Angiotensin II type 2 receptor signalling as a pain target: Bench, bedside and back-translation.

Translating promising preclinical pain relief data for novel molecules from drug discovery to positive clinical trial outcomes is challenging. The angiotensin II type 2 (AT2) receptor is a clinically-validated target based upon positive proof-of-concept clinical trial data in patients with post-herpetic neuralgia. This trial was conducted because AT2 receptor antagonists evoked pain relief in rodent models of neuropathic pain. EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain.

Non-clinical characterization of the disposition of EMA401, a novel small molecule angiotensin II type 2 receptor (AT2R) antagonist.

EMA401, (the S-enantiomer of 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), also known as Olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT2 R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain. The main purpose of the present work was to investigate the disposition of a single 14 C- labeled EMA401 in non-clinical studies. The in vitro metabolism studies of EMA401 were undertaken to understand the hepatic biotransformation pathways in animal species used in toxicology studies and how they compare to human. Furthermore, investigation of EMA401's PK was carried out in vivo in rats. The study demonstrates the rapid absorption and distribution of drug-related material mainly to the tissues associated with absorption and elimination (GI tract, liver, and kidney). EMA401was then readily eliminated metabolically via the bile (95% of dose) predominantly in the form of the direct acylglucuronide (40% of dose), which was further hydrolysed by the intestinal flora to the active parent drug. Other metabolic pathways such as dealkylations and hydroxylation were also involved in the elimination of EMA401 to a lesser extent. EMA401 was metabolically unstable in hepatocytes of all species investigated and the key metabolites produced in the in vitro model were also detected in vivo. Independent of the dosing route, the S-enantiomer EMA401 showed a good in vivo chiral stability. Overall, the present study provides the first full characterization of the disposition of EMA401 in preclinical species.

Fimasartan: A New Angiotensin Receptor Blocker.

Fimasartan is the ninth, and most recent, angiotensin II receptor antagonist approved as an antihypertensive agent. Fimasartan, a pyrimidin-4(3H)-one derivative of losartan with the imidazole ring replaced, which enables higher potency and longer duration than losartan. Fecal elimination and biliary excretion are the predominant elimination pathways of fimasartan and the urinary excretion was found to be less than 3 % 24 h after administration. Fimasartan is primarily catabolized by cytochrome P450 isoform 3A and no significant drug interaction was observed when used in combination with hydrochlorothiazide, amlodipine, warfarin, or digoxin. Fimasartan at a dosage range of 60-120 mg once daily showed an antihypertensive effect over 24 h. In a large, population-based observational study, fimasartan showed an excellent safety profile. Anti-inflammatory and organ-protecting effects of fimasartan have been shown in various preclinical studies, including aortic balloon injury, myocardial infarct ischemia/reperfusion, doxorubicin cardiotoxicity, and ischemic stroke models.

Angiotensin II type 2-receptor: new clinically validated target in the treatment of neuropathic pain.

Neuropathic pain is a large unmet medical need. The angiotensin II type 2 (AT2 ) receptor is a target with promising data in rodent models of peripheral neuropathic pain. The AT2 receptor has attracted attention on the basis of human data from a proof-of-concept clinical trial showing that oral EMA401, a highly selective, peripherally restricted, small molecule AT2 receptor antagonist, at 100 mg twice-daily for 4 weeks, alleviated postherpetic neuralgia, an often intractable type of peripheral neuropathic pain.

Small molecule angiotensin II type 2 receptor (AT2R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats.

OBJECTIVE: Neuropathic pain is an area of unmet clinical need. The objective of this study was to define the pharmacokinetics, oral bioavailability, and efficacy in rats of small molecule antagonists of the angiotensin II type 2 receptor (AT2R) for the relief of neuropathic pain. DESIGN AND METHODS: Adult male Sprague-Dawley (SD) rats received single intravenous (1-10 mg/kg) or oral (5-10 mg/kg) bolus doses of EMA200, EMA300, EMA400 or EMA401 (S-enantiomer of EMA400). Blood samples were collected immediately pre-dose and at specified times over a 12- to 24-hour post-dosing period. Liquid chromatography tandem mass spectrometry was used to measure plasma drug concentrations. Efficacy was assessed in adult male SD rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve. RESULTS: After intravenous administration in rats, mean (±standard error of the mean) plasma clearance for EMA200, EMA300, EMA400, and EMA401 was 9.3, 6.1, 0.7, and 1.1 L/hour/kg, respectively. After oral dosing, the dose-normalized systemic exposures of EMA400 and EMA401 were 20- to 30-fold and 50- to 60-fold higher than that for EMA300 and EMA200, respectively. The oral bioavailability of EMA400 and EMA401 was similar at ∼30%, whereas it was only 5.9% and 7.1% for EMA200 and EMA300, respectively. In CCI rats, single intraperitoneal bolus doses of EMA200, EMA300, and EMA400 evoked dose-dependent pain relief. The pain relief potency rank order in CCI rats was EMA400 > EMA300 > EMA200 in agreement with the dose-normalized systemic exposure rank order in SD rats. CONCLUSION: The small molecule AT2R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain.

