Combination Of Losartan Research Articles

EFFECT OF COMBINING LOSARTAN AND PERINDOPRIL IN DIABETIC PATIENTS WITH PROTEINURIA

Objective: This retrospective study compared the efficacy and safety of losartan monotherapy versus losartan and perindopril combination therapy in diabetic patients with hypertension and albuminuria. Factors affecting the change in albuminuria were identified.Methods: Through quota sampling, the study recruited patients from a tertiary care hospital. Outcome parameters included urinary albumin creatinine ratio (UACR), blood pressure (BP), serum creatinine, and estimated glomerular filtration rate (eGFR). Both pre- and post-treatment measurements were traced from patient’s medical records.Results: No significant differences (p=0.615) were detected in the pre- and post-treatment change in UACR between the monotherapy group (−38.3 mg/g, interquartile range [IQR]:−618.8-0) and combination therapy group (−88.4 mg/g, IQR: −729.3-+375.7). There was a considerably higher percentage of patients attaining the target BP of <125/75 mmHg in the combination group (66.7%; p<0.001). In terms of safety, combined losartan and perindopril caused more hypotension (p=0.003), higher rise in serum creatinine (p=0.481), and greater drop in eGFR (p=0.861). Body mass index was shown to have significant negative correlation with UACR reduction (r=−0.449; p=0.036).Conclusion: The main finding of this study was that losartan alone was as equally efficacious as combined losartan and perindopril in lowering UACR and BP among diabetic patients.

PP.12.08] EVALUATION OF EFFICACY AND SAFETY OF AMOSARTAN IN PATIENTS WITH ESSENTIAL HYPERTENSION; 2-YEAR, NON-INTERVENTIONAL, MULTICENTER, RETROSPECTIVE OBSERVATIONAL STUDY

Objective: Studies have shown that combination of amlodipine and losartan resulted in significantly greater decrease in BP compared with amlodipine or losartan monotherapy in patients with essential hypertension. Amosartan is the first ARB/CCB (losartan/amlodipine) combination to be made and used in Korea, yet the safety and efficacy of chronic use has not been addressed. The objective of this study was to determine the safety and efficacy of long term Amosartan use in patients with essential hypertension. Design and method: A non-interventional, multicenter, retrospective observational study was conducted on 1000 healthy subjects. Subjects were hypertensive patients administered with Amosartan for at least 2 years with no more than 10 consecutive weeks of withdrawal period, and the duration of Amosartan therapy being more than 80% of the total follow-up period. The change in SBP and DBP 2 years in relation to baseline was analyzed as visit-to-visit BP variability during Amosartan follow-up period. SBP and DBP was measured and charted in each visit. Results: The percentage of patients who reached target SBP and both target SBP and DBP increased with prolonged duration of Amosartan treatment. However, there were reductions in the percentage of patients who reached target DBP at 3 months and 6 months after Amosartan treatment compared to baseline. 90% of total patients reached target SBP at 24 months after Amosartan treatment compared to 51% at baseline. 94% of total patients reached target DBP at 24 months after Amosartan treatment compared to 90% at baseline. 86% of total patients reached both target SBP and DBP at 24 months after Amosartan treatment compared to 45% at baseline. The mean SBP and DBP were consistently lower than the baseline values during the entire follow-up period after Amosartan treatment. The reduction in SBP and DBP in comparison to baseline was greatest at both 18 and 24 months after Amosartan treatment. Conclusions: The results of this study indicate that the long-term administration of Amosartan is effective in reducing and maintaining target blood pressure in patients with essential hypertension.

Cerebrovascular recovery after stroke with individual and combined losartan and captopril treatment of SHRsp

