Antihypertensive Losartan Research Articles

Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-β1-42 (Aβ1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aβ1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan

The human cytochrome P450 (CYP) 1, 2 and 3 families of enzymes are responsible for the biotransformation of a majority of the currently available pharmaceutical drugs. The highly polymorphic CYP2C9 predominantly metabolizes many drugs including anticoagulant S-warfarin, anti-hypertensive losartan, anti-diabetic tolbutamide, analgesic ibuprofen, etc. There are >80 single nucleotide changes identified in CYP2C9, many of which significantly alter the clearance of important drugs. Here we report the structural and biophysical analysis of two polymorphic variants, CYP2C9*14 (Arg125His) and CYP2C9*27 (Arg150Leu) complexed with losartan. The X-ray crystal structures of the CYP2C9*14 and *27 illustrate the binding of two losartan molecules, one in the active site near heme and another on the periphery. Both losartan molecules are bound in an identical conformation to that observed in the previously solved CYP2C9 wild-type complex, however, the number of losartan differs from the wild-type structure, which showed binding of three molecules. Additionally, isothermal titration calorimetry experiments reveal a lower binding affinity of losartan with *14 and *27 variants when compared to the wild-type. Overall, the results provide new insights into the effects of these genetic polymorphisms and suggests a possible mechanism contributing to reduced metabolic activity in patients carrying these alleles.

Formulation, In-vitro and In-vivo Evaluation of Chronology-based Mucoadhesive Drug Delivery System of an Antihypertensive Drug

Current research aimed to prepare and estimate chronology-based mucoadhesive PDDS of antihypertensive drug losartan potassium through formulation of fast-dissolving core tablet and incorporation of core tablet to polymer coating to formulate bioadhesive PDDS through direct compression system. The coating was done by using polymers ethyl cellulose and carbopol 934. Pre-compression and post-compression parameters, drug release, lag time and mucoadhesive examination was assessed for the formulation. The expected lag time for hypertension is 8 hours; hence, this lag time was achieved by using a bioadhesive pulsatile system. The optimized formulation showed 8 hours lag time with appropriate mucoadhesion for an equivalent period. Moreover, in-vitro as well as in-vivo mucoadhesion investigations reflected the positive outcomes. Consequently, the BPDDS was the finest preventative substitute for drugs with the highest absorption in the stomach and for drugs used to treat diseases related to circadian rhythm

Persulfate Activation Using Biochar from Pomegranate Peel for the Degradation of Antihypertensive Losartan in Water: The Effects of Pyrolysis Temperature, Operational Parameters, and a Continuous Flow Reactor

Biochar derived from pomegranate peel at different pyrolysis temperatures (450, 600, and 850 °C) was synthesized and characterized by BET, XRD, FTIR, and SEM-EDX. Its catalytic efficiency in the degradation of the antihypertensive losartan (LOS) in the presence of sodium persulfate was examined. The biochar pyrolyzed at 850 °C exhibited higher catalytic activity, which was correlated with the greater surface area and higher concentration of minerals on its surface. Interestingly, despite adsorption being favored at alkaline pH, pH 3 showed the highest LOS degradation. LOS decomposition followed pseudo-first-order kinetics. The addition of persulfate significantly increased LOS reduction, while the presence of inorganic and organic water matrix constituents such as sodium chloride, bicarbonate, and humic acid inhibited the oxidation. Experiments conducted with radical scavengers revealed that both hydroxyl and sulfate radicals, as well as singlet oxygen, participated in LOS decomposition, with the former being the dominant species. Using a continuous flow reactor, the system exhibited a satisfactory steady-state performance of 90% LOS removal for 114 h. Afterward, a moderate decrease in performance was observed, which can be attributed to the alteration of the catalyst’s surface and mineral dissolution due to acidity.

Electrochemical oxidation of losartan on a BDD electrode: Influence of cathodes and electrolytes on the degradation kinetics and pathways

In this work, the influence of supporting electrolytes (sodium sulfate and sodium chloride) on the electrochemical oxidation of the antihypertensive drug losartan (LOS) was studied under different operating conditions such as current density (4.1–12.5 mA cm−2), electrolyte concentration (0.05–0.5 M), initial pollutant concentration (250–1000 μg L−1) and solution pH. The role of cathodes on the removal of LOS has been investigated using five different cathodes with carbonaceous cathodes showing better LOS removal. The effect of matrix composition has been studied using simulated water spiked with various constituents and real water matrices such as bottled water (BW) and wastewater (WW). The removal of LOS was pronounced while using a chloride electrolyte as compared to the sulfate electrolyte. The apparent rate constant increased on adding persulfate (PS) up to concentrations of 150 mg L−1 and decreased in the presence of bicarbonates and organic matter. The transformation products (TPs) formed during the electrochemical oxidation depended on the supporting electrolyte and two common TPs were identified in both electrolytes with a total of 4 TPs identified in the chloride medium and 7 TPs in the sulfate medium. Degradation pathways for LOS in both electrolytes have also been proposed.

