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General Discussion on ARBs and Drugs
 Moderated by: Prof Trevor Marshall  

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Markt9452
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 Posted: Sat Sep 17th, 2011 13:16

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Good gravy.... That sounds like a whole lot of immune suppression to me. :shock:

PXR, CAR, VDR, ah who needs those silly master controller receptors anyways.



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Phillyguy
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 Posted: Mon Sep 19th, 2011 00:25

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Interesting. HDAC2 also inhibits functioning of these receptors through repression of RXRa. I wonder if metformin increases HDAC2 activity.

Last edited on Mon Sep 19th, 2011 00:32 by Phillyguy

Bane
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 Posted: Tue Oct 4th, 2011 10:47

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Development and characterization of nanosuspensions of olmesartan medoxomil for bioavailability enhancement

http://www.ncbi.nlm.nih.gov/pubmed/21966165

BACKGROUND: Olmesartan medoxomil (OLM), an anti-hypertensive agent administered orally has absolute bioavailability of only 26% due to the poor aqueous solubility (<7.75 μg/ml). The present investigation aimed at enhancing the oral bioavailability of OLM by improving its solubility and dissolution rate by preparing nanosuspensions.

MATERIALS AND METHODS: The nanosuspensions of OLM were prepared using media milling technique followed by its lyophilization using mannitol as a cryoprotectant. Various formulation as well as process parameters were optimized in order to achieve desirable size and saturation solubility. Characterization of the prepared nanosuspension was done with respect to particle size, zeta potential, saturation solubility, dissolution rate, morphology study (TEM), in-vitro and exvivo drug diffusion study. Evaluation of the crystalline state before and after particle size reduction was done by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD).

RESULTS: The results indicated that the initial crystalline state is preserved following particle size reduction and that the saturation solubility, dissolution velocity and diffusion rate of the drug from the nanosuspension is significantly higher than that of the plain drug suspension as well as from the marketed tablet formulation.

CONCLUSION: Nanosuspension seems to be a promising approach for bioavailability enhancement because of the simple method of its preparation and its universal applicability.

ChrisMavo
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 Posted: Tue Oct 4th, 2011 11:00

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Very interesting Bane! 

I hope Dr Marshall can perhaps explain how this study relates to pure olmesartan.  I was surprised to read that only 26% of OM appears to be bioavailable in the currently available tablet form. 

I have been concerned for some time that due to my large body size I am not getting enough olmesartan to my CNS.  26% does not seem like a good percentage that is getting through. 

Last edited on Tue Oct 4th, 2011 11:02 by ChrisMavo



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Jigsaw
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 Posted: Fri Oct 7th, 2011 06:30

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Are there any ideas whether azilsartan medomixil File:Azilsartan medoxomil.svg - Wikipedia, the free encyclopedia
may have VDR liganding activity?

Last edited on Fri Oct 7th, 2011 06:30 by Jigsaw



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Bane
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 Posted: Thu Oct 13th, 2011 11:21

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In situ intestinal permeability and in vivo absorption characteristics of olmesartan medoxomil in self-microemulsifying drug delivery system.

http://www.ncbi.nlm.nih.gov/pubmed/21988221

To characterize the intestinal absorption behavior of olmesartan medoxomil (OLM) and to evaluate the absorption-improving potential of a self-microemulsifying drug delivery system (SMEDDS), we performed in situ single-pass intestinal perfusion (SPIP) and in vivo pharmacokinetic studies in rats. The SPIP study revealed that OLM is absorbed throughout whole intestinal regions, favoring proximal segments, at drug levels of 10-90 μM. The greatest value for effective permeability coefficient (P(eff)) was 11.4 × 10(-6) cm/s in the duodenum (90 μM); the lowest value was 2.9 × 10(-6) cm/s in the ileum (10 μM). A SMEDDS formulation consisting of Capryol 90, Labrasol, and Transcutol, which has a droplet size of 200 nm and self-dispersion time of 21 s, doubled upper intestinal permeability of OLM. The SMEDDS also improved oral bioavailability of OLM in vivo: a 2.7-fold increase in the area under the curve (AUC) with elevated maximum plasma concentration (C(max)) and shortened peak time (T(max)) compared to an OLM suspension. A strong correlation (r(2) = 0.955) was also found between the in situ jejunal P(eff) and the in vivo AUC values. Our study illustrates that the SMEDDS formulation holds great potential as an alternative to increased oral absorption of OLM.