We assessed whether the superior restoration of cerebrovascular function after hemorrhagic stroke by losartan versus captopril treatment was due to better BP, uremia, uricaemia, or aldosterone control in Kyoto Wistar stroke-prone-hypertensive rats and evaluated whether elevated angiotensin II (A2) levels enhanced the effectiveness of losartan treatment. Constriction was studied in the middle cerebral arteries (MCAs) using a pressure myograph. Post-stroke survival increased from 21 to 310 and 189days respectively with losartan and captopril treatment. Neither treatment reduced BP, both reversed uremia and hyperaldosteronism equally after 7days. Plasma uric acid remained low. At stroke, MCA constriction to pressure (PDC), protein kinase C (PKC) activation, depolarization, and sarcoplasmic Ca2+ were attenuated. Endothelial-dependent-vasodilation by bradykinin and endogenous NO release were lost. Both treatments recovered these functions within 7days. These functions deteriorated after 116days of captopril but not losartan treatment. Inhibiting A2 formation during losartan treatment didn't alter BP or vascular recovery. The superior recovery of PDC by losartan over captopril was not produced by better BP, uremia or aldosterone control or elevated A2. PDC recovery was associated with improved PKC function and enhanced basal NO release. The re-establishment of PDC could reduce cerebrovascular over-perfusion and hematoma expansion after stroke.

Losartan in combination with propranolol slows the aortic root dilatation in neonatal Marfan syndrome

Neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is characterized by rapidly progressive multi-valvular cardiac disease and death from congestive heart failure, typically within the first year of life. Due to the rarity of this condition, treatment for neonatal Marfan syndrome has not been well studied. In this report, a combination of losartan and propranolol reduced the aortic root dilatation rate after three months of losartan therapy. Genetic analysis in this patient revealed a mutation in exon 25 of the FBN1 gene, which typically results in a shorter life expectancy. However, the patient's heart failure was controlled by losartan, propranolol and other anti-congestive medications, which may have prolonged his survival.

ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design.

To test two interventions to reduce interleukin (IL)-6 levels, an indicator of low-grade chronic inflammation and an independent risk factor for impaired mobility and slow walking speed in older adults. The ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot Study was a multicenter, double-blind, placebo-controlled randomized pilot trial of two interventions to reduce IL-6 levels. Five university-based research centers. Target enrollment was 300 men and women aged 70 and older with an average plasma IL-6 level between 2.5 and 30 pg/mL measured twice at least 1 week apart. Participants had low to moderate physical function, defined as self-reported difficulty walking one-quarter of a mile or climbing a flight of stairs and usual walk speed of less than 1 m/s on a 4-m usual-pace walk. Participants were randomized to losartan, omega-3 fish oil (ω-3), combined losartan and ω-3, or placebo. Randomization was stratified depending on eligibility for each group. A titration schedule was implemented to reach a dose that was safe and effective for IL-6 reduction. Maximal doses were 100 mg/d for losartan and 2.8 g/d for ω-3. IL-6, walking speed over 400 m, physical function (Short Physical Performance Battery), other inflammatory markers, safety, tolerability, frailty domains, and maximal leg strength were measured. Results from the ENRGISE Pilot Study will provide recruitment yields, feasibility, medication tolerance and adherence, and preliminary data to help justify a sample size for a more definitive randomized trial. The ENRGISE Pilot Study will inform a larger subsequent trial that is expected to have important clinical and public health implications for the growing population of older adults with low-grade chronic inflammation and mobility limitations.

