-
Basic & Clinical Pharmacology &... Oct 2017Azilsartan (AZL) medoxomil was approved by the United States Food and Drug Administration in 2011 for the treatment of hypertension and has shown promising results both... (Review)
Review
Azilsartan (AZL) medoxomil was approved by the United States Food and Drug Administration in 2011 for the treatment of hypertension and has shown promising results both in blood pressure (BP) reduction and in tolerability, but has not yet been taken into practice to the same extent as other angiotensin II receptor blockers (ARBs) that have been on the market for a longer period. AZL antagonizes the AT receptor for angiotensin II (ANG II), whereas angiotensin-converting enzyme inhibitors block the conversion of angiotensin I to ANG II, but not alternative routes of formation of ANG II. The bioavailability of AZL is about 60% and it has a t of 1.5-3 hr and a half-life of approximately 11 hr. With its IC of 7.4 nM after 5 hr of drug washout in radioligand assays, AZL has a tighter and longer-lasting binding to the AT receptor by several orders of magnitude than other ARBs, which might lead to a more effective reduction in BP. Clinical studies have revealed that AZL doses of 40 and 80 mg/day reduce BP significantly better than maximal clinical doses of valsartan or olmesartan, while being well tolerated and exhibiting a spectrum of adverse effects comparable to those of other ARBs. These properties of AZL might lower the risk of cardiovascular disease and thereby reduce mortality rates. However, the existing mortality studies have not found this correlation, which should be further investigated.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Clinical Trials as Topic; Humans; Hypertension; Oxadiazoles; Renin-Angiotensin System; Signal Transduction; Treatment Outcome
PubMed: 28444983
DOI: 10.1111/bcpt.12800 -
Drug Design, Development and Therapy 2019Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an...
BACKGROUND
Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an angiotensin II receptor blocker (ARB) and has been shown to exhibit renoprotective effects on a streptozotocin (STZ)-induced diabetic rat model. Yet, whether OM affects DN progression and renal injury in db/db mice, a type 2 diabetic murine model, has not been established.
METHODS
Wild-type (n = 15) and db/db mice (n = 15) were treated with control saline or OM via oral gavage. The physiological and biochemical parameters were evaluated and histological examinations of kidney specimens were performed.
RESULTS
Compared with saline-treated db/db mice, db/db mice administered with OM showed ameliorated diabetic physiological and biochemical parameters. In addition, OM decreased urinary albumin excretion and plasma creatinine level in db/db mice. Moreover, histologically, OM reduced glomerular hypertrophy and injury, and also ameliorated tubular injury, thus suggesting that OM improves renal function and minimizes renal pathological deterioration in db/db mice.
CONCLUSION
Our study reveals a beneficial role of OM in ameliorating DN in db/db mice, which is associated with its renoprotective function.
Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Animals; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Male; Mice; Olmesartan Medoxomil
PubMed: 31695333
DOI: 10.2147/DDDT.S217826 -
Drug Design, Development and Therapy 2016The pill burden of patients with hypertension and dyslipidemia can result in poor medication compliance. This study aimed to evaluate the efficacy and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of fixed-dose combination therapy with olmesartan medoxomil and rosuvastatin in Korean patients with mild to moderate hypertension and dyslipidemia: an 8-week, multicenter, randomized, double-blind, factorial-design study (OLSTA-D RCT: OLmesartan rosuvaSTAtin from Daewoong).
The pill burden of patients with hypertension and dyslipidemia can result in poor medication compliance. This study aimed to evaluate the efficacy and safety of fixed-dose combination (FDC) therapy with olmesartan medoxomil (40 mg) and rosuvastatin (20 mg) in Korean patients with mild to moderate hypertension and dyslipidemia. This multicenter, randomized, double-blind, factorial-design study included patients aged ≥20 years with mild to moderate essential hypertension and dyslipidemia. Patients were randomly assigned to receive FDC therapy (40 mg olmesartan medoxomil, 20 mg rosuvastatin), 40 mg olmesartan medoxomil, 20 mg rosuvastatin, or a placebo. The percentage change from baseline in low-density lipoprotein cholesterol levels was compared between FDC therapy and olmesartan medoxomil, and the change from baseline in diastolic blood pressure was compared between FDC therapy and rosuvastatin 8 weeks after treatment. A total of 162 patients were included. The least square mean percentage change (standard error) from baseline in low-density lipoprotein cholesterol levels 8 weeks after treatment was significantly greater in the FDC than in the olmesartan medoxomil group (-52.3% [2.8%] vs -0.6% [3.5%], P<0.0001), and the difference was -51.7% (4.1%) (95% confidence interval: -59.8% to -43.6%). The least square mean change (standard error) from baseline in diastolic blood pressure 8 weeks after treatment was significantly greater in the FDC group than in the rosuvastatin group (-10.4 [1.2] mmHg vs 0.1 [1.6] mmHg, P<0.0001), and the difference was -10.5 (1.8) mmHg (95% confidence interval: -14.1 to -6.9 mmHg). There were 50 adverse events in 41 patients (22.7%) and eight adverse drug reactions in five patients (2.8%). The study found that FDC therapy with olmesartan medoxomil and rosuvastatin is an effective, safe treatment for patients with hypertension and dyslipidemia. This combination may improve medication compliance in patients with a large pill burden.
