Telmisartan-induced sprue-like enteropathy: a case report and a review of patients using non-olmesartan angiotensin receptor blockers

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.

Consumo crónico de olmesartán como causa de enteropatía "sprue-like" / Chronic consumption of olmesartan as a cause of "sprue-like" enteropathy

La diarrea es un efecto secundario habitual a la toma de fármacos, y en algunas ocasiones la enteropatía perdedora de proteínas tipo "sprue like" puede estar detrás de esta patología. El estudio de esta enfermedad puede suponer un desafío importante para el clínico, sobre todo en los casos que cursan con serología negativa para enfermedad celiaca. La atrofia vellositaria duodenal secundaria a la ingesta de micofenolato-mofetil y metotrexate es bien conocida y descrita desde hace tiempo, pero desde la inclusión en la posológica habitual de olmesartán como antihipertensivo de primera elección hemos objetivado un repunte importante de esta entidad. Debido al amplio uso de esta medicación, queremos poner de manifiesto esta enteropatía iatrogénica a través de dos casos clínicos ocurridos en nuestro hospital en 2014.(AU()

Diarrhea is a common side effect of medical treatment. "Sprue like" enteropathy may be behind this pathology. The study of this disease can be an important clinical challenge, especially in those cases with negative serology for celiac disease. Duodenal villous atrophy secondary to the intake of mycophenolate mofetil and methotrexate have been well known and described but since the inclusion of olmesartán as a first-line antihypertensive, we have seen an important rebound of this entity. Due to the wide use of this medication we want to report this iatrogenic effect through two clinical cases that occurred in our hospital in 2014.(AU)

Enteropatia associada à Olmesartana / Olmesartan associated enteropathy

A enteropatia induzida por olmesartana é uma entidade reconhecida recentemente como diagnóstico diferencial de atrofia vilosa. A apresentação clínica é semelhante à doença celíaca, porém a não resposta à retirada do glúten e sorologia antitransglutaminase negativa são chaves para o diagnóstico diferencial. A fisiopatologia é incerta, havendo especulações quanto à predisposição genética e mecanismo de ação da própria droga. A melhora clínica e histológica após a suspensão da medicação é a principal característica. Aqui reportamos um caso de enteropatia induzida por olmesartana de apresentação clínica aguda.(AU)

The olmesartan induced enteropathy is a recently recognized entity in the differential diagnosis of villous atrophy. The clinical presentation is similar to celiac disease, but transglutaminase negative sorology and noimprovement after gluten removal are key to the differential diagnosis. The pathophysiology is uncertain, withspeculations about genetic predisposition and the medication's mechanism of action itself. The clinical and histological improvement after drug discontinuation is the main feature. Here we report a case of Olmesartaninduced enteropathy with acute clinical presentation.(AU)

Desenvolvimento de sistemas multiparticulados de liberação imediata e modificada para associação de fármacos anti-hipertensivos / Development of immediate and modified release multiparticulate systems for antihypertensive drugs association

