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Scientia Pharmaceutica 2015Drug product purity and potency are of most significance in the regulatory market as we notice many recalled batches worldwide, particularly in the US and Japan....
Drug product purity and potency are of most significance in the regulatory market as we notice many recalled batches worldwide, particularly in the US and Japan. Olmesartan Medoxomil is an anti-hypertensive drug. The present invention relates to a process for the preparation of Olmesartan Medoxomil with 99.9% purity in an overall 62% yield. The synthesis includes three isolations and one purification with easy plant operations. This process describes the formation and control of each individual impurity in all stages. This process for Olmesartan Medoxomil and its intermediates is competent for industrial production in very short reaction time intervals with an appreciable yield and high purity.
PubMed: 26839831
DOI: 10.3797/scipharm.1502-04 -
Basic & Clinical Pharmacology &... Jul 2016Amiodarone (AD) is one of the most frequently prescribed anti-arrhythmic agents worldwide, but its effectiveness is limited due to the development of pulmonary toxicity....
Amiodarone (AD) is one of the most frequently prescribed anti-arrhythmic agents worldwide, but its effectiveness is limited due to the development of pulmonary toxicity. Several lines of evidence have suggested that AT1 receptor antagonists can attenuate pulmonary fibrosis in different animal models. This study was performed to evaluate the effect of olmesartan medoxomil (OM) on lung injury induced in rats by AD which was assessed biochemically (hydroxyproline content, MDA level and SOD activity), histologically (Ashcroft criteria and Masson's trichrome stain) and immunohistochemically (TGF-β1 expression in lung tissue). The expression levels of TGF-β1 and type I collagen mRNA were also determined by quantitative real-time polymerase chain reaction. Forty-eight adult male rats were randomized into six equal groups: control group, OM control groups, AD group received 40 mg/kg/day, p.o. for 4 weeks to induce pulmonary injury in rats and OM-treated groups received 0.6 and 6 mg/kg/day, p.o. concomitantly with AD for the same period. The results indicated that OM significantly decreased collagen deposition and hydroxyproline content, ameliorated pathological score and decreased the elevation in type I collagen and TGF-ß1 mRNA expression in lung tissue. Furthermore, it attenuated the AD-induced increase in the MDA level and increased SOD activity in lung tissue. It can be concluded that OM exerts a protective effect against AD-induced lung damage in rats which is attributed to modulation of pro-fibrogenic cytokine (TGF-β1) and antioxidant effect.
Topics: Amiodarone; Animals; Collagen Type I; Disease Models, Animal; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Lung; Lung Injury; Male; Olmesartan Medoxomil; RNA, Messenger; Random Allocation; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1
PubMed: 26781185
DOI: 10.1111/bcpt.12551 -
Journal of Hypertension Apr 2016Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent ARB for the treatment of stages 1-2 hypertension. We compared the efficacy, safety, and metabolic effects of AZL-M to both valsartan (VAL) and olmesartan (OLM), separately in patients with impaired fasting glucose (prediabetes mellitus) and T2DM.
METHODS
A pooled analysis of 3821 patients from three separate randomized placebo-controlled trials comparing the effects of AZL-M (40 and 80 mg), OLM (40 mg), VAL (320 mg), and placebo on changes in ambulatory and clinic blood pressure (BP) among patients with hypertension and prediabetes mellitus or T2DM was performed. Two analysis pools were created to facilitate comparisons: Pool A included patients who received placebo, AZL-M or OLM and Pool B included those who received AZL-M or VAL. Within each pool, patients were stratified by glycemic subgroups (normoglycemic, prediabetes mellitus, or T2DM) based on hemoglobin A1c values. Changes from baseline in both 24-h and clinic SBP were the primary efficacy assessments.
RESULTS
Baseline 24-h mean SBPs were approximately 145 and 146 mmHg in the prediabetes mellitus and T2DM subgroups, respectively; corresponding clinic SBPs were approximately 158 and 159 mmHg. Baseline hemoglobin A1c values for each subgroup (both pools) were normoglycemic, 5.3%; prediabetes mellitus, 6.0%; and T2DM, 6.9%. Changes from baseline in 24-h or clinic SBP were significantly greater with AZL-M, 80 mg compared with either OLM 40 mg or VAL 320 mg in all subgroups in each pool. Safety and tolerability were similar among the active treatment and placebo subgroups.