Topics: Antihypertensive Agents; Double-Blind Method; Drug Combinations; Dyslipidemias; Female; Humans; Hypertension; Male; Middle Aged; Olmesartan Medoxomil; Republic of Korea; Rosuvastatin Calcium
PubMed: 27574399
DOI: 10.2147/DDDT.S112873 -
High Blood Pressure & Cardiovascular... Mar 2023Blood pressure control remains an unmet clinical need. Only about half of patients achieve their blood pressure (BP) targets and of these, the majority require... (Review)
Review
Blood pressure control remains an unmet clinical need. Only about half of patients achieve their blood pressure (BP) targets and of these, the majority require combination and double or triple therapies. International guidelines recommend the association of drugs with complementary mechanisms of action and, in particular, the combination of renin-angiotensin system (RAS) inhibitors, calcium channel blockers (CCBs), and diuretics. Among the various angiotensin receptor blockers, olmesartan (OM) is available as a monotherapy and in dual and triple single-pill combinations (SPCs) with amlodipine (AML) and/or hydrochlorothiazide (HCTZ). Several phase III and IV studies, together with real-world studies, have demonstrated the additional benefits of combining OM either with AML or with HCTZ in terms of BP control and target BP achievements both in the general population and in special subgroups of hypertensive patients, such as the elderly, diabetic, chronic kidney disease or obese patients. Ambulatory BP monitoring studies assessing 24h BP have also demonstrated that dual, as well as triple, OM-based SPCs induce a more sustained and smoother BP reduction than placebo and monotherapy. Furthermore, triple OM-based SPC has been shown to improve therapeutic adherence in hypertensive patients compared to free combinations. The availability of OM combined with HCTZ, AML or both at different dosages makes it a valuable option to customize therapy based on the levels of BP and the clinical characteristics of hypertensive patients.
Topics: Humans; Aged; Antihypertensive Agents; Blood Pressure; Olmesartan Medoxomil; Drug Therapy, Combination; Hypertension; Amlodipine; Hydrochlorothiazide; Leukemia, Myeloid, Acute
PubMed: 36696054
DOI: 10.1007/s40292-023-00563-8 -
Clinical Drug Investigation Nov 2012There is limited information on the long-term efficacy and safety of olmesartan medoxomil in the management of hypertension in Chinese patients. We therefore conducted... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVES
There is limited information on the long-term efficacy and safety of olmesartan medoxomil in the management of hypertension in Chinese patients. We therefore conducted the present multicentre, single-arm, prospective, observational study to investigate the 24-week efficacy and safety of olmesartan medoxomil in patients with mild to moderate hypertension.
METHODS
Eligible patients (diastolic blood pressure [BP] 90-109 mmHg and systolic BP <180 mmHg off antihypertensive medication) were started on olmesartan medoxomil 20 mg once daily, with the possible up-titration to 40 mg once daily during 24 weeks of follow-up, to control clinic BP to the target level (<140/90 and <130/80 mmHg in diabetes mellitus). In a subset of enrolled patients, 24-h ambulatory and home BP monitoring were also performed.
RESULTS
In the intent-to-treat analysis (n = 348), at 24 weeks of follow-up, the mean ± SD changes from baseline in clinic systolic/diastolic BP were 21.2 ± 14.2/16.0 ± 8.8 mmHg (p < 0.001). The proportions of patients who achieved the goal BP for systolic, diastolic and both were 81, 80 and 75 %, respectively. Olmesartan medoxomil also significantly (p < 0.001) reduced systolic/diastolic BP measured at patients' homes by 17.7 ± 13.1/12.1 ± 7.9 mmHg from baseline (n = 109), and reduced mean 24-h, daytime and night-time ambulatory BP by 13.3 ± 16.3/7.6 ± 9.5 mmHg, 13.9 ± 17.4/8.0 ± 10.4 mmHg and 12.3 ± 18.1/6.8 ± 10.2 mmHg, respectively (n = 87). Seven (2.0 %) serious adverse events were reported during follow-up.
CONCLUSION
In Chinese hypertensive patients, olmesartan medoxomil is efficacious in lowering BP as assessed by three different BP-measuring methods and has an acceptable long-term safety and tolerability profile.
Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Asian People; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Chi-Square Distribution; China; Humans; Hypertension; Imidazoles; Intention to Treat Analysis; Middle Aged; Office Visits; Olmesartan Medoxomil; Predictive Value of Tests; Prospective Studies; Tetrazoles; Time Factors; Treatment Outcome
PubMed: 23018282
DOI: 10.1007/s40261-012-0003-7 -
Integrated Blood Pressure Control 2010Hypertension remains a significant health burden in the United States, with almost one in three adults affected, and is an independent risk factor for cardiovascular and...
Hypertension remains a significant health burden in the United States, with almost one in three adults affected, and is an independent risk factor for cardiovascular and renal disease. The goal of antihypertensive treatment is to reduce cardiovascular and renal morbidity and mortality by reducing blood pressure (BP). Guidelines recommend a target BP of <140/90 mmHg, with a more stringent goal of <130/80 mmHg for patients with diabetes and chronic renal disease. However, BP goal attainment rates remain low and most patients require therapy with two or more antihypertensive agents. Combination antihypertensive therapy usually employs agents from different classes, thus benefitting from complementary mechanisms of action to achieve greater BP control with fewer side effects. Patient adherence to therapy is enhanced by formulating treatments as fixed-dose (single-pill) combinations. One example is the combination of amlodipine, a dihydropyridine calcium channel blocker (CCB), with olmesartan medoxomil, an angiotensin receptor blocker (ARB). Here, the rationale for the use of CCB/ARB combination therapy is discussed, as well as the pharmacology and tolerability of the amlodipine/olmesartan medoxomil combination and its efficacy in terms of achieving BP goal in patients with hypertension. Advantages of its use from the patient's perspective are also discussed.
PubMed: 21949625
DOI: 10.2147/ibpc.s9691 -
The Journal of Biological Chemistry Apr 2010Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. Herein, we describe the...
Olmesartan medoxomil (OM) is a prodrug type angiotensin II type 1 receptor antagonist widely prescribed as an antihypertensive agent. Herein, we describe the identification and characterization of the OM bioactivating enzyme that hydrolyzes the prodrug and converts to its pharmacologically active metabolite olmesartan in human liver and intestine. The protein was purified from human liver cytosol by successive column chromatography and was identified by mass spectrometry to be a carboxymethylenebutenolidase (CMBL) homolog. Human CMBL, whose endogenous function has still not been reported, is a human homolog of Pseudomonas dienelactone hydrolase involved in the bacterial halocatechol degradation pathway. The ubiquitous expression of human CMBL gene transcript in various tissues was observed. The recombinant human CMBL expressed in mammalian cells was clearly shown to activate OM. By comparing the enzyme kinetics and chemical inhibition properties between the recombinant protein and human tissue preparations, CMBL was demonstrated to be the primary OM bioactivating enzyme in the liver and intestine. The recombinant CMBL also converted other prodrugs having the same ester structure as OM, faropenem medoxomil and lenampicillin, to their active metabolites. CMBL exhibited a unique sensitivity to chemical inhibitors, thus, being distinguishable from other known esterases. Site-directed mutagenesis on the putative active residue Cys(132) of the recombinant CMBL caused a drastic reduction of the OM-hydrolyzing activity. We report for the first time that CMBL serves as a key enzyme in the bioactivation of OM, hydrolyzing the ester bond of the prodrug type xenobiotics.
Topics: Amino Acid Sequence; Angiotensin II Type 1 Receptor Blockers; Biotransformation; Carboxylic Ester Hydrolases; Cell Line; Cytosol; DNA Primers; Enzyme Inhibitors; Female; Humans; Imidazoles; In Vitro Techniques; Intestines; Kinetics; Liver; Male; Molecular Sequence Data; Mutagenesis, Site-Directed; Olmesartan Medoxomil; Pregnancy; Prodrugs; RNA, Messenger; Recombinant Proteins; Sequence Homology, Amino Acid; Tetrazoles; Tissue Distribution
PubMed: 20177059
DOI: 10.1074/jbc.M109.072629 -
AAPS PharmSciTech 2009Two simple, economical, rapid, precise, and accurate methods for simultaneous determination of olmesartan medoxomil and hydrochlorothiazide in combined tablet dosage...
Ratio spectra derivative and zero-crossing difference spectrophotometric determination of olmesartan medoxomil and hydrochlorothiazide in combined pharmaceutical dosage form.