EFFICACY OF A FIXED COMBINATION OF LOSARTAN AND AMLODIPINE IN PATIENTS WITH ARTERIAL HYPERTENSION: SEASONAL FEATURES

The goal is to evaluate the efficacy and security of treatment of patients with arterial hypertension (AH) during the heat wave of a fixed combination of ARBS+ACC (losartan+amlodipine).Materials and methods. Included 26 patients with hypertension 1 and 2 degrees from 42 to 81 years. All patients underwent measurement of office blood pressure, 24h ambulatory BP monitoring, Self-measurement of BP (Home BP ), electrocardiography, biochemical analysis of blood, estimation of osmolarity of blood, questionnaire: visual analogue scale, a questionnaire for patients exposed to heat, the test of adherence to treatment Moriscos-Green. Estimated diaries of self-control of blood pressure. The inclusion visit took place in spring 2016, 1st visit was in May-June 2016, 2nd - during heat waves, 3rd -September-October 2016.Results. The observed decrease in systolic blood pressure and diastolic blood pressure (p=0.000) to the target values, preserved for the whole period of observation. According to the diaries of selfcontrol of blood pressure controlled blood pressure 81% of patients. During a heat wave, this value decreased to 58%, in autumn - to 63%. The 3rd visit achieved a reduction in heart rate at -6.0 (-11.1; and 2.8) beats/min; p=0.007; the decline in uric acid level c of 415.3 to 346.2 mmol/l (p=0.04) and creatinine on the 2nd visit compared to baseline (p=0.02). According to 24h ambulatory BP monitoring, 24h ambulatory BP monitoring, during a single visit, the mean SBP decreased from 139 to 121 mm Hg. (P=0.04) and DBP from 88 to 76 mm Hg. (P=0.04) in the daytime and the tendency to decrease SBP variability from 12 to 10 mm (p=0.07). At the end of the study, the indicators remained stable. The mean value of SBP decreased at night to the third visit from 116 to 110.5 mm Hg. (P=0.04). During the heat wave, a larger mean SBP and DBP was recorded compared with the third visit (p=0.04). A correlation was found between the mean DBP value (r=0.725, p=0.03), the SBP time index (r=0.695, p=0.04) and the SBP time (r=0.787, p=0.02) at night and Quality of life Electrolyte shifts and increasing the osmolarity of the blood during heat waves have not been identified. There is a growing commitment therapy (p=0.04) and quality of life to 20.0 (7.4; 23.3); p=0.000 by visual analogue scale.Conclusion. Fixed combination of losartan and amlodipine (Lorenza) is an effective, safe and may be recommended for hypertensive patients during heat wave and seasonal cold snap.

Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis.

Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4-I) are oral glucose-lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4-I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin-angiotensin system by angiotensin-II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non-diabetic non-alcoholic steatohepatitis (NASH) in a rat model. To induce NASH, Fischer 344 rats were fed a choline-deficient L-amino acid-defined diet for 12weeks. We elucidated the chemopreventive effects of sitagliptin + losartan, especially in conjunction with hepatic stellate cell (HSC) activation, angiogenesis, and oxidative stress, all known to play important roles in the progression of NASH. Sitagliptin + losartan suppressed choline-deficient L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. The combination treatment exerted a greater inhibitory effect than monotherapy. These inhibitory effects occurred almost concurrently with the suppression of HSC activation, neovascularization, and oxidative stress. In vitro studies showed that sitagliptin + losartan inhibited angiotensin II-induced proliferation and expression of transforming growth factor-β1 and α1 (I)-procollagen mRNA of activated HSC and in vitro angiogenesis, in parallel with the suppression observed in in vivo studies. The widely and safely used sitagliptin + losartan combination treatment in clinical practice could be an effective strategy against NASH.

TGF-B1 inhibition with losartan in combination with FOLFIRINOX (F-NOX) in locally advanced pancreatic cancer (LAPC): Preliminary feasibility and R0 resection rates from a prospective phase II study.

386 Background: F-NOX is utilized in LAPC due to improved response over gemcitabine, with theoretical potential for curative resection. However the response rate remains well below 50%. Preclinical data suggest that inhibition of the renin-angiotensin system with losartan reduces the activity of TGF-B1, enhancing intratumoral penetration of chemotherapy by remodeling desmoplastic stroma and improving vascular perfusion. In this study, we evaluate the feasibility of adding losartan to F-NOX in LAPC. Methods: Pts ECOG PS 0-1 with LAPC (NCCN criteria) were enrolled in a single institution, NCI-sponsored phase II study (NCT01821729). Pts received F-NOX/losartan for 8 cycles. If the tumor was radiographically resectable after chemotherapy, pts received short-course chemoradiation (CRT) in 5 fractions (protons 25 GyE, capecitabine 825 mg/m2 bid). If it was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. The primary endpoint was proportion of pts remaining progression-free after 8 cycles of F-NOX/losartan. Results: 32 pts were enrolled from 8/2013 to 6/2016. One pt withdrew prior to treatment, 6 pts are still receiving F-NOX/losartan or CRT. 25 were included in this analysis. Median age was 62y (46-75). Median tumor size was 42mm (22-68). Tumor was in the head of the pancreas in 16 (64%) pts. Of evaluable pts, 18 (72%) completed F-NOX/losartan followed by CRT. Reasons for discontinuation included losartan intolerance (3), failure to thrive (2), investigator discretion (1), and progression (1). Grade 3 or greater toxicity occurred in 11 (40%) pts, including diarrhea (4, 16%), thrombocytopenia (3, 12%), nausea (3, 12%), neutropenia (2, 8%), and febrile neutropenia (1, 4%). Two pts (8%) had short course CRT, 16 (64%) had long course CRT. In evaluable pts, 4 remained unresectable while one pt had R1 resection. R0 resection was achieved in 13 (52%). Conclusions: Based on the low discontinuation rate of the F-NOX/losartan combination, it met criteria for feasibility. The high R0 resection rate in the feasibility cohort has prompted expansion as a phase II study with an R0 resection endpoint. Clinical trial information: NCT01821729.