Abstract 14132: The Crystal Structures Of Human Cytochrome P450 2C9 Provide Insights Into The Effect Of Genetic Variation And The Binding Of Losartan

The human cytochrome P450 2C9 (CYP2C9) enzyme metabolizes many of the currently available medications that include anti-coagulant warfarin, anti-hypertensive losartan, anti-diabetics tolbutamide and glimepiride. Genetic variations in CYP2C9 that include the common alleles *2 and *3 have resulted in reduced enzyme activity leading to altered metabolism of various drug substrates compared with the wild-type (WT). The CYP2C9*2 genetic variant represent an amino acid change from arginine to cysteine at position 144. The crystal structure of CYP2C9 WT and the *2 variant complexed with losartan were recently published. However, the structure of these enzymes in the absence of any ligand or losartan is not available. Thus, the aim was to determine the ligand free structure of these enzymes and assess the hypothesis that the drug binding orchestrates the conformational change and leads to reorientation of amino acid sidechains to interact with losartan in the active site. The data for the CYP2C9 WT and the CYP2C9*2 crystals in the absence of any ligands was collected remotely at the Stanford Synchrotron Radiation Light Source and the structures were solved using x-ray crystallography. The ligand-free structure of the *2 variant revealed markedly different conformation compared to the recently published structure in complex with losartan. The changes in the F, F’, G and G’ helices indicate an open conformation in the absence of losartan compared to the losartan complex. Whereas the ligand-free structure of the WT illustrated similarity in the overall conformation to the previously published structures with losartan bound. Comparison of the ligand free structure of the CYP2C9 WT or the *2 variant with the losartan bound structure identified the amino acid sidechains important for interaction with the drug in the active site. Furthermore, the structure of the *2 variant in the absence or presence of losartan provided a useful framework to investigate the effect of amino acid substitution that leads to altered binding of the drug. In conclusion, the structural characterization of the CYP2C9 WT and the *2 variant yield insights into the conformational changes that occur upon binding of losartan and help understand the effect of genetic polymorphisms on drug metabolism.

Losartan to slow the progression of mild-to-moderate Alzheimer’s disease through angiotensin targeting: the RADAR RCT

Background Medications that modify the renin–angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression. Objective This study investigated whether taking the antihypertensive drug losartan, in addition to normal care, would slow the progression of Alzheimer’s disease when compared with a placebo. Design A double-blind multicentre randomised controlled trial, after a 4-week open-label phase, with follow-up at 14 days and at 3, 6, 9 and 12 months. The primary outcome was based on measured imaging differences in brain volume between baseline and 12 months. Setting Twenty-three NHS hospital trusts across England, Scotland and Northern Ireland. Participants Patients diagnosed with mild-to-moderate Alzheimer’s disease were eligible to participate if they met the following criteria: (1) aged ≥ 55 years; (2) a Mini Mental State Examination score of 15–28; (3) a modified Hachinski Ischaemic Score of ≤ 5; (4) a previous computerised tomography, single-photon emission computed tomography or magnetic resonance imaging scan consistent with a diagnosis of Alzheimer’s disease; (5) a study companion who was willing to participate in the study; and (6) capacity to consent for themselves. Patients were ineligible if they were (1) taking or intolerant to renin–angiotensin system-related medications, (2) unlikely to undergo magnetic resonance imaging or (3) unlikely to complete the trial protocol. People who had blood pressure outside the normal ranges, defined cardiovascular issues, impaired liver or renal function, or a primary neurodegenerative disease that was not Alzheimer’s disease were also excluded, as were women who had not reached menopause and were unwilling to take relevant protocol-specific safety precautions. Intervention The intervention was either 100 mg of overencapsulated losartan (Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) daily or a matched placebo for 12 months. Main outcome measures Difference in brain atrophy, represented by measurement of whole-brain volume before and following 12 months of treatment post randomisation, was measured using volumetric MRI and determined by boundary shift interval analysis. Secondary outcomes included changes in rates of Alzheimer’s disease progression (as assessed using the ADAS-Cog, Mini Mental State Examination and Neuropsychiatric Inventory), the volume of white matter hyperintensities, cerebral blood flow (assessed by magnetic resonance imaging), blood pressure, magnetic resonance imaging measures of atrophy and association with measures of cognitive decline, and drug compliance and tolerability. Results A total of 261 participants entered the open-label phase, of whom 211 were randomised to the intervention (n = 105) or placebo (n = 106) arms. Of the 197 people (93%) who completed the study, 81% (n = 171) had a valid primary outcome. The difference in brain volume between arms was consistent with chance (–2.79 ml, 95% confidence interval –6.46 to 0.89 ml; p = 0.19), and there was no evidence of benefit for any of the secondary outcome measures. Limitations Our study had 82% power to detect treatment-based changes and, as a result, may have been underpowered or, more likely, the intervention, which may not have crossed the blood–brain barrier as much as expected, may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes. Conclusions Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease. Future work Other related ‘sartans’ could be tested in patient groups with mild cognitive impairment and for longer to fully test this hypothesis. Trial registration Current Controlled Trials ISRCTN93682878 and EudraCT 2012-003641-15. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 19. See the NIHR Journals Library website for further project information.