 

Angiotensin II Receptor Blocker Partially Ameliorated Intra-renal Hypoxia in Chronic Kidney Disease Patients: A Pre/Post Study.

http://www.ncbi.nlm.nih.gov/pubmed/21988608

Chronic intra-renal hypoxia has been regarded as a pathogenic factor of progressive renal damage. However, the lack of available human data has impeded the progress in this field. In this work, blood oxygenation level-dependent (BOLD) MRI was used to determine intra-renal oxygen status pre- and post-angiotensin receptor blockade (ARB), (olmesartan) treatment in normal subjects, diabetes chronic kidney disease (CKD) patients, and non-diabetes CKD patients. The mean R(2) *, which represents intra-renal oxygenation, was significantly lower in the control group than in the CKD group (12.42 ± 0.53 s(-1) vs. 18.89 ± 3.15 s(-1) , p < 0.01), indicating the presence of intra-renal hypoxia in the CKD patients. The olmesartan treatment induced a 16.2 ± 7.7 % decrement of the mean R(2) * in CKD patients, suggesting that this drug had an intra-renal hypoxia ameliorating effect.

Last edited on Thu Oct 13th, 2011 11:25 by Bane

Phillyguy
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 Posted: Fri Oct 14th, 2011 03:30

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http://www.sciencedaily.com/releases/2011/10/111013184815.htm

Gut Bacteria May Affect Whether a Statin Drug Lowers Cholesterol

Joyful
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 Posted: Fri Oct 14th, 2011 07:54

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Quote from Phillyguy's link:

"It's no doubt that metabolites from bacteria are playing an important role in regulating our systems."



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Bane
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 Posted: Mon Oct 24th, 2011 00:06

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Commonly used 3-drug regimen for idiopathic pulmonary fibrosis found harmful

http://www.eurekalert.org/pub_releases/2011-10/nhla-cut102111.php

"This study, called PANTHER-IPF (Prednisone, Azathioprine, and N-acetylcysteine: A Study that Evaluates Response in Idiopathic Pulmonary Fibrosis) was designed and conducted by the Idiopathic Pulmonary Fibrosis Clinical Research Network, funded by the NHLBI. The PANTHER-IPF study was designed to evaluate whether this commonly used triple-therapy regimen could slow disease progression and improve lung function in people with moderate IPF"

Bane
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 Posted: Tue Oct 25th, 2011 10:20

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Olmesartan medoxomil and azelnidipine therapy in patients with hypertension and chronic kidney disease in Japan.

http://www.ncbi.nlm.nih.gov/pubmed/22020401

In the present investigation we extracted data on hypertensive patients with chronic kidney disease (CKD) who were enrolled in 3 studies - 2 studies of the angiotensin receptor blocker (ARB) olmesartan medoxomil (OLM), lasting 12 weeks and 2 years, respectively, and one of the calcium channel blocker (CCB) azelnidipine (AZ) lasting 12 weeks - to assess the effects of OLM and AZ on blood pressure (BP), estimated glomerular filtration rate (eGFR) and proteinuria in hypertensive patients with CKD in the setting of daily clinical practice. Methods: The 3 studies followed open prospective cohort designs that represented daily clinical practice in Japan. Patients with CKD at baseline were selected. Change of BP, eGFR and proteinuria on OLM therapy or AZ therapy were analyzed. Results: At 12 weeks, OLM (n=1,317) and AZ (n=952) therapies exhibited similar BP-lowering effects. AZ led to a significantly (p=0.0069) greater increase of eGFR compared with OLM, while OLM tended to improve proteinuria to a greater extent than AZ. Treatment with OLM for 2 years (n=109) significantly improved proteinuria but did not alter eGFR. Conclusion: This study shows that OLM and AZ reduced BP and proteinuria without decreasing eGFR in Japanese hypertensive patients with CKD in the setting of daily clinical practice.