A fixed combination of amlodipine and losartan: effectiveness and safety in abnormal weather conditions in patients with arterial hypertension

Actuality. The effect of drugs on adaptation to abnormal temperatures is one of the most important questions put to practical medicine by the heat waves of recent years. One of the controversial issues - safety of use during the heat wave of calcium channel blockers (ACC) and blockers of receptors for angiotensin II (ARBS). The goal is to evaluate the efficacy and security of treatment of patients with arterial hypertension (AH) during the heat wave of a fixed combination of ARBS+ACC (Lortenza, KRKA). Materials and methods. Included 26 patients with hypertension 1 and 2 degrees from 42 to 81 years. All patients underwent measurement of office blood pressure, electrocardiography, body sphygmography with the determination of the pulse wave velocity and selectively CAVI, biochemical analysis of blood, estimation of osmolarity of blood, questionnaire: visual analogue scale, a questionnaire for patients exposed to heat, the test of adherence to treatment Moriscos-Green. Estimated diaries of self-control of blood pressure. The inclusion visit took place in spring 2016, 1st visit was in May - June 2016, 2nd - during heat waves, 3rd - September - October 2016. Results. The observed decrease in systolic blood pressure and diastolic blood pressure (p=0.000) to the target values, preserved for the whole period of observation. According to the diaries of self-control of blood pressure controlled blood pressure 81% of patients. During a heat wave, this value decreased to 58%, in autumn - to 63%. The 3rd visit achieved a reduction in heart rate at -6.0 (-11.1; and 2.8) beats/min; p=0.007. A noticeable decrease of the pulse wave velocity from 15.2±3.4 to 14.4 V±3.0 m/s; p=0.01 and CAVI in of-2.1 (to -2.9; -0.65); p=0.01; the decline in uric acid level c of 415.3 to 346.2 mmol/l (p=0.04) and creatinine on the 2nd visit compared to baseline (p=0.02). Electrolyte shifts and increasing the osmolarity of the blood during heat waves have not been identified. There is a growing commitment therapy (p=0.04) and quality of life to 20.0 (7.4; 23.3); p=0.000 by visual analogue scale. Conclusion. Fixed combination of losartan and amlodipine (Lorenza) is an effective, safe and may be recommended for patients receiving AG in the hottest period.

PS 14-45 URIC ACID METABOLISM AND RENAL FUNCTION IN PATIENTS TREATED WITH A FIXED DOSE COMBINATION OF ANTIHYPERTENSIVE MEDICATIONS

Objective: Improvement of serum uric acid (SUA) is thought to have a favorable influence on blood pressure (BP) and renal function in hypertensive patients irrespective of diuretic therapy. The effects of switching therapy to a fixed dose combination (FDC) of losartan (LOS) 50 mg with hydrochlorothiazide (HCTZ) 15 mg (LOS/HCTZ) on BP, UA metabolism, and renal function were assessed in hypertensive patients treated with a FDC of telmisartan (TEL) 40 mg with HCTZ 15 mg (TEL/HCTZ) and compared those of a FDC of TEL with amlodipine (AM) 5 mg (TEL/AM). Design and Method: Sixty-seven hypertensive patients were allocated either LOS/HCTZ (n = 36) or TEL/AM group (n = 31), respectively. Results: Both LOS/HCTZ and TEL/AM were effective in reducing SUA but caused no change in BP after 12 months. LOS/HCTZ increased percent fractional excretion of UA (FEUA) but caused no change in estimated glomerular filtration rate (eGFR). TEL/AM increased eGFR, but trend for increase in FEUA was not significant. Although UA metabolism improved, urinary albumin/creatinine excretion ratio (UACR) increased in two groups. The increase in UACR of TEL/AM was greater than that of LOS/HCTZ. The change in UACR was positively correlated with the changes in eGFR but not with SUA or FEUA. Conclusions: The switching therapy equally controlled BP and improved UA metabolism. Although both LOS-induced inhibitory action of urate transporter 1 and deletion of HCTZ-induced plasma volume reduction were associated with improvement of UA metabolism in the patients, it did not support the beneficial effect of SUA lowering therapy on renal protection.