CONCLUSION
These analyses indicate that AZL-M, 80 mg/day lowers SBP by a greater magnitude than OLM or VAL at maximally approved doses in patients with prediabetes mellitus and T2DM. These findings have important clinical implications for this high-risk patient group.
Topics: Adult; Aged; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Imidazoles; Male; Middle Aged; Oxadiazoles; Prediabetic State; Tetrazoles; Valsartan
PubMed: 26766564
DOI: 10.1097/HJH.0000000000000839 -
Trials Jan 2016Epicardial adipose tissue (EAT) is a newly discovered independent risk factor for coronary atherosclerosis. There is a scarcity of information on the reduction of EAT... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy study of olmesartan medoxomil on coronary atherosclerosis progression and epicardial adipose tissue volume reduction in patients with coronary atherosclerosis detected by coronary computed tomography angiography: study protocol for a randomized controlled trial.
BACKGROUND
Epicardial adipose tissue (EAT) is a newly discovered independent risk factor for coronary atherosclerosis. There is a scarcity of information on the reduction of EAT volume to reduce atherosclerosis risk. Coronary computed tomography angiography (CCTA) has emerged as a noninvasive imaging method for the analysis of coronary atherosclerosis and EAT volume. The purpose of this trial is to determine whether olmesartan medoxomil is effective at both treatment of coronary atherosclerosis progression and EAT volume reduction in patients with coronary atherosclerosis detected by CCTA.
METHODS/DESIGN
This study is a prospective, single-center, open-label, randomized controlled clinical trial aimed at exploring the efficacy of olmesartan medoxomil on coronary atherosclerosis and EAT. A total of 194 patients with coronary stenosis greater than 30 % and less than 70 % detected by CCTA will be randomly divided into olmesartan medoxomil or conventional antihypertensive medication groups (1:1 ratio). The primary outcome measures include coronary atherosclerosis progression and EAT volume reduction, as detected by CCTA at 12 months. The secondary outcome measures include the levels of blood lipids, glucose, high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, TNF-α, matrix metalloproteinase 9, NO, endothelin 1, adiponectin, and leptin at baseline and after 6 and 12 months.
DISCUSSION
Treatments aimed at reducing EAT volume can eventually achieve an antiatherosclerotic effect. This is the first trial designed to explore the effect of olmesartan medoxomil on both coronary atherosclerosis progression and EAT volume reduction in patients with coronary atherosclerosis detected by CCTA.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT02360956 .
Topics: Adipose Tissue; Clinical Protocols; Coronary Angiography; Coronary Artery Disease; Disease Progression; Humans; Olmesartan Medoxomil; Pericardium; Prospective Studies; Sample Size; Tomography, X-Ray Computed
PubMed: 26739013
DOI: 10.1186/s13063-015-1097-z -
American Journal of Cardiovascular... Apr 2016This study was to evaluate the efficacy and safety of triple fixed-dose combination (FDC) therapy with olmesartan medoxomil (OM) 20 mg, amlodipine (AML) 5 mg, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety Study of Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide Combination Therapy in Patients with Hypertension Not Controlled with Olmesartan Medoxomil and Hydrochlorothiazide Combination Therapy: Results of a Randomized, Double-Blind, Multicenter Trial.
BACKGROUND
This study was to evaluate the efficacy and safety of triple fixed-dose combination (FDC) therapy with olmesartan medoxomil (OM) 20 mg, amlodipine (AML) 5 mg, and hydrochlorothiazide (HCTZ) 12.5 mg (OM/AML/HCTZ 20/5/12.5) in Korean patients with moderate hypertension not controlled with dual FDC therapy (OM/HCTZ 20/12.5).