Bane
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 Posted: Tue Oct 25th, 2011 10:30

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Double duty for blood pressure drugs: how they could revolutionize how we treat valve disease

http://www.eurekalert.org/pub_releases/2011-10/hasf-ddf101811.php

Compared to the individuals who were on no medication, those who were on ACE inhibitors had less rapid narrowing of their valve. But the biggest difference was seen in patients on ARBs, where the receptors of angiotensin II are blocked. In those patients, the progress of the disease was slowed considerably – three times slower than in the individuals who weren't taking any medication, reports Dr. Pibarot.

In effect, he says that with ARBs the current is slower, like on a calmer river.

In the absence of a drug treatment for AS, Dr. Pibarot's findings are potentially very significant, says Heart and Stroke Foundation spokesperson Dr. Beth Abramson.

"Open heart surgery can be effective, but is risky for many patients because of their age," says Dr. Abramson. "ARBs have the potential of slowing aortic stenosis significantly, so that we can prolong life without surgery."

She says that the need to find a medication solution is even more urgent when you consider that with the aging population the prevalence of valvular heart disease is expected to double within 15 years.

Bane
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 Posted: Fri Oct 28th, 2011 11:48

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ARBs May Cut Risk for Alzheimer's Disease

http://www.medscape.com/viewarticle/752445

October 27, 2011 — Controlling blood pressure with an angiotensin II receptor blocker (ARB) rather than other antihypertensive agents may significantly reduce the risk for Alzheimer's disease (AD) and vascular dementia (VaD), suggest results of a large observational study from the United Kingdom.

In the study, the risk for AD was 53% lower in older adults prescribed an ARB compared with those prescribed other antihypertensive agents. The risk was 24% lower in those prescribed an angiotensin converting enzyme (ACE) inhibitor.

Patrick G. Kehoe, PhD, coleader of the Dementia Research Group at Frenchay Hospital, Bristol, and colleagues report their study in the October issue of the Journal of Alzheimer's Disease.

Dr. Kehoe and colleagues say their findings support those of a recent study in a predominantly male population from the United States. In that study, reported previously by Medscape Medical News, men prescribed ARBs had a lower incidence and rate of progression of AD than those prescribed ACE inhibitors or other cardiovascular drugs.

The accumulating observational and biological evidence in favor of ARBs protecting against dementia "strengthens the need for them to be studied more rigorously in the future," Dr. Kehoe and colleagues conclude.

Although "interesting, these are not conclusive findings," coauthor Richard M. Martin, PhD, from the University of Bristol, notes in a statement. "We now need to do the clinical trials to properly test our observations."

Accumulating Evidence

The study was a nested-case control study within the UK general practice research database. It was designed to see whether ARBs and ACE inhibitors are more strongly associated with AD, VaD, and other dementias relative to other antihypertensive drugs such as calcium channel blockers, beta-blockers, or thiazide diuretics.

Although both ARBs and ACE inhibitors reduce angiotensin II signaling, "now believed to be involved in the pathobiology of AD, ARBs are unlikely to interrupt ACE-mediated [amyloid-beta] degradation," unlike ACE inhibitors, the researchers note in their article. "These mechanisms of action suggest that ARBs may have benefits over [ACE inhibitors] in the etiology of AD," they write.

Included in the analysis were 9197 patients, aged 60 years and older, who were diagnosed between 1997 and 2008 with probable or possible AD (n = 5797), VaD (n = 2186), or unspecified/other dementia (n = 1214). Each case patient was matched by age, general practice, and sex to up to 4 control patients (n = 39,166).