Comparisons of the pharmacokinetics and tolerability of fixed-dose combinations of amlodipine besylate/losartan and amlodipine camsylate/losartan in healthy subjects: a randomized, open-label, single-dose, two-period, two-sequence crossover study.

BackgroundA fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects.Subjects and methodsA randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography–tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration (Cmax) and the area under the concentration curve from time zero to the last quantifiable time point (AUC0–t) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once.ResultsThe PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the Cmax and AUC0–t were 0.98 (0.94−1.01) and 0.97 (0.93−1.01), respectively. The corresponding values for losartan were 0.91 (0.81−1.02) and 1.05 (0.98−1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated.ConclusionAn FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on Cmax and AUC0–t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects.

The "Rise-Peak-Fall" Pattern of Time Dependency of the Cardiovascular Pleiotropic Effects of Treatment With Low-dose Atorvastatin, Losartan, and a Combination Thereof in Rats.

Treatment with low, subtherapeutic doses of statins and sartans expresses beneficial pleiotropic effects on the arterial wall. The present study explored whether these effects depend on treatment duration. Wistar rats were randomly divided into 4 groups and received low-dose atorvastatin, low-dose losartan, their combination, or saline (control) daily. After 4, 6, 8, and 10 weeks of treatment, the animals were anesthetized, blood samples taken, and hearts and thoracic aortas isolated. Thoracic aorta endothelium-dependent relaxation and parameters of the isolated heart exposed to ischemic-reperfusion injury were assessed along with blood serum parameters and vasoactive genes expression. Low-dose atorvastatin, losartan, and especially their combination showed the characteristic time dependency of all studied parameters (thoracic aorta relaxation, isolated heart parameters, C-reactive protein values, genes encoding endothelial nitric oxide synthase, and CD40). The peak in efficacy was observed after 6 weeks of treatment and subsequently steadily declined. The peak versus control values were significant for all measured parameters. Only a combination of atorvastatin and losartan increased nitric oxide and decreased asymmetric dimethylarginine. A characteristic time-dependent "rise-peak-fall" pattern of the cardiovascular pleiotropic effects of statins and sartans in subtherapeutic low doses was revealed. Evidently, resistance to the explored treatment occurs after a certain period.

Changes of blood pressure, abdominal visceral fat tissue and gene expressions in fetal programming induced rat model after amlodipine-losartan combination treatment.

BackgroundThere are a number of complications that can occur if there is under-nutrition during pregnancy followed by a period of rapid catch-up growth, including a higher chance of adult obesity, insulin resistance and hypertriglyceridemia. The purposes of this study were to investigate the effects of fetal under-nutrition during late pregnancy and lactation on blood pressure, visceral fat tissue, gene expressions and to evaluate changes after amlodipine- losartan combination treatment.MethodsThe rats were divided into three groups: the control (C) group, the food restriction (FR: 50 % food restricted diet) group, and the CX group, which was treated with Cozaar XQ (amlodipine- losartan combination drug) in FR rats from postnatal 4 to 20 weeks. Masson’s trichrome staining was performed in the heart tissues. The amount of abdominal visceral fat tissues was measured. Western blot analysis such as angiotensin converting enzyme (ACE), angiotensin II receptor type IA (ATIA), troponin I (Tn I) and endothelial nitric oxide synthase (eNOS) were performed.ResultsBody weights were significantly higher in the FR group compared with the C group at weeks 8 and 20 and lower in the CX group at week 20. Blood pressure was significantly higher in the FR group compared with the C group at week 20 and lower in the CX group at weeks 12 and 20. The amount of abdominal visceral fat was significantly higher in the FR group compared with the C group at weeks 8, 12 and 20 and significantly lower in the CX group at weeks 16 and 20. Protein expression of ATIA and eNOS were significantly reduced in the CX group at weeks 16 and 20. ACE was significantly reduced in the CX group at week 20 and Tn I was significantly reduced in the CX group at week 16.ConclusionsWhen there is fetal under-nutrition during pregnancy, it leads to obesity, high blood pressure, hypertriglyceridemia and several gene changes in offspring. Amlodipine-losartan combination treatment was able to lower obesity, hypertension, hypertriglyceridemia and several gene changes in rats suffering from fetal under-nutrition during pregnancy.