Two simple, economical, rapid, precise, and accurate methods for simultaneous determination of olmesartan medoxomil and hydrochlorothiazide in combined tablet dosage form have been developed. The first method is based on ratio spectra derivative spectrophotometry, and the second method is zero-crossing difference spectrophotometry. The amplitudes in the first derivative of the corresponding ratio spectra at 231.0 and 271.0 nm were selected to determine olmesartan medoxomil and hydrochlorothiazide, respectively. Measurements of absorbance were carried out at zero-crossing wavelengths 257.8 and 240.2 nm for olmesartan medoxomil and hydrochlorothiazide by zero-crossing difference spectrophotometric method. Beer's law is obeyed in the concentration range of 08-24 microg/mL for olmesartan medoxomil (OLM) and 05-15 microg/mL for hydrochlorothiazide (HCT) by ratio spectra derivative and 05-30 microg/mL for OLM and HCT by zero-crossing difference spectrophotometric method. The results of the assay were found to be 100.46+/-0.95 for OLM and 100.4+/-0.27 for HCT by ratio spectra derivative and 99.06+/-1.14 for OLM and 100.05+/-0.90 for HCT by zero-crossing difference spectrophotometric method. These methods passes F test and t test. Both methods were validated statistically and by performing recovery study.
Topics: Calibration; Drug Combinations; Hydrochlorothiazide; Imidazoles; Olmesartan Medoxomil; Spectrophotometry, Ultraviolet; Tablets; Tetrazoles
PubMed: 19862625
DOI: 10.1208/s12249-009-9318-y -
Biological & Pharmaceutical Bulletin Feb 2018Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and hydrolyzes compounds at both sites. Although the hydrolytic interaction of ester-type... (Comparative Study)
Comparative Study
Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and hydrolyzes compounds at both sites. Although the hydrolytic interaction of ester-type drugs with other drugs by HSA has been reported, there are only a few studies concerning the effect of pharmaceutical excipients on the hydrolysis of ester-type drugs by HSA. In the present study, we investigated the effect of ethanol (2 vol%; 345 mM) on the hydrolysis of aspirin, p-nitrophenyl acetate, and olmesartan medoxomil, which are ester-type drugs, with 4 different lots of HSA preparations. The hydrolysis activities of HSA toward aspirin, p-nitrophenyl acetate, and olmesartan medoxomil were measured from the pseudo-first-order degradation rate constant (k) of salicylic acid, p-nitrophenol, and olmesartan, respectively, which are the HSA-hydrolyzed products. Ethanol inhibited hydrolysis of aspirin by HSA containing low levels of fatty acids, but not by fatty acid-free HSA. Ethanol inhibited hydrolysis of p-nitrophenyl acetate by both fatty acid-free HSA and HSA containing low levels of fatty acids. In contrast, the hydrolysis of olmesartan medoxomil by HSA was insignificantly inhibited by ethanol, but inhibited not only by warfarin and indomethacin but also by naproxen, which are site I binding drugs and a site II binding drug, respectively. These results suggest that the inhibitory action of ethanol on the hydrolysis of ester-type drugs by HSA differs between site I binding drugs and site II binding drugs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Antihypertensive Agents; Aspirin; Binding Sites; Drug Stability; Ethanol; Excipients; Fatty Acids, Nonesterified; Humans; Hydrolysis; Indomethacin; Kinetics; Ligands; Naproxen; Nitrophenols; Olmesartan Medoxomil; Preservatives, Pharmaceutical; Serum Albumin, Human; Warfarin
PubMed: 29176265
DOI: 10.1248/bpb.b17-00680 -
Integrated Blood Pressure Control 2011Hypertension affects nearly one-third of all individuals in the US, yet one-half of all treated patients achieve blood pressure (BP) controlled to recommended goals. The...
Hypertension affects nearly one-third of all individuals in the US, yet one-half of all treated patients achieve blood pressure (BP) controlled to recommended goals. The percentage of patients with uncontrolled BP is likely to be much higher when considering the number of patients who are not even aware of their hypertensive state. Elevated BP is associated with increased risks of cardiovascular events and end-organ damage. Antihypertensive monotherapy is not always sufficient to achieve BP goals, and thus more aggressive treatment regimens need to be considered. Antihypertensive combination therapy, which may improve tolerability, offers the benefit of targeting different mechanisms of action. Numerous outcomes studies support the use of a renin-angiotensin system inhibitor as a first-line choice in antihypertensive therapy. This review discusses the benefits of combination therapy with the angiotensin type II receptor blocker olmesartan medoxomil (OM) paired with the thiazide diuretic hydrochlorothiazide (HCTZ). The pharmacokinetic properties of OM will be reviewed in addition to efficacy studies that support OM + HCTZ combination therapy over other possible antihypertensive combinations. Finally, a rationale for choosing HCTZ over another diuretic, chlorthalidone, will also be discussed based on pharmacokinetic differences, clinical concerns, and trends in use.
PubMed: 22253546
DOI: 10.2147/IBPC.S12214