Ecotoxicity of losartan potassium in aquatic organisms of different trophic levels

The intensive use of the antihypertensive losartan potassium (LOS) has culminated in its high occurrence in aquatic environments. However, insufficient studies had investigated its effects in non-target organisms. In this study, ecotoxicity of LOS was assessed in aquatic organisms from distinct trophic levels (Desmodesmus subspicatus, Daphnia magna, and Astyanax altiparanae). Genotoxicity was assessed by the comet assay in D. magna and A. altiparanae, and biochemical biomarkers for the fish. LOS was more toxic to D. subspicatus (EC50(72h) = 27.93 mg L−1) than D. magna (EC50 = 303.69 mg L−1). Subsequently, this drug showed to induce more DNA damage in D. magna than A. altiparanae, when exposed to 2.5 mg L−1. No significant stress responses were observed by the fish biomarkers, suggesting that higher trophic levels organisms are more tolerant to LOS toxicity. LOS showed relatively low toxic potential for a short period of exposure, but with different patterns of toxicity for the organisms from distinct trophic levels, contributing to further risk assessment of LOS.

Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan

We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10–11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6–19.0), P = 0.038 and 13.4 (25.4–2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10–11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.

Unveiling the Thermodynamic Aspects of Drug-Cyclodextrin Interactions Through Isothermal Titration Calorimetry.

Due to their low toxicity and high aqueous solubility, cyclodextrins have emerged as a distinctive class of supramolecules with wide application in the pharmaceutical and food industry. Their ability to improvethe water solubility, stability and pharmacokinetic profile of small molecules has established them as a rich toolkit for drug formulation. In order to improve the physicochemical characteristics and the pharmacokinetic profile of a drug through cyclodextrin inclusion, the proper cyclodextrin type has to be selected among the existing great variety consisting of both natural and synthetic variants. The selection of the most proper cyclodextrin variant comes after drug-cyclodextrin screening studies targeting the characterization of the complex formation and evaluation of the affinity and interaction forces participating in the complexation. Numerous analytical, spectroscopic, separation and electrochemical techniques have been applied to elucidate the interaction profile in a cyclodextrin-drug complex. Herein, we describe the application of Isothermal Titration Calorimetry (ITC) on cyclodextrin-drug complexes that enables the charting of the binding affinity and the thermodynamic profile of the inclusion complexes. We focus on the experimental design and present technical tips of the ITC application. To better illustrate the technique's rationale, the interaction between 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and the antihypertensive drug losartan is investigated.

Structure of Cytochrome P450 2C9*2 in Complex with Losartan: Insights into the Effect of Genetic Polymorphism.

