comme on s'y attendait, que le NO a un impact important sur la pression centrale qui est directement liée à la fréquence des incidents cardivasculaires.

vinsse a écrit:

Recent research has been directed toward development of antihypertensive agents that are NO donors or that modulate NO bioactivity aimed at increasing antihypertensive efficacy, promoting vascular and end-organ protection, and improving outcomes.22 Administration of nitrates, alone or in combination with other antihypertensive therapy, has been limited by potential side effects, such as hypotension, as well as by potential development of nitrate tolerance.22

Ce § est important et contribue à expliquer ama l'"échec" des premières molécules sur lesquelles ont travaillé Merck et Nicox. J'ai tendance à penser que les résultats sur l'AIx de ces molécules devaient être bons mais qu'il y avait certainement qq inconvénients (probablement un peu du même type que pour le naprox finalement). D'où probablement la mise au point d'une nouvelle technique de libération du NO qui pourrait résoudre ces pbs. Espérons le.


Dernière édition par sffcc9296 (Sylvie) le Lun 3 Jan - 19:36, édité 1 fois
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MessageSujet: Re: résultats études merck Losartan+ismn   Lun 3 Jan - 13:12

tout cela me laisse penser que Merck s'intéresse énormément au NO, et que le 8266 est un composé qui induit ou qui libère du NO (référence de l'indicateur AIx, et du NO dans les critères d'inclusion et d'exclusion). D'ici à penser que c'est un composé NicOx, à chacun son avis, mais pour moi ça ne fait pas de doute.
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MessageSujet: Re: résultats études merck Losartan+ismn   Lun 3 Jan - 19:42

L'isosorbide mononitrate (ISMN) est un médicamenrt génériqué,
posologie de 20 à 80mg voir plus,
effet secondaire: pas trop important pour les dosages de 20 à 60mg quotidien

Whttp://en.wikipedia.org/wikj/Isosorbide-mononitrate

La question:Losartan+ISMN associés à l'aide d'un pont chimique ou sans ?
est ce la nouvelle techno..?
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MessageSujet: Re: résultats études merck Losartan+ismn   Lun 3 Jan - 20:04

Non, losartan et ismn-er pris séparément (2 comprimé pris en même temps).

Je comprends pour ma part que le défi pour Merck et Nicox est de trouver une méthode de libération du NO qui soit au moins aussi efficace (voire plus) que la prise concomitante des 2 comprimés et qui permette en plus d'éliminer certains inconvénients :

vinsse a écrit:

Administration of nitrates, alone or in combination with other antihypertensive therapy, has been limited by potential side effects, such as hypotension, as well as by potential development of nitrate tolerance.22

La première technique ne devait pas être satisfaisante de ce point de vue, d'où la mise au point d'une nouvelle. (amha)

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