Фиксированная комбинация лозартана и амлодипина: эффективность и безопасность в аномальных погодных условиях у больных артериальной гипертонией (исследование РЕШЕНИЕ)

Actuality. The effect of drugs on adaptation to abnormal temperatures is one of the most important questions put to practical medicine by the heat waves of recent years. One of the controversial issues - safety of use during the heat wave of calcium channel blockers (ACC) and blockers of receptors for angiotensin II (ARBS). The goal is to evaluate the efficacy and security of treatment of patients with arterial hypertension (AH) during the heat wave of a fixed combination of ARBS+ACC (Lortenza, KRKA). Materials and methods. Included 26 patients with hypertension 1 and 2 degrees from 42 to 81 years. All patients underwent measurement of office blood pressure, electrocardiography, body sphygmography with the determination of the pulse wave velocity and selectively CAVI, biochemical analysis of blood, estimation of osmolarity of blood, questionnaire: visual analogue scale, a questionnaire for patients exposed to heat, the test of adherence to treatment Moriscos-Green. Estimated diaries of self-control of blood pressure. The inclusion visit took place in spring 2016, 1st visit was in May - June 2016, 2nd - during heat waves, 3rd - September - October 2016. Results. The observed decrease in systolic blood pressure and diastolic blood pressure (p=0.000) to the target values, preserved for the whole period of observation. According to the diaries of self-control of blood pressure controlled blood pressure 81% of patients. During a heat wave, this value decreased to 58%, in autumn - to 63%. The 3rd visit achieved a reduction in heart rate at -6.0 (-11.1; and 2.8) beats/min; p=0.007. A noticeable decrease of the pulse wave velocity from 15.2±3.4 to 14.4 V±3.0 m/s; p=0.01 and CAVI in of-2.1 (to -2.9; -0.65); p=0.01; the decline in uric acid level c of 415.3 to 346.2 mmol/l (p=0.04) and creatinine on the 2nd visit compared to baseline (p=0.02). Electrolyte shifts and increasing the osmolarity of the blood during heat waves have not been identified. There is a growing commitment therapy (p=0.04) and quality of life to 20.0 (7.4; 23.3); p=0.000 by visual analogue scale. Conclusion. Fixed combination of losartan and amlodipine (Lorenza) is an effective, safe and may be recommended for patients receiving AG in the hottest period.

PP.21.10

Objective: To compare cardiovascular outcomes depending on the albuminuria decrease due to combined antihypertensive therapy. Design and method: 59 patients with arterial hypertension (AH) 2–3 degrees were included in prospective study. We constructed a Markov model on the basis of the influence on albuminuria(AU) and glomerular filtration rate (GFR) and the results of a cohort study, containing the most comprehensive information on the incidence of cardiovascular hypertension complications and mortality depending on these parameters. As an alternative to the model were: the treatment of the original fixed combination of valsartan / amlodipine and generic free combination of losartan / amlodipine. Results: Antihypertensive drugs for 12 weeks allowed to firm decrease in urinary albumin excretion in both groups, with 19,2 ± 22,6 to 7,8 ± 9,9 ml / min / m2 (p < 0.05) in group V/A a and 17,6 ± 19,8 to 12,7 ± 14,6 (p < 0.05) in the L /A. There were obtained significant group differences in the more pronounced reduction of albuminuria due to influence of drugs B/A -44,8 ± 44,4 vs. -20,5 ± 31,6 (p < 0.05). Significant changes in GFR (increase) in the treatment from 74 ± 16,8 to 78,8 ± 16,2 (p < 0.05) were obtained in the group B/A. In group L/A showed a slight decline in GFR (74 ± 19,7 and 73,2 ± 16,2, respectively). In the modeling results was obtained that the death chance within 5 years in group B/A will be 81 per 1,000 people, in the groupL/A - 96 by 1000. The probability of stroke - 27 and 32 per 1,000 people; infarction - 54 and 61 respectively. That is a fixed combination therapy original V/A avoids 15 deaths, 5 strokes and 7 myocardial infarctions for every 1,000 patients. Conclusions: So that more pronounced nephroprotective effect of original fixed combination of V/A can further prevent fatal and non-fatal cardiovascular events.