Os sistemas multiparticulados são aqueles nos quais a dose do fármaco está dividida em pequenas unidades funcionais, tendo assim, uma série de vantagens sobre os sistemas monolíticos convencionais. Este trabalho teve por objetivo desenvolver formulações multiparticuladas de uso oral para fármacos anti-hipertensivos que serão utilizados na composição de associações. O material está dividido em seis capítulos, sendo inicialmente apresentada uma revisão da literatura a respeito da caracterização física destas pequenas unidades. Ensaios como análise granulométrica, morfologia, densidade, porosidade, avaliação de resistência mecânica e desintegração são os mais empregados para esta finalidade, possibilitando ao formulador conhecer os fatores de maior impacto relacionados às matérias primas e ao processo de fabricação no comportamento das formulações produzidas. Os demais capítulos seguem com o desenvolvimento dos sistemas multiparticulados, que foram embasados em diferentes delineamentos experimentais, seja pela utilização de planejamento fatorial fracionado ou projeto de mistura. Para o metoprolol, fármaco de alta solubilidade, foram produzidas formulações de liberação controlada, sendo a estratégia dividida em três etapas: (I) Produção de minicomprimidos revestidos, nos quais foram avaliadas diferentes combinações do polímero modulador de liberação; (II) otimização do perfil de liberação do fármaco, com avaliação de misturas das formulações produzidas na primeira etapa; (III) Processo de extrusão a quente, no qual diferentes proporções de fármaco e polímero hidrofóbico foram avaliadas. Para os fármacos hidroclorotiazida e olmesartana medoxomila, ambos de baixa solubilidade, a estratégia adotada foi a incorporação de uma dispersão dos fármacos e agentes solubilizantes em grânulos inertes obtidos por extrusão/revestimento. Adicionalmente, também foram produzidas formulações por extrusão a quente de diferentes proporções destes fármacos em polímero hidrofílico. De acordo com os resultados obtidos, foi possível obter formulações de minicomprimidos e grânulos com perfil de dissolução satisfatório, semelhantes aos apresentados pelos medicamentos adotados como referência. Em relação à extrusão a quente foi possível avaliar a influência do processo e polímeros empregados no perfil de dissolução dos grânulos produzidos

Multiparticulate systems are dosage forms in which dose is divided into small functional units presenting some advantages over monolithic conventional systems. The objective of this work was developing multiparticulate formulations for oral use containing antihypertensive drugs to be used in association. The thesis is divided into six issues, been first presented a literature review about physical characterization of multiparticulate systems. Granulometric analysis, morphology, density, porosity, mechanical strength and disintegration are the most used physical characterization tests, enabling formulator knowing the major impact factors related to raw materials and manufacturing process in the performance of the produced formulations. The other issues present the development of the multiparticulate systems based on different statistical experimental design, as fractional factorial design or mixture project. For metoprolol, a highly soluble drug, controlled release formulations were obtained, and the strategy was divided into three steps: (I) coated minitablets production, where different combinations of the controlled release polymer were analyzed; (II) drug release profile optimization, evaluating formulations mixtures produced in the first step; (III) hot melt extrusion process, where different drug: hydrophobic polymer ratios were evaluated. For hydrochlorothiazide and olmesartan medoxomil, both low soluble drugs, the strategy was incorporating a dispersion containing the drugs and solubilizing agents in inert granules obtained by extrusion/coating processes. Additionally, formulations containing different ratios of these drugs and hydrophilic polymers were produced by hot melt extrusion. According to the results, it was possible to obtain minitablets and granules with good dissolution profile, similar to the reference products. Regarding to hot melt extrusion, it was possible to evaluate the influence of process and polymers used in the dissolution profile of the produced granules

Pharmacokinetics and bioequivalence of two different 20 mg olmesartan tablets: A randomized, single-dose, two-period crossover study in healthy Korean male volunteers

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.

Efficacy and safety of olmesartan medoxomil versus losartan potassium in Chinese patients with mild to moderate essential hypertension / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of olmesartan medoxomil compared with losartan potassium in patients with mild to moderate essential hypertension.</p><p><b>METHOD</b>This 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.</p><p><b>RESULTS</b>(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.</p><p><b>CONCLUSION</b>This 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).</p>

A novel synthesis of olmesartan medoxomil and examination of its related impurities / 药学学报

<p><b>AIM</b>To develop a new synthetic route for olmesartan medoxomil.</p><p><b>METHODS</b>Olmesartan 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.</p><p><b>RESULTS</b>Synthesis 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%.</p><p><b>CONCLUSION</b>A novel synthetic route for olmesartan medoxomil was developed successfully. The olmesartan medoxomil regio-isomer is reported for the first time.</p>

Olmesartan inhibits the expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha and improves vascular remodeling after vascular injury in mouse / 中华创伤杂志(英文版)

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>Vascular 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.</p><p><b>RESULTS</b>We 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.</p><p><b>CONCLUSIONS</b>Our results demonstrate that blockade of AT1 receptor inhibits MCP-1 and TNF-alpha expression and thereby improves vascular remodeling.</p>