The researchers observed that patients ever prescribed either ARBs or ACE inhibitors were less likely to develop AD, VaD, or other dementia than patients ever prescribed other antihypertensive medications. The associations were stronger for ARBs than for ACE inhibitors.

These associations did not differ by age, comorbidities, or blood pressure, suggesting little confounding by observed comorbidities, the researchers say. There was also evidence of a dose–response relationship between ARBs and AD (P = .009).

In analyses restricted to patients exposed either to ARBs or ACE inhibitors as their only therapy, there was an inverse association of ARB sole therapy (OR, 0.63; 95% CI, 0.45 - 0.88), but not ACE inhibitor sole therapy (OR, 1.01; 95% CI, 0.91 - 1.12).

"Preaching to the People"

Reached for comment, Gustavo C. Román, MD, medical director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, Texas, who was not involved in the study, said it "reaffirms the need to control blood pressure, and the sooner, the better."

Dr. Román said he has been "preaching to the people that you need to keep your blood pressure under good control because it really seems that vascular disease, and especially hypertension, opens the gate to the amyloid-beta changes, although the mechanism is not very clear.

"Whatever the mechanism, it has been demonstrated over and over that vascular disease, in particular hypertension, is a risk factor for the development of [AD]," he added.

Bane
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 Posted: Tue Nov 1st, 2011 14:55

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ACE, ARB May Benefit Aortic Regurg

http://en.wikipedia.org/wiki/Aortic_insufficiency

http://www.medpagetoday.com/Cardiology/CHF/29359

"The odds of dying from any cause were a significant 44% lower during 4.4 years of follow-up for those who received an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) among the more than 2,200 such patients studied by Chim C. Lang, of the University of Dundee, Scotland, and colleagues"

Bane
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 Posted: Thu Nov 17th, 2011 12:26

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Paraoxonase 1 as a Major Bioactivating Hydrolase for Olmesartan Medoxomil in Human Blood Circulation: Molecular Identification and Contribution to Plasma Metabolism.

http://www.ncbi.nlm.nih.gov/pubmed/22086979

http://en.wikipedia.org/wiki/PON1

Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist. The OM-hydrolyzing enzyme responsible for the prodrug bioactivation, was purified from human plasma by successive column chromatography and was molecularly identified by N-Terminal amino acid sequencing, resulting in the identical sequence of 20 amino acids to that of human paraoxonase 1 (PON1). Two recombinant allozymes of human PON1 (PON1(192QQ) and PON1(192RR)) were constructed and clearly demonstrated to hydrolyze OM, where hydrolysis by the latter allozyme was slightly faster than by the former. Also, we evaluated the contribution of PON1 to the OM bioactivation in human plasma. Enzyme kinetic studies demonstrated that OM is more effectively hydrolyzed by the recombinant PON1 proteins than by purified albumin. The OM-hydrolyzing activities of the recombinant PON1 proteins as well as diluted plasma were greatly reduced in the absence of calcium ions. Immunoprecipitation with anti-PON1 IgG completely abolished the OM-hydrolyzing activity in human plasma, while it was partially inhibited with anti-albumin IgG. The distribution pattern of the OM-hydrolyzing activity in human serum lipoprotein fractions and lipoprotein deficient serum was examined, and showed that most of the OM-hydrolyzing activity was located in the HDL fraction with which PON1 is closely associated. In conclusion, we identified for the first time PON1 as the OM bioactivating hydrolase in human plasma on a molecular basis and demonstrated that PON1, but not albumin, plays a major role in the OM bioactivation in human plasma.

Prof Trevor Marshall
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 Posted: Thu Nov 17th, 2011 13:54

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Note that GI tract absorption may not be the same mechanism as in plasma.

http://ukpmc.ac.uk/abstract/MED/20177059

"Human carboxymethylenebutenolidase as a bioactivating hydrolase of olmesartan medoxomil in liver and intestine" (a Pseudomonas homolog).