High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer.

The network of collagen I in tumors could prevent the penetration of drugs loaded in nanoparticles, and this would lead to impaired antitumor efficacy. In this study, free losartan (an angiotensin inhibitor) was injected before treatment to reduce the level of collagen I, which could facilitate the penetration of nanoparticles. Then the pH-sensitive cleavable liposomes (Cl-Lip) were injected subsequently to exert the antitumor effect. The Cl-Lip was constituted by PEG(5K)-Hydrazone-PE and DSPE-PEG(2K)-R8. When the Cl-Lip reached to the tumor site by the enhanced permeability and retention (EPR) effect, PEG(5K)-Hydrazone-PE was hydrolyzed from the Cl-Lip under the low extra-cellular pH conditions of tumors, then the R8 peptide was exposed, and finally liposomes could be internalized into tumor cells by the mediation of R8 peptide. In vitro experiments showed both the cellular uptake of Cl-Lip by 4T1 cells and cytotoxicity of paclitaxel loaded Cl-Lip (PTX-Cl-Lip) were pH sensitive. In vivo experiments showed the Cl-Lip had a good tumor targeting ability. After depletion of collagen I, Cl-Lip could penetrate into the deep place of tumors, the tumor accumulation of Cl-Lip was further increased by 22.0%, and the oxygen distributed in tumor tissues was also enhanced. The antitumor study indicated free losartan in combination with PTX-Cl-Lip (59.8%) was more effective than injection with PTX-Cl-Lip only (37.8%) in 4T1 tumor bearing mice. All results suggested that depletion of collagen I by losartan dramatically increased the penetration of PTX-Cl-Lip and combination of free losartan and PTX-CL-Lip could lead to better antitumor efficacy of chemical drugs. Thus, the combination strategy might be a promising tactic for better treatment of solid tumors with a high level of collagen I.

English

Hypertension is an important health problem that frequently requires multidrug treatment, whether due to monotherapy failure or in a concomitant manner. This situation has impulsed the development of some fixed dose combination products with the idea of improve the efficacy, the safety or the adherence of the treatment. In this study, the efficacy and safety of a fixed dose combination product composed by losartan, hydrochlorothiazide and simvastatin was compared with the mixture of losartan and hydrochlorothiazide plus simvastatin, in hypertensive and hypercholesterolemia patients. In this double-blinded, randomized and controlled clinical trial, one hundred and forty four (144) hypertensive and hypercholesterolemia patients received a daily capsule with losartan 50 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg plus a tablet of placebo; or a daily tablet with losartan 50 mg and hydrochlorothiazide 12.5 mg plus a capsule of simvastatin 20 mg, during 81 days. Both treatments produced similar reductions on blood pressure and low-density lipoprotein-cholesterol levels, and more than 90% of treated patients achieved recommended values in these parameters. It is concluded that the fixed dose combination of losartan, hydrochlorothiazide and simvastatin, is as effective and safe as the fixed dose of losartan and hydrochlorothiazide plus simvastatin, in hypertensive and hypercholesterolemic patients. Key words: Hydrochlorothiazide, hypercholesterolemia, hypertension, losartan, simvastatin.

The effect of combined antihypertensive therapy on left ventricular diastolic function in resting and postexercise patients with arterial hypertension

The correction of left ventricular diastolic function abnormalities hasn’t been well investigated in arterial hypertension.The aim of the study was to determine the effects of two antihypertensive combinations (perindopril/amlodipine and losartan/amlodipine) on the state of diastolic function at rest and after exercise in patients with arterial hypertension.Results. The early diastolic transmitral flow velocity and mitral annular tissue doppler velocities increased under fixed-dose combination of perindopril and amlodipine. The combination shortened the transmitral E-wave deceleration time and isovolumetric left ventricular relaxation time. The prevalence of diastolic dysfunction decreased from 55.8% to 31% on therapy with perindopril and amlodipine (p&lt;0.05). The treatment reduced the frequency of pathologic results of diastolic exercise stress test. These changes were associated with improved exercise tolerance. Therapy with amlodipine and losartan shortened the deceleration time of early diastolic flow at rest and after exercise. The combination of amlodipine and losartan hasn’t reduced the prevalence of left ventricular diastolic dysfunction and hasn’t improved exercise tolerance.Conclusions. The six-month treatment with fixed-dose combination of perindopril and amlodipine has a pronounced effect on improving ofLV diastolic function compared with a combination of losartan and amlodipine.