METHODS
In this multicenter, randomized, double-blind, parallel-group study, Korean patients aged 20 to 75 years with stage 2 hypertension who had a mean seated diastolic blood pressure (msDBP) ≥100 mmHg were enrolled when their BP was uncontrolled [mean seated systolic BP (msSBP)/msDBP >140/90 mmHg or msSBP/msDBP >130/80 mmHg with diabetes or chronic kidney disease] with 4-week dual FDC therapy (OM/HCTZ 20/12.5). The patients were randomized to receive either OM/AML/HCTZ 20/5/12.5 or OM/HCTZ 20/12.5 once daily for 8 weeks. At the end of 8 weeks, patients with uncontrolled BP were assigned to receive either OM/AML/HCTZ 40/5/12.5 or OM/AML/HCTZ 20/5/12.5 in an additional 8-week open-label extension period.
RESULTS
A total of 623 patients received a 4-week run-in treatment with OM/HCTZ, 341 patients were randomized, and finally, 167 patients in the OM/AML/HCTZ group and 171 patients in the OM/HCTZ group were analyzed for the full analysis set. Non-responders after the 8 weeks of double-blind treatment continued the 8-week open-label treatment with OM/AML/HCTZ 40/5/12.5 mg (n = 32) or OM/AML/HCTZ 20/5/12.5 mg (n = 71). After 8 weeks of double-blind treatment, the changes in msDBP were -9.50 (8.46) mmHg in the OM/AML/HCTZ group and -4.23 (7.41) mmHg in the OM/HCTZ group (both p < 0.0001 vs. baseline; p < 0.0001 between groups). The response rates for both msSBP and msDBP at week 8 were 65.27 % in the OM/AML/HCTZ group and 37.43 % in the OM/HCTZ group (p < 0.0001 between groups). The response rates for both msSBP and msDBP at week 16 after open-label treatment were 18.75 % in the OM/AML/HCTZ 40/5/12.5 group and 46.48 % in the OM/AML/HCTZ 20/5/12.5 group (p = 0.0073 between groups). All medications were well tolerated.
CONCLUSION
In Korean patients with moderate hypertension not controlled with dual FDC therapy (OM/HCTZ 20/12.5) as first-line therapy, switching to triple FDC therapy (OM/AML/HCTZ 20/5/12.5) was associated with significant BP reductions and greater achievement of BP goals, and was well tolerated (ClinicalTrials.gov Identifier: NCT01838850).
Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Olmesartan Medoxomil; Young Adult
PubMed: 26691333
DOI: 10.1007/s40256-015-0156-x -
Molecules (Basel, Switzerland) Dec 2015During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along...
Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?
During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their ¹H, (13)C and (15)N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers.
Topics: Angiotensin II Type 1 Receptor Blockers; Chromatography, High Pressure Liquid; Drug Contamination; Magnetic Resonance Spectroscopy; Molecular Structure; Olmesartan Medoxomil; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Infrared; Tetrazoles; X-Ray Diffraction
PubMed: 26633332
DOI: 10.3390/molecules201219762 -
Wiener Klinische Wochenschrift Dec 2015
Topics: Aged, 80 and over; Antihypertensive Agents; Chronic Disease; Diagnosis, Differential; Diarrhea; Female; Humans; Intestinal Diseases; Olmesartan Medoxomil; Thinness; Weight Loss
PubMed: 26610650
DOI: 10.1007/s00508-015-0882-8 -
Clinical Interventions in Aging 2015In this paper, we present the results of a reanalysis of the data of two large randomized, double-blind, parallel group studies with a similar design, comparing the... (Randomized Controlled Trial)
Randomized Controlled Trial
Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double-blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines.
In this paper, we present the results of a reanalysis of the data of two large randomized, double-blind, parallel group studies with a similar design, comparing the efficacy of an angiotensin-receptor blocker (olmesartan medoxomil) with that of an angiotensin-converting enzyme inhibitor (ramipril), by applying two different blood pressure targets recently recommended by hypertension guidelines for all patients, irrespective of the presence of diabetes (<140/90 mmHg), and for elderly hypertensive patients (<150/90 mmHg). The efficacy of olmesartan was not negatively affected by age, sex, hypertension type, diabetes status or other concomitant clinical conditions, or cardiovascular risk factors. In most cases, olmesartan provided better blood pressure control than ramipril. Olmesartan was significantly more effective than ramipril in male patients, in younger patients (aged 65-69 years), in those with metabolic syndrome, obesity, dyslipidemia, preserved renal function, diastolic ± systolic hypertension, and, in general, in patients with a high or very high cardiovascular risk. Interestingly, patients previously untreated or treated with two or more antihypertensive drugs showed a significantly larger response with olmesartan than with ramipril. Thus, our results confirm the good efficacy of olmesartan in elderly hypertensives even when new blood pressure targets for antihypertensive treatment are considered. Such results may be relevant for the clinical practice, providing some hint on the possible different response of elderly hypertensive patients to two different drugs acting on the renin-angiotensin system, when patients are targeted according to the blood pressure levels recommended by recent hypertension guidelines.
Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Double-Blind Method; Female; Humans; Hypertension; Imidazoles; Male; Practice Guidelines as Topic; Ramipril; Tetrazoles; Treatment Outcome
PubMed: 26491273
DOI: 10.2147/CIA.S88195 -
Alimentary Pharmacology & Therapeutics Dec 2015Olmesartan-associated enteropathy (OAE) is characterised by diarrhoea, nausea, vomiting, abdominal pain, weight loss and severe sprue-like enteropathy, all of which are...
BACKGROUND
Olmesartan-associated enteropathy (OAE) is characterised by diarrhoea, nausea, vomiting, abdominal pain, weight loss and severe sprue-like enteropathy, all of which are resolved after discontinuation of olmesartan medoximil.
AIM
To determine the mechanistic similarities of OAE with coeliac sprue.
METHODS
Duodenal biopsies were extracted from OAE patients before (n = 11) or after (n = 17) discontinuation of olmesartan medoxomil (on or off olmesartan medoxomil). There were seven 'on/off' paired samples. Formalin-fixed biopsies were stained for CD8, CD4, FoxP3, IL-15R and psmad 2/3. Caco2 cells (human colonic epithelial line) were treated with olmesartan medoxomil and stained for IL-15, IL-15R and ZO-1.
RESULTS
In the 'on olmesartan medoxomil' duodenal biopsies, a significant increase in the numbers of CD8+ cells and the number of cells that are FoxP3+ (a regulatory T-cell marker) are present in the duodenum as compared to the duodenal biopsies from patients who discontinued olmesartan medoxomil. IL15R expression is also increased with olmesartan medoxomil use. Evaluation of the effect of olmesartan medoxomil upon Caco-2 cells demonstrated that IL15 expression is increased in response to olmesartan medoxomil treatment. Further, ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil-treated Caco-2 cells.
CONCLUSIONS
Olmesartan-associated enteropathy shares many features with coeliac disease, including symptoms and immunopathogenic pathways, such as increased numbers of CD8+ cells and corresponding overexpression of IL15 by epithelial cells. Taken together, the treatment of epithelial cells with olmesartan medoxomil induces a response by intestinal epithelial cells that is similar to the innate effects of gluten upon the epithelium of coeliac patients.
Topics: Abdominal Pain; Biopsy; Caco-2 Cells; Celiac Disease; Diarrhea; Duodenum; Female; Humans; Male; Nausea; Olmesartan Medoxomil; T-Lymphocytes, Regulatory; Vomiting
PubMed: 26423313
DOI: 10.1111/apt.13413 -
BMJ Case Reports Sep 2015Olmesartan use has been associated with chronic diarrhoea and weight loss due to severe sprue-like enteropathy, yet this is still not well known among clinicians. We...
Olmesartan use has been associated with chronic diarrhoea and weight loss due to severe sprue-like enteropathy, yet this is still not well known among clinicians. We present the unique case of an 84-year-old Filipino woman diagnosed with olmesartan-induced sprue-like enteropathy after an extensive work up for chronic diarrhoea, and without improvement despite multiple empiric treatments for nearly 15 months. Withdrawal of olmesartan resulted in clinical and histological improvement. This case provides further evidence for olmesartan-induced sprue-like enteropathy, and emphasises the importance of its awareness and recognition among gastroenterologists and primary care physicians alike.
Topics: Aged, 80 and over; Atrophy; Celiac Disease; Diarrhea; Female; Humans; Imidazoles; Intestinal Diseases; Intestines; Olmesartan Medoxomil; Tetrazoles
PubMed: 26370634
DOI: 10.1136/bcr-2015-212318