The human CYP2C9 plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The *2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity toward many important drug substrates has been demonstrated by CYP2C9*2, which represents an amino acid variation at position 144 from arginine to cysteine. The crystal structure of CYP2C9*2 in complex with an antihypertensive drug losartan was solved using X-ray crystallography at 3.1-Å resolution. The Arg144Cys variation in the *2 complex disrupts the hydrogen-bonding interactions that were observed between the side chain of arginine and neighboring residues in the losartan complex of CYP2C9 and the wild-type (WT) ligand-free structure. The conformation of several secondary structural elements is affected, thereby altering the binding and orientation of drug and important amino acid side chains in the distal active site cavity. The new structure revealed distinct interactions of losartan in the compact active site of CYP2C9*2 and differed in occupancy at the other binding sites previously identified in the WT-losartan complex. Furthermore, the binding studies in solution using losartan illustrated lower activity of the CYP2C9*2 compared with the WT. Together, the findings yield valuable insights into the decreased hydroxylation activity of losartan in patients carrying CYP2C9*2 allele and provide a useful framework to investigate the effect of a single-nucleotide polymorphism that leads to altered metabolism of diverse drug substrates. SIGNIFICANCE STATEMENT: The *2 allele of the human drug-metabolizing enzyme CYP2C9 is found in different populations and results in significantly reduced activity toward various drug substrates. How the CYP2C9*2 variant induces altered drug metabolism is poorly understood given that the Arg144Cys variation is located far away from the active site. This work yield insight into the effect of distal variation using multitude of techniques that include X-ray crystallography, isothermal titration calorimetry, enzymatic characterization, and computational studies.

Abstract P118: Antihypertensive Treatment Guided By Genetics: Pearl-ht, The Randomized Proof-of-concept Trial Comparing Rostafuroxin With Losartan

Primary hypertension contributes to more than 50% of all the worldwide cardiovascular deaths. Current antihypertensive therapy is still targeting the physiological mechanisms regulating blood pressure, but not the “causal” ones. So far, genetic studies have been unable to prove gene causation in human primary hypertension. In this study we compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension (PEARL-HT trial registration: EudraCT: 2010-022073-34, ClinicalTrials.gov: NCT01320397). Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10 -11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in Office Systolic Blood Pressure (OSBP) after two-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis ( LSS and HSD3B1 ), EO transport ( MDR1/ABCB1 ), adducin ( ADD1 and ADD3 ); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6-19.0), P =0.038 and 13.4 (25.4-2.5), P =0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former ( P =0.038); this difference was abolished by rostafuroxin at 10 -11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that the selective blockade of mutant adducin and endogenous ouabain pressor mechanisms by rostafuroxin improves the therapy of primary hypertension in in Caucasians carriers of the related gene variants.

Losartan attenuates neuroinflammation and neuropathic pain in paclitaxel-induced peripheral neuropathy.

Paclitaxel‐induced peripheral neuropathy (PIPN) is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous system. Antihypertensive drug losartan, an angiotensin II receptor type 1 (AT1R) blocker, was shown to have anti‐inflammatory and neuroprotective effects in disease models, predominantly via activation of peroxisome proliferator‐activated receptor gamma (PPARγ). Here, the effect of systemic losartan treatment (100 mg/kg/d) on mechanical allodynia and neuroinflammation was evaluated in rat PIPN model. The expression of pro‐inflammatory markers protein and mRNA levels in dorsal root ganglia (DRGs) and spinal cord dorsal horn (SCDH) were measured with Western blot, ELISA and qPCR 10 and 21 days after PIPN induction. Losartan treatment attenuated mechanical allodynia significantly. Paclitaxel induced overexpression of C‐C motif chemokine ligand 2 (CCL2), tumour necrosis alpha (TNFα) and interleukin‐6 (IL‐6) in DRGs, where the presence of macrophages was demonstrated. Neuroinflammatory changes in DRGs were accompanied with glial activation and pro‐nociceptive modulators production in SCDH. Losartan significantly attenuated paclitaxel‐induced neuroinflammatory changes and induced expression of pro‐resolving markers (Arginase 1 and IL‐10) indicating a possible shift in macrophage polarization. Considering the safety profile of losartan, acting also as partial PPARγ agonist, it may be considered as a novel treatment strategy for PIPN patients.

