Recent studies have identified sprue-like illness associated with the use of the antihypertensive agent olmesartan medoxomil. However, whether this condition is specific to the use of olmesartan or is associated with the use of drugs belonging to the class of “sartans” remains to be clarified. A 45-year-old woman with chronic kidney disease along with hypothyroidism and hypertension presented with chronic diarrhea and significant weight loss. Endoscopy of the upper gastrointestinal tract showed scalloping and grooving of the duodenum, and histopathological examination showed subtotal villous atrophy. She was on telmisartan for hypertension, which was discontinued. Subsequently, diarrhea ameliorated dramatically, and she regained weight. To our knowledge, this is the first study to report telmisartan-associated sprue-like enteropathy. Further, we have reviewed the cases of patients with sprue-like enteropathy caused by valsartan, irbesartan, and eprosartan.
Angiotensin Receptor Antagonists* ; Angiotensins* ; Atrophy ; Celiac Disease ; Diarrhea ; Duodenum ; Endoscopy ; Female ; Humans ; Hypertension ; Hypothyroidism ; Middle Aged ; Olmesartan Medoxomil ; Pectinidae ; Renal Insufficiency, Chronic ; Upper Gastrointestinal Tract ; Valsartan ; Weight Loss

Olmesartan is an angiotensin receptor blocker (ARB) and is widely used in clinical practice to treat hypertension. To compare the pharmacokinetic (PK) parameters and tolerability of two oral formulations of olmesartan (test drug: OMETAN(R) 20 mg tablet, reference drug: OLMETEC(R) 20 mg tablet) and assess their bioequivalence, a randomized, single dose, two-treatment crossover clinical study was conducted. At each period, 40 subjects received the test drug or the reference drug. Blood samples were collected at pre-dose and up to 48 h after study drug administration of each period. Plasma concentrations of olmesartan were measured using liquid chromatography-tandem mass spectrometry. To evaluate PK profiles, maximum plasma concentration (C(max)) and area under the concentration-time curve from zero to last measurable time (AUC(last)) were estimated using a non-compartmental method. Tolerability was evaluated based on the incidence of adverse events, vital signs, electrocardiograms, and laboratory tests. A total of 39 subjects completed the study. The geometric mean ratio and 90% confidence intervals (CI) of test drug to reference drug were 1.027 (0.969-1.088) for C(max) and 1.014 (0.957-1.074) for AUC(last), respectively. There were no serious adverse events and both formulations of olmesartan were well tolerated. The OMETAN 20 mg tablet was judged to be bioequivalent to the OLMETEC 20 mg tablet.
Angiotensins ; Cross-Over Studies* ; Electrocardiography ; Humans ; Hypertension ; Incidence ; Male* ; Mass Spectrometry ; Pharmacokinetics* ; Plasma ; Tablets* ; Therapeutic Equivalency* ; Vital Signs ; Volunteers* ; Olmesartan Medoxomil*

OBJECTIVETo evaluate the efficacy and safety of olmesartan medoxomil compared with losartan potassium in patients with mild to moderate essential hypertension.

METHODThis is a randomized, double-blind, double-dummy, active-controlled, parallel, multi-center study. After a 2-week placebo run-in period, a total of 287 eligible subjects were randomized at 1:1 ratio to receive olmesartan medoxomil 20 mg or losartan potassium 50 mg, once daily for 8 weeks. The blood pressure was assessed after 4 weeks treatment. If the subject's seating diastolic blood pressure (SeDBP) was still >or=90 mm Hg, the dosage was doubled for another 4 weeks; for those subjects whose SeDBP was <90 mm Hg after 4-week treatment, the initial dosage remained unchanged and the treatment continued until completion of the study.

RESULTS(1) The mean trough reduction in SeDBP from baseline in olmesartan group was significantly greater than that in losartan group after 4 weeks (11.72 mm Hg vs 9.23 mm Hg, P=0.004) and 8 weeks treatment (12.94 mm Hg vs 11.01 mm Hg, P=0.035). (2) The number and percentage of responders in olmesartan group (81, 65.3%) were statistically higher than those (68, 52.7%) in losartan group (P=0.028) after 4 weeks treatment and were similar between the two groups after 8 weeks treatment (P>0.05). (3) Individual and overall trough/peak ratios of DBP and SBP in 24-hour ambulatory blood pressure monitoring were higher in olmesartan group than losartan group. The hypotensive effect of olmesartan was more durable than losartan at 24 hour interval. (4) The incidence of study drug-related adverse events (AEs) in olmesartan group (10.5%) was similar as that in losartan group (13.9%, P>0.05). Most of these AEs were mild and transient.