Antagonistas de los receptores de la angiotensina II en el tratamiento de la hipertensión arterial, las enfermedades cardiovasculares y las renales. Realidad y futuro / No disponible

Los antagonistas de los receptores de angiotensina II (ARA II) y los inhibidores de la enzima de conversión de la angiotensina (IECA) son las 2 clases terapéuticas más utilizadas en el tratamiento de la hipertensión arterial, y en la prevención y tratamiento de las enfermedades cardiovascular y renal. Los estudios con ARA II han demostrado una replicación de los beneficios obtenidos anteriormente en los estudios con IECA, al igual que una efectividad preventiva similar en los estudios de comparación directa. En otros estudios comparativos frente a otras estrategias terapéuticas han demostrado prevenir la enfermedad cardiovascular en todos sus estadios evolutivos, así como una superioridad frente a otros fármacos en la prevención primaria y secundaria del ictus. Añadido a esta efectividad terapéutica, los ARA II son la clase terapéutica cardiovascular asociada a una mejor tolerabilidad. Este fenómeno se traduce en una mayor adherencia al tratamiento prescrito, así como en su mayor persistencia. Todo parece indicar que, a largo plazo, este hecho se traduce en la mejor protección posible frente a la enfermedad cardiovascular. Asimismo, todo apunta a que tanto los IECA como los ARA II contienen fármacos de largo recorrido en el tratamiento de varias generaciones y deberán convivir en indicaciones similares. Salvo que aparezcan nuevos datos en el futuro, a igualdad de efectividad, la mejor tolerabilidad de los ARA II los posiciona como la forma preferente del bloqueo del sistema renina-angiotensina en el tratamiento de enfermedades crónicas asintomáticas, como la hipertensión arterial (AU)

Angiotensin receptor antagonists (ARB) and angiotensin converting-enzyme (ACE) inhibitors are the two most widely used drug classes in the treatment of hypertension and in the prevention and treatment of cardiovascular and renal diseases. Studies with ARB have been able to replicate the benefits previously obtained in studies with ACE inhibitors, while direct-comparison studies have shown the two drugs to have a similar preventive efficacy. Other studies comparing ARB with other therapeutic strategies have shown these drugs to prevent cardiovascular disease at all stages of its development and progression and to be superior to other drugs in the primary and secondary prevention of stroke. In addition to this therapeutic efficacy, ARB are the cardiovascular drug class associated with the most favorable tolerability, leading to greater treatment adherence and persistence. All the evidence seems to indicate that, in the long term, this phenomenon possibly improves protection against cardiovascular disease. Likewise, the evidence also indicates that both ACE inhibitors and ARB are drug classes that include agents with a long future in the treatment of several generations and that they will probably be used in similar indications. Unless new data appear in the future, given the equal effectiveness of both drug classes, the better tolerability of ARB places them in a preferential position as renin-angiotensin system blockers in the treatment of chronic asymptomatic diseases such as hypertension (AU)

Olmesartán: evidencia y práctica clínica / Olmesartan: evidence and clinical practice

Olmesartán medoxomilo es un antagonista no peptídico del receptor AT1 de la angiotensina con afinidad superior a la de otros fármacos del grupo. Ha demostrado en numerosos ensayos clínicos su eficacia antihipertensiva y su buena tolerabilidad. Se ha comparado en ensayos clínicos con otros fármacos del grupo (azilsartán, candesartán, irbesartán, losartán y valsartán). En general, el efecto de olmesartán administrado por vía oral, una sola vez al día a dosis de entre 20 y 40 mg, ha sido superior en cuanto a la reducción de cifras tensionales, se ha iniciado antes y ha persistido durante 24 h. Varios metaanálisis han confirmado estas ventajas de olmesartán. Hay algunos estudios que demuestran propiedades organoprotectoras, en especial de restauración de la función endotelial. El patrón y la frecuencia de las reacciones adversas son comparables a los del placebo. Como consecuencia de sus propiedades farmacodinámicas y farmacocinéticas, olmesartán puede presentar ventajas sobre otros fármacos antagonistas del receptor de la angiotensina en el tratamiento de la hipertensión arterial (AU)

