Cardioprotective Effect of Fimasartan, a New Angiotensin Receptor Blocker, in a Porcine Model of Acute Myocardial Infarction

Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F-18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI.

A Novel Angiotensin Type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin-induced Cardiotoxicity in Rats

Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX-CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low-fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High-fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP.

Angiotensin II antagonists: clinical experience in the treatment of hypertension, prevention of cardiovascular outcomes and renal protection in diabetic nephropathy and proteinuria / Antagonistas da angiotensina II: experiência clínica com o tratamento da hipertensão, prevenção de desfechos cardiovasculares e proteção renal na nefropatia diabética e proteinúria

Angiotensin II antagonists (AIIAs) were introduced to treat hypertension about 10 years ago. During this period they were evaluated not only in terms of efficacy and safety but also in several large studies with clinical outcomes. They are efficacious in all clinical forms of hypertension and are effective also in all ethnic groups. Cardiovascular and renal protection in proteinuric diabetic nephropathy beyond blood pressure reduction was proved in major clinical studies: Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan (RENAAL) and Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT). Their blood pressure independent protective effect is also mentioned by the blockade of AT1 receptor. As a class AIIs have a tolerability profile similar to placebo.

Os antagonistas da angiotensina II (AAIIs) foram introduzidos para o tratamento da hipertensão arterial há cerca de 10 anos. Durante esse período eles foram avaliados não apenas em termos de eficácia e segurança, mas também em vários estudos grandes com desfechos clínicos. Os AAIIs são eficazes em todas as formas clínicas de hipertensão e, também, em todos os grupos étnicos. Os principais estudos clínicos em pacientes diabéticos com nefropatia e proteinúia comprovaram, além da redução da pressão arterial, proteção cardiovascular e renal: "Losartan Intervention For Endpoint reduction in hypertension study" (LIFE), "Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan" (RENAAL) e "Irbesartan Type 2 Diabetic Nephropathy Trial" (IDNT). O seu efeito protetor independente da pressão sanguínea também é mencionado pelo bloqueio do receptor AT1. Os AAIIs, como classe medicamentosa, apresentam um perfil de tolerabilidade semelhante ao placebo.

Efficacy of Irbesartan on Left Ventricular Mass and Arterial Stiffness in Hypertensive Patients

BACKGROUND: Increased aortic stiffness measured by pulse wave velocity (PWV) and left ventricular hypertrophy (LVH) are independent risk factors of cardiovascular events in hypertensive patients. We have conducted a prospective study to examine the effects of the angiotensin II receptor antagonist (irbesartan) on PWV and LVH in hypertensive patients. METHODS: A total of 52 untreated hypertensive patients (age:53.3+/-8.0 yrs) were enrolled; they had no evidence of associated cardiovascular complications. Blood pressure, heart rate, aortic PWV and left ventricular mass index (LVMI) by 2-D echocardiography were measured at baseline and after irbesartan treatment (150 mg or 300 mg/day) at 12 weeks and 24 weeks. RESULTS: Blood pressure was significantly decreased after 12 weeks and 24 weeks of treatment compared to baseline (SBP: 134.6+/-13.3 mmHg, 134.0+/-11.0 mmHg vs 163.7+/-13.8 mmHg p<0.001, DBP: 86.0+/-10 mmHg, 83.07 mmHg vs 102.4+/-9.6 mmHg p<0.001, respectively) without significant change in heart rate. LVMI decreased at 12 weeks and at 24 weeks after treatment compared to baseline (from 145.5+/-35.1 g/m2 at baseline to 137.5+/-35.4 g/m2 at 12 weeks, p=0.017 and 135.3+/-35.4 g/m2 at 24 weeks, p=0.008). Aortic PWV was decreased after irbesartan treatment at 12 weeks (from 9.6+/-2.8 m/sec to 8.7+/-3.1 m/sec at 12 weeks, p=0.064) and at 24 weeks (from 9.6+/-2.9 m/sec to 7.7+/-2.1 m/sec at 24 weeks, p=0.007). CONCLUSIONS: Long-term treatment with irbesartan may reduce arterial stiffness and regression of LVH in hypertensive patients. The pleiotropic effects of irbesartan, further decreasing PWV without change of BP between 12 and 24 weeks of treatment, may have favorable vascular effects on arterial stiffness and LVH.

Antiamoebic activity of 3,3'-fluro-4,4'-di-(pyrrolidine-2-ylidene amino)-diphenyl (liroldine), against experimentally infected intestinal and hepatic amoebiasis.

HL 707, Liroldine, a novel synthetic compound, was found effective against both extraintestinal and intestinal amoebiasis in animal models. Its activity against hepatic infection in golden hamsters is comparable with that of different derivatives of nitroimidazoles used for human treatment. Against intestinal amoebiasis in Wistar rats, the activity was superior to nitroimidazoles and chloroquine. Paramomycin was comparable and diloxanide furoate was marginally superior. The comparative in vitro and in vivo studies with standard marketed drugs and Liroldine indicate an excellent profile of the compound against experimental amoebiasis. LD50 of Liroldine determined in mice is 910 mg/kg x 1, po and 940 mg/kg x 1 ip).

Effects of losartan on neuroleptic-induced catalepsy in mice

Neuroleptic-induced catalepsy remains a useful method to study central dopaminergic function in rodents. Evidence obtained in several studies indicates that this phenomenon can be modified by cholinergic, histaminergic and serotonergic manipulation. Angiotensin II is a central neurotransmitter acting through AT1 and AT2 receptors. There are few data on the effect of angiotensinergic drugs on dopaminergic transmission. We investigated the effect of losartan, a nonpeptide antagonist of central and peripheral AT1 receptors, on neuroleptic-induced catalepsy. Adult male albino mice, 26-35 g, were used. Catalepsy was induced with haloperidol (H; l mg/kg, ip) and measured at 30-min intervals by means of a bar test. Losartan (10 or 100 ng/kg) or saline (control; 0.13 ml) was injected intraperitoneally 20 min before H, with each animal (7 per group) being used only once. Losartan (10 and 100 ng/kg) significantly (P<0.05) potentiated the cataleptic effect of H in comparison to the control group (e.g. 264 ñ 26 and 299 ñ 68 sec, respectively, vs 89 ñ 24 sec for the control group, 90 min after H). No differences were demonstrable 120, 150 or 180 min after H. Considering the high selectivity and the pharmacokinetic properties of losartan, these data suggest that central angiotensin AT1 receptors play a role in neuroleptic-induced catalepsy. However, further studies are necessary to confirm this hypothesis and to clarify the mechanism(s) involved in this process.