CONCLUSIONThis study shows that olmesartan medoxomil, at oral dose of 20 mg-40 mg once daily was effective and safe for hypertension treatment and the hypotensive effect was superior to losartan potassium (50 mg-100 mg once daily).

Adolescent ; Adult ; Aged ; Antihypertensive Agents ; administration & dosage ; China ; Double-Blind Method ; Female ; Humans ; Hypertension ; drug therapy ; physiopathology ; Imidazoles ; adverse effects ; therapeutic use ; Losartan ; adverse effects ; therapeutic use ; Male ; Middle Aged ; Olmesartan Medoxomil ; Tetrazoles ; adverse effects ; therapeutic use

AIMTo develop a new synthetic route for olmesartan medoxomil.

METHODSOlmesartan medoxomil was prepared from ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate via hydrolysis and lactonization to afford 4,4- dimethyl-2-propyl-4,6-dihydrofuro [3,4-d]-1H-imidazole-6-one which was condensed with 2-(triphenylmethyl)-5-[4'-(bromomethylbiphenyl)-2-yl] tetrazole, followed by esterification with 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and deprotection. The chemical structure of the major impurity in condensation reaction is the regio-isomer in the imidazole moiety, and confirmed by single crystal X-ray diffraction. The corresponding regio-isomer of olmesartan medoxomil was synthesized from the impurity by similar method. Optimization of the condensation conditions reduced the impurity to a negligible quantity.

RESULTSSynthesis of olmesartan medoxomil by the new route gave a product of 60% yield and above 99.0% purity. The content of olmesartan medoxomil regio-isomer was effectively controlled to less than 0.1%.

CONCLUSIONA novel synthetic route for olmesartan medoxomil was developed successfully. The olmesartan medoxomil regio-isomer is reported for the first time.

Angiotensin II Type 1 Receptor Blockers ; chemical synthesis ; chemistry ; Animals ; Antihypertensive Agents ; chemical synthesis ; chemistry ; pharmacology ; Blood Pressure ; drug effects ; Imidazoles ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Olmesartan Medoxomil ; Rats ; Stereoisomerism ; Tetrazoles ; chemical synthesis ; chemistry ; pharmacology

OBJECTIVETo investigate the neointima formation and the expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in cuff-induced vascular injury in mouse model, and to examine the effect of angiotensin II type 1 receptor (AT1) blocker, olmesartan, on MCP-1 and TNF-alpha expression and consequently vascular remodeling.

METHODSVascular injury was induced by polyethylene cuff-placement around the mouse femoral artery. Some mice were treated with AT1 receptor blocker, olmesartan, at the dose of 3 mg.kg(-1).day(-1) with an osmotic minipump. Neointima formation and the proliferation of vascular smooth muscle cells (VSMCs) were measured by morphometric analysis and bromodeoxyuridine (BrdU) incorporation. MCP-1 and TNF-alpha expression was detected by Western blot and immunohistochemical staining.

RESULTSWe observed neointima formation 14 days after cuff placement as well as VSMCs proliferation in the media and neointima. Cuff placement also induced MCP-1 and TNF-alpha expression in the media and neointima that the VSMCs specifically existed. Treatment of mice with olmesartan at a dose of 3 mg.kg(-1).day(-1), which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs. Olmesartan also inhibited MCP-1 and TNF-alpha expression in the injured arteries.

CONCLUSIONSOur results demonstrate that blockade of AT1 receptor inhibits MCP-1 and TNF-alpha expression and thereby improves vascular remodeling.

Analysis of Variance ; Animals ; Blotting, Western ; Cell Division ; drug effects ; physiology ; Cells, Cultured ; Chemokine CCL2 ; analysis ; Disease Models, Animal ; Imidazoles ; pharmacology ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred C57BL ; Monocytes ; cytology ; drug effects ; Muscle, Smooth, Vascular ; cytology ; drug effects ; Neovascularization, Physiologic ; drug effects ; physiology ; Olmesartan Medoxomil ; Probability ; Sensitivity and Specificity ; Tetrazoles ; pharmacology ; Tumor Necrosis Factor-alpha ; analysis ; drug effects ; Tunica Intima ; drug effects ; pathology ; Vascular Diseases ; physiopathology