UV-assisted chemical oxidation of antihypertensive losartan in water

Population growth and deteriorating health issues have led to an increase in the consumption of angiotensin receptor blockers (ARBs), such as losartan (LOR), for treating high blood pressure and, as a result, to the frequent detection of these drugs in water and wastewater. The present study focuses on the oxidation of LOR by UV photolysis, UV(/Fe2+)-activated persulfate (PS) and hydrogen peroxide (H2O2) systems. The effects of operating parameters including pH value, reaction time, concentration of oxidant and activator on the efficacy of treatment were studied. The target compound degradation by direct UV photolysis, UV/PS and UV/H2O2 systems proved to be efficient and followed a pseudo-first-order kinetic model. The application of UV/oxidant systems even at lower PS or H2O2 concentrations resulted in more than 95% of LOR degradation in 10 min. In addition, the use of UV/Fe2+-activated oxidant systems led to a further increase in the kobs by improving the LOR oxidation in aqueous solution. The effectiveness of LOR mineralization based on total organic carbon (TOC) removal was also considered. The optimized results of the studied systems obtained in ultrapure water were used in groundwater to assess the effectiveness of LOR decomposition in more complex environmental matrix. Moreover, the acute toxicity of LOR solutions before and after the UV/Fe2+-activated PS and H2O2 oxidation to luminous bacteria (Vibrio fischeri) was investigated.

Performance of organoclay in adsorptive uptake of antihypertensive losartan potassium: A comparative batch study using micro-grain activated carbon

The antihypertensive losartan potassium is an emerging pharmaceutical contaminant that has been traced in aquatic media; hence, up-to-date water treatment methods are urged. This paper is the first of its kind to examine losartan uptake by adsorption using an organophilic clay, Spectrogel. In comparison, a micro-grain activated carbon (μGAC) was employed. Adsorption kinetics, isotherms and thermodynamics were examined and characterizations were performed. Pseudo-first order, pseudo-second order, external diffusion, surface diffusion and pore diffusion models were adjusted to kinetic data, and Langmuir, Freundlich and Dubinin-Radushkevich models were correlated to isotherms. Adsorption mechanisms were elucidated for surface features and surface chemistry. The latter was unraveled to have a crucial role on losartan removal by Spectrogel. The best adsorbent dosage was stablished as 6 g/L and initial solution pH (2.5–10) had no significant impact on the process. Spectrogel exhibited faster kinetics and superior maximum adsorption capacity (∼2200 min, 0.0820 mmol/g) than μGAC (∼2600 min, 0.0441 mmol/g). Compared to water or ethanol eluents, methanol showed the highest efficiency as desorption agent (65%). The results indicate that Spectrogel organoclay is a potential non-traditional adsorbent for losartan remediation.

Comparison of the effect of losartan versus candasartan on uric acid levels in hypertensive patients

Background: It have been suggested by some studies that uric acid plays a causal role in the development of cardiovascular disease where as other studies concluded that uric acid merely reflects other concomitant risk factors, such as hypertension, insulin resistance, obesity, or lipid abnormality . Sartan drugs or angiotensin II receptor blockers do appear to lower uric acid levels (SUA). The clinical importance of this finding to patients with hypertension, or gout, or both is not yet known. The present study was aimed to compare the effects of the antihypertensive drugs losartan and candasartan on blood pressure and uric acid level in hypertensive patients. Materials and Methods: A total of 80 newly diagnosed hypertensive patients were divided into two groups, with 40 patients in each group. Group 1 was given losartan (50 mg/day) and group 2 was given candasartan (8mg/day). A control group of 50 apparently healthy individuals was included. Blood pressure and uric acid were measured for controls and patients before and after drug administration. Results:A significant increase in blood pressure and uric acid were found in hypertensive patients before starting treatment (P<0.001), as compared with controls. After 2 months of treatment, the systolic and diastolic BP were significantly reduced in the both losartan and candasartan groups (P<0.001). Both drugs were similarly effective in reducing the blood pressure in patients with hypertension with no statistical significant difference between the two treatments. Serum uric acid levels were only significantly reduced after 2 months of treatment with losartan (P < 0.001) but not with candasartan. Conclusions: Our findings suggest that both losartan and candasartan therapy were similarly effective in reducing blood pressure in patients with hypertension. Losartan, but not candasartan, was associated with a significant reduction in serum uric acid levels. Our findings suggest that the losartan is the drug of choice in patients with hypertension and hyperuricemia and gout.