Olmesartan medoxomil is a nonpeptide angiotensin II-type I receptor (AT1) antagonist with greater affi nity for this receptor than other drugs in this class. Several clinical trials have demonstrated its effi cacy in lowering blood pressure and its good tolerability. This drug has been compared in clinical trials with other drugs in the same class (azilsartan, candesartan, irbesartan, losartan and valsartan). In general, olmesartan administered orally at a dose of between 20 and 40 mg has provided superior effi cacy in lowering blood pressure; this effect is initiated earlier than with other drugs and persists for 24 hours. The advantages of olmesartan have been confi rmed by several meta-analyses. Some studies show organ protective properties, especially in restoring endothelial function. The pattern and frequency of adverse reactions are similar to those of placebo. As a result of its pharmacodynamic and pharmacokinetic properties, olmesartan could offer advantages over other angiotensin receptor antagonists in the treatment of hypertension (AU)

Olmesartán con diuréticos o con antagonistas del calcio: ¿a qué perfil de paciente hipertenso? / Calcium channel blockers or diuretics as an add-on to olmesartan in hypertension: indication according to patient profile

La combinación de olmesartán, tanto con diurético tiazídico como con amlodipino, ha demostrado un efecto antihipertensivo adicional, con buena tolerabilidad y una menor aparición de efectos secundarios. Hay pocos estudios que hayan evaluado las diferencias entre esquemas terapéuticos que incluyan olmesartán en asociación con diuréticos o con amlodipino. Dichas diferencias dependerán, fundamentalmente, de los efectos no relacionados con el descenso de la presión arterial (PA) de los fármacos que acompañan a olmesartán, ya que ambas combinaciones son similares en cuanto a eficacia antihipertensiva. En este artículo se revisan los efectos de ambas combinaciones en diferentes situaciones clínicas, como el riesgo metabólico del paciente hipertenso, su edad, la variabilidad de la PA o de la PA central (AU)

The combination of olmesartan both with a thiazide diuretic or with amlodipine has been shown to confer an additional blood pressure-lowering effect, with good tolerability and fewer adverse effects. Few studies have evaluated differences among therapeutic regimens that include olmesartan in association with diuretics or amlodipine. These differences are due mainly to effects unrelated to the blood pressure-lowering effects of drugs used in combination with olmesartan, since both combinations are similar in their antihypertensive efficacy. This article reviews the effects of both combinations, bearing in mind several factors such as the metabolic risk of hypertensive patients, their age, blood pressure variability, and central blood pressure (AU)

Aspectos prácticos de la combinación de 3 fármacos antihipertensivos a dosis fijas / Practical features of triple-antihypertensive fixed-dose drug combinations

Recientes estudios realizados en España demuestran un incremento en el grado de control de la hipertensión arterial (HTA) asociado a una mayor utilización de la terapia combinada. La combinación de fármacos antihipertensivos, como señalan todos los ensayos clínicos de morbimortalidad, es una condición fundamental para lograr los objetivos de control tensional y reducir las complicaciones cardiovasculares asociadas a la HTA. Sin embargo, en la práctica clínica todavía queda un largo recorrido hasta alcanzar unos niveles de control aceptables. Dos de las barreras más ampliamente reconocidas son el incumplimiento terapéutico por parte del paciente y la actitud conservadora de algunos médicos (inercia). Las combinaciones de 3 fármacos a dosis fijas pueden ayudar a vencer dichas barreras, entre otras razones, por la simplificación del tratamiento que comporta su uso. Algunos estudios, entre los que destaca el TRINITY, demuestran que una combinación de olmesartán, amlodipino e hidroclorotiazida puede conseguir tasas de control de hasta el 80%. Además, en relación con la tolerabilidad de las combinaciones triples actualmente disponibles en España, tiene la ventaja, al incluir un antagonista de los receptores de la angiotensina II (ARA II) en su composición, de reducir la incidencia de efectos adversos clínicos (edema periférico de los antagonistas del calcio) y metabólicos (hipopotasemia de las tiazidas). Los posibles candidatos a recibir una triple combinación fija son los pacientes no controlados con 2 fármacos o aquellos con cifras de presión arterial en objetivo tratados con 3 fármacos, con una combinación fija de 2 y 1 en asociación libre (AU)