Bane
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 Posted: Wed Nov 30th, 2011 18:32

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Four-year clinical outcomes of the OLIVUS-Ex (impact of Olmesartan on progression of coronary atherosclerosis: Evaluation by intravascular ultrasound) extension trial.

http://www.ncbi.nlm.nih.gov/pubmed/22119063

RESULTS: Cumulative event-free survival was significantly higher in the Olmesartan group than in the control group (p=0.04; log-rank test). By adjusting for validated prognosticators, Olmesartan administration was identified as a good predictor of MACCE (p=0.041). On the other hand, patients with adverse events (n=31) had larger annual atheroma progression than the rest of the population (23.8% vs. 2.1%, p<0.001).

CONCLUSIONS: Olmesartan therapy appears to confer improved long-term clinical outcomes. Atheroma volume changes, assessed by IVUS, seem to be a reliable surrogate for future major adverse cardio- and cerebrovascular events in this study cohort.

Bane
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 Posted: Wed Dec 14th, 2011 15:04

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Olmesartan Medoxomil Is Associated with Decreased Plasma AGEs, Pentosidine, and N-(Epsilon)-Carboxymethyl-Lysine Levels in Hemodialysis Patients
http://www.ncbi.nlm.nih.gov/pubmed/22149003

Advanced glycation end products (AGEs) are associated with comorbidity and death among patients on hemodialysis (HD). Angiotensin II type 1 receptor blockers (ARBs) can decrease the formation of AGEs in vitro. This study examines the ability of various ARBs to decrease plasma AGE levels in hypertensive patients on HD. Methods. This preliminary randomized prospective study included 24 hypertensive patients on HD who were treated with candesartan (8 mg/day). The patients were randomly assigned to an olmesartan (20 mg/day, n = 12) or a telmisartan (40 mg/day, n = 12) group and followed up 24 weeks. Blood pressure was monitored before each HD session, and plasma pentosidine, N-(epsilon)-carboxymethyl-lysine (CML), serum malondialdehyde-low-density lipoprotein (LDL), high-sensitive CRP, and serum total free radical (TFR) were measured at baseline, and at 4, 12, and 24 weeks. Results. Olmesartan was significantly associated with decreased systolic blood pressure compared with telmisartan. After 24 weeks of treatment, plasma pentosidine and CML levels were significantly decreased and serum TFR levels tended to be decreased in the olmesartan group, but remained unchanged in the telmisartan group. Conclusions. These results suggest that olmesartan can help to decrease plasma AGE levels in patients on HD.

Phillyguy
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 Posted: Thu Dec 15th, 2011 03:47

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Accumulation of AGEs are one of Aubrey's 7 causes of aging. In addition to reducing AGEs, olmesartan antagonizes RAGE, the receptor for aged glycation end products. Pretty cool.

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 Posted: Fri Dec 16th, 2011 20:22

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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017974

AGEs Secreted by Bacteria Are Involved in the Inflammatory Response

Advanced Glycated End Products (AGEs) are formed by non-enzymatic protein glycation and are implicated in several physiological aspects including cell aging and diseases. Recent data indicate that bacteria – although short lived – produce, metabolize and accumulate AGEs. Here we show that Escherichia coli cells secret AGEs by the energy-dependent efflux pump systems. Moreover, we show that in the presence of these AGEs there is an upshift of pro-inflammatory cytokins by mammalian cells. Thus, we propose that secretion of AGEs by bacteria is a novel avenue of bacterial-induced inflammation which is potentially important in the pathophysiology of bacterial infections. Moreover, the sensing of AGEs by the host cells may constitute a warning system for the presence of bacteria.





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 Posted: Fri Dec 16th, 2011 21:28

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Does this suggest that the bacteria somehow benefit from the inflammation?



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