Bioequivalence of Losartan/Amlodipine Fixed Dose Combination Tablets (Losanet AM) Compared with Concomitant Administration of Single Components of Losartan and Amlodipine Tablets in Healthy Human Volunteers

A fixed dose combination of losartan, an angiotensin receptor blocker and amlodipine, a calcium channel blocker, can potentially provide complementary mechanism of action to improve blood pressure control and clinical outcomes. The current study was conducted to compare the pharmacokinetics of a new combination product of losartan potassium and amlodipine besylate with separate co-administration of losartan potassium and amlodipine besylate tablets in 40 healthy human volunteers after a single oral dose in a randomized three-period crossover study. The study protocol was prepared in accordance to the requirements set in the EMA guidance for conducting bioequivalence studies. Reference (Cozaar 100 mg, Merck Sharp & Dohme Ltd, UK and Norvasc 10 mg, Pfizer, Canada) and test (Losanet AM, Pharmaline, Lebanon) drugs were administered to fasted volunteers and blood samples were collected up to 168 hours and assayed for losartan, carboxylic acid losartan metabolite and amlodipine using a validated LC-MS/MS method. The pharmacokinetic parameters AUC0-t, AUC0- ∞,Cmax, Tmax, T1/2, MRTinf, residual area (%) and elimination rate constant were determined from plasma concentration-time profile by non-compartmental analysis method using WinNonlin V5.3. The analysis of variance did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence (80-125%). The resulting data demonstrated that when administered as fixed dose combination or individual tablets, the pharmacokinetics of losartan and amlodipine were bioequivalent and were well-tolerated.

Antihypertensive effectiveness of combination therapy with losartan/hydrochlorothiazide for 'real world' management of isolated systolic hypertension.

The guidelines for hypertension require the presence of compelling indications for pharmacological management of hypertension associated with various diseases. Data mainly obtained through randomized controlled trials have provided evidence supporting effectiveness of the combination of losartan (Lo) and hydrochlorothiazide (HCTZ) for management of hypertensive patients. However, there have been few reports discussing the effectiveness of Lo/HTCZ (losartan 50 mg/hydrochlorothizide 12.5 mg) in the 'real world' in the management of isolated systolic hypertension (ISH). This study was designed to investigate the 'real world' effectiveness of Lo/HTCZ-based treatment of ISH associated with various diseases. This was a retrospective, uncontrolled analysis of data derived from a large, cross-sectional web-based clinical database collected by physicians. Of 24,825 eligible patients, 20,726 were followed during a 6-month period. Among these, subjects for analysis included those with systolic blood pressure (SBP) >140 mmHg and diastolic BP (DBP) <90 mmHg; patients with diabetes mellitus and chronic kidney disease were excluded. A total of 15,846 patients were analysed. Among the various complications, hypercholesterolemia was the most frequent concomitant cardiovascular (CV) risk factor (48.1%), followed by obesity (16.3%). Associated clinical conditions were cerebrovascular diseases (9.6%), ischemic heart disease (7.9%) and left ventricular hypertrophy (4.6%). Total numbers of patients exhibiting any type of complications were 62% (≤64 years old), 69% (65-74 years old) and 67% (≥75 years old) (stratification of age). Mean SBP/DBP measurements (mm Hg) were 156/78 at the start, 140/72 at 1 month and 134/72 at 6 months. Blood pressure (BP) reductions associated with various diseases were similar among patients. Laboratory data including serum levels of total cholesterol, uric acid, hemoglobin A1c and serum potassium did not change during the study. Adverse effects such as orthostatic hypotension and considerable reductions in BP (>30 mmHg SBP) were rare. Lo/HTCZ is safe and effective in reducing and improving BP control in a 'real world' setting. Treatment with Lo/HTCZ enabled a substantial proportion of hypertensive patients with associated diseases to achieve the recommended goal of <140 mm Hg.