Recent studies performed in Spain show an increase in hypertension (HT) control associated with greater use of combination therapy. As indicated by all clinical trials analyzing morbidity and mortality, antihypertensive combinations are essential to achieve blood pressure targets and reduce the cardiovascular complications of HT. However, in clinical practice, blood pressure values are still far from acceptable. Two of the most widely recognized barriers to acceptable control are lack of patient adherence and the conservative attitudes of some physicians (inertia). Triple-drug fixed-dose combinations for the treatment of HT can help to overcome these barriers as, among other reasons, these regimens simplify the treatment. Some studies, notably the TRINITY trial, have shown that the combination of olmesartan, amlopidine and hydrochlorothiazide can achieve blood pressure control rates of 80%. Moreover, by including angiotensin II receptor antagonists, the triple combinations currently available in Spain have the advantage of reducing the incidence of clinical adverse effects (the peripheral edema associated with calcium channel blockers) and metabolic adverse effects (thiazide hypokalemia), thus increasing tolerability. Possible candidates for receiving fixed-dose triple-drug combination therapy are patients poorly controlled with two drugs or those with blood pressure values on target receiving triple therapy, with a fixed combination of two and a free combination of a third (AU)

Selección de olmesartán en monoterapia, combinación o triple terapia en función del descenso necesario de la presión arterial / Selection of mono-, combination or triple therapy with olmesartan according to target decrease in blood pressure

Para minimizar el riesgo cardiovascular derivado de la hipertensión arterial (HTA) es de vital importancia alcanzar los objetivos terapéuticos, idealmente en el menor tiempo posible. La capacidad hipotensora de los diferentes fármacos está bien determinada por los diferentes estudios que avalan su uso. Por ello, el clínico debería elegir el tratamiento con criterio basándose en el descenso de presión arterial que requiera el paciente y utilizar un fármaco o combinación cuya potencia antihipertensiva permita prever que se logre el objetivo terapéutico. Olmesartán es un antagonista de los receptores de la angiotensina II (ARA II) de notable potencia hipotensora, bien tolerado y cuya combinación con dihidropiridinas y/o hidroclorotiazidas se halla bien establecida. En este artículo se revisan las evidencias que justifican el uso de olmesartán o sus combinaciones en el contexto actual del manejo de la HTA. Se presta especial atención en determinar la potencia hipotensora demostrada del fármaco para precisar los casos en los que es esperable alcanzar los objetivos terapéuticos, su comparación con otros fármacos de uso común, las evidencias en el control de la presión arterial durante las 24 h y la eficacia de las combinaciones terapéuticas (AU)

Achieving therapeutic targets is essential to reduce the cardiovascular risk of hypertension, ideally in as short a time as possible. The hypotensive effectiveness of the distinct drugs has been well characterized by the various studies supporting their use. Therefore, clinicians should base their selection of the drug to be used on the target blood pressure decrease required in each patient and prescribe a drug or drug combination with sufficient antihypertensive potency to achieve the desired reduction. Olmesartan is an angiotensin II receptor antagonist with marked hypotensive potency that is well tolerated and whose use in combination with dihydropyridines and/or hydrochlorothiazide has been well established. The present article reviews the evidence supporting the use of olmesartan as monotherapy or in combination treatment in the current context of the management of hypertension. Special attention is paid to determining the demonstrated blood pressure-lowering potency of this drug in situations in which the therapeutic targets can realistically be achieved; we compare this agent with other commonly used drugs and discuss the evidence on 24-hour blood pressure control, as well as the effectiveness of therapeutic combinations (AU)

Farmacoeconomía de olmesartán en combinaciones a dosis fijas para el tratamiento de la hipertensión arterial / Pharmacoeconomics of fixed-dose combinations with olmesartan in the treatment of hypertension

La hipertensión arterial constituye uno de los principales factores de riesgo por su elevada prevalencia y riesgo de complicaciones. Se ha progresado en la inercia clínica de la enfermedad, aunque el control de la presión arterial sigue siendo mejorable en colectivos específicos. La farmacoeconomía es una aplicación de la economía de la salud que nos permite conocer cuál es la eficiencia de las diferentes alternativas terapéuticas utilizables para tratar la hipertensión. Los antagonistas de los receptores de la angiotensina II (ARA II) han demostrado ser fármacos antihipertensivos efectivos y seguros, aunque la comparación entre los diferentes ARA II presenta resultados contradictorios. Olmesartán medoxomilo es un fármaco eficaz y bien tolerado, similar o ligeramente más eficaz que otros ARA II, tanto en monoterapia como en combinación fija (doble o triple). La hipertensión arterial no diagnosticada o no tratada es la principal causa de disminución de la efectividad y eficiencia en situación de práctica clínica habitual; su tratamiento requiere desarrollar estrategias basadas en análisis de coste-eficiencia, para reducir los costes sanitarios y maximizar los resultados. Los escasos estudios publicados sugieren que olmesartán en monoterapia, en comparación con otros ARA II, reduce de forma similar o superior el riesgo cardiovascular y las complicaciones a un menor coste. La terapia combinada con 2 o 3 antihipertensivos también parece tener un perfil de costeefectividad favorable, a pesar de que el coste del tratamiento es mayor. Cabe destacar la escasez de datos de coste-efectividad sobre el uso de dosis fijas de ARA II en general y de olmesartán en particular en terapias de combinación (AU)

Hypertension is a major risk factor due to its high prevalence and the risk of complications. Clinical inertia has been reduced, although blood pressure control could still be improved in certain specific groups. Pharmacoeconomics is an application of health economics that can be used to determine the efficiency of the various therapeutic alternatives available to treat hypertension. Angiotensin II receptor antagonists (ARA II) have been shown to be safe and effective hypotensive drugs, although comparisons among the distinct ARA II have yielded contradictory results. Olmesartan medoxomil is an effective and well tolerated drug with similar or slightly superior efficacy to other ARA II, both in monotherapy and in fixed-dose double- or triple-combination therapy. Undiagnosed or untreated hypertension is the main cause of reduced effectiveness and efficiency in routine clinical practice; treatment requires the development of strategies based on cost-efficiency analyses to reduce health costs and optimize results. The few published studies suggest that olmesartan monotherapy produces a similar or greater reduction in cardiovascular risk and complications than other ARA II and at a lower cost. Combination therapy with two or three antihypertensive agents also seems to have a favorable cost-effectiveness profile, even though the cost of treatment is higher. Importantly, in combination therapies, there is a scarcity of cost-effectiveness data on the use of fixed-doses of ARA II in general and of olmesartan in particular (AU)

Pharmacokinetics of olmesartan medoxomil in pediatric patients with hypertension.

BACKGROUND: The prevalence and importance of hypertension in younger patients is becoming increasingly recognized; however, only a limited number of clinical trials have been conducted in the pediatric population. OBJECTIVE: The aim of this study was to characterize the pharmacokinetics and short-term safety of olmesartan medoxomil in children and adolescents with hypertension. METHODS: An open-label, multicenter, single-dose study was conducted in children and adolescents aged 12 months-16 years who were receiving treatment for hypertension or, if not currently treated for hypertension, had either a systolic blood pressure (SBP) or diastolic blood pressure (DBP).≥95th percentile, or SBP or DBP ≥90th percentile if diabetic or with a family history of hypertension. Patients were stratified by age: 12-23 months (Group 1; none enrolled), 2-5 years (Group 2; n = 4), 6-12 years (Group 3; n = 10), and 13-16 years (Group 4; n = 10). All patients received a single oral dose of olmesartan medoxomil based on the individual's age and bodyweight. Patients aged <6 years received an oral suspension of olmesartan medoxomil at a dose of 0.3 mg/kg of bodyweight (not to exceed 20 mg), those aged ≥6 years who weighed ≥35 kg received olmesartan medoxomil 40 mg tablets, and those who weighed <35 kg received olmesartan medoxomil 20 mg tablets. RESULTS: In Groups 2, 3, and 4, the weight-adjusted apparent total body clearance (CL/F) of olmesartan medoxomil was 0.100 ± 0.034, 0.062 ± 0.020, and 0.072 ± 0.022 L/h/kg, respectively, and the weight-adjusted apparent volume of distribution (Vd/F) was 0.32 ± 0.16, 0.33 ± 0.14, and 0.49 ± 0.23 L/kg, respectively. CL/F and Vd/F in Groups 3 and 4 were not significantly different. Statistical comparisons between Groups 3 or 4 and Group 2 were not performed due to the small sample size of Group 2 (n = 4). Plasma elimination half-life and time to maximum plasma concentration were similar across the three groups. In Groups 3 and 4, considerable interindividual variability was seen in maximum plasma concentration (C(max)), area under the curve (AUC) from time zero to the last measurable concentration, and apparent clearance, with AUC and C(max) approximately 30% greater in Group 3. Four of 24 (16.7%) patients experienced treatment-emergent adverse events that were all mild in severity and considered not drug-related. No deaths, serious adverse events, or discontinuations due to adverse events occurred in the study. CONCLUSIONS: Olmesartan medoxomil was well tolerated and demonstrated a pharmacokinetic profile in pediatric patients similar to that of adults when adjusted for body size. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00151814

Antagonistas de los receptores de la angiotensina II en combinación con antagonistas del calcio. Focus en la asociación de olmesartán con amlodipino / No disponible

No disponible