Crystal Structure of CYP2C9*2 Genetic Variant in Complex with an Angiotensin II Receptor Blocker Drug Losartan

Cytochrome P450 (CYP)‐dependent monooxygenases are a superfamily of heme‐containing enzymes involved in the metabolism of various xenobiotics. The drug metabolizing CYP2C9 enzyme metabolizes up to 20% of the clinical drugs that include losartan, warfarin, ibuprofen, tolbutamide, and glimepiride. The CYP2C9*2 and *3 are the two prevalent genetic variants that demonstrate significant reduction of the catalytic activity compared to the wild‐type (WT) enzyme for many important CYP2C9 substrates. Despite the abundant structural information available regarding various CYPs, the structural information about the effect of genetic polymorphisms on drug binding has remained scant. The CYP2C9*2 variant represents an amino acid change from arginine to cysteine at position 144, also referred to as R144C. To understand how genetic variation in CYP2C9 affects drug binding and oxidation, we solved the crystal structure of CYP2C9*2 in complex with the antihypertensive drug losartan using X‐ray crystallography. The prodrug losartan is an angiotensin II receptor antagonist that is predominantly metabolized by CYP2C9 and CYP3A4. The overall structure of the CYP2C9*2‐losartan complex illustrate remarkable differences compared to the WT complex. These include altered conformation of important secondary structural elements and residue side chains previously shown to be responsible for binding interactions with different substrates. Furthermore, the new structure revealed significant changes in binding of losartan compared to the previously solved losartan complexes of the CYP2C9 WT, *3 and *30. The structure highlights how single nucleotide polymorphism affects drug binding and yield insights into altered metabolism. Overall, the structural complex provides a useful framework to study, computationally as well as biophysically, the binding of different substrates to genetic variants of CYP2C9 and understand the effect of amino acid substitution in decreased hydroxylation activity of the enzyme.Support or Funding InformationThe authors are grateful to Albany College of Pharmacy and Health Sciences for funding.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Advanced oxidation of antihypertensives losartan and valsartan by photo-electro-Fenton at near-neutral pH using natural organic acids and a dimensional stable anode-gas diffusion electrode (DSA-GDE) system under light emission diode (LED) lighting.

In this work photo-electro-Fenton (PEF) processes using a dimensionally stable anode-gas diffusion electrode (DSA-GDE) system under light emission diodes (LED)-type radiation were used in the degradation of the angiotensin-II-receptor antagonists (ARA II), valsartan (VAL), and losartan (LOS), which are used in the treatment of hypertension diseases, and are considered among the emerging contaminants (ECs). Organic acids as citric, tartaric, and oxalic acids were used as complexing agents of iron ions in order to maintain the performance of the Fenton reaction at near-neutral pH value. The results show that at 3.42mA/cm2 after 90min of electro-Fenton (EF) treatment, degradation of 70% of VAL and 100% of LOS were observed. Total degradation of VAL and LOS was reached with a PEF process at the same time with mineralization of 30%. When citric and tartaric acids were used instead of oxalic acid, similar results were obtained, i.e., total degradation of both compounds, LOS and VAL, after 90min of treatment. The degradation performance can be attributed to the increase of the initial dissolved iron in the system, facilitating the Fe3+/Fe2+ turnover in the catalytic photo-Fenton reaction and consequently, hydroxyl radical (•OH) production. In addition, the increased photo-activity of the complexes can be associated with their high capability to complex Fe3+ and to promote ligand-to-metal charge transfer, which is of key importance to feed Fe2+ to the Fenton process. The results show that the system evaluated was more efficient to eliminate sartan family compounds using LED lighting in comparison with traditional UV-A lamps used in this kind of work. Moreover, three transformation products of VAL degradation and two transformation products of LOS degradation were identified by high-resolution mass spectrometry (HRMS) using hybrid quadrupole-time-of-flight (QTOF) MS and, at the end of the PEF system, the several organic compounds accumulated and no mineralized were effectively treated in a subsequent aerobic biological system.

Angiotensin Regulation of Amygdala Response to Threat in High-Trait-Anxiety Individuals

BackgroundThe antihypertensive drug losartan has been shown to improve memory in humans as well as learning and fear extinction in rodent models, highlighting its potential to have similar synergistic effects on exposure-based cognitive behavioral therapy for anxiety disorders. This study investigated the effect of losartan on neural correlates of processing threat versus safety stimuli in highly anxious individuals to identify potential pathways of how the drug might facilitate psychological treatment. MethodsThirty healthy volunteers high in trait anxiety were randomly assigned to a single dose of losartan (50 mg) versus placebo before undergoing functional magnetic resonance imaging. We measured brain response to happy and fearful faces presented for 80 seconds to assess emotional processing and habituation over time. ResultsThe placebo group showed similarly high left amygdala activation early on during presentation of fearful and happy faces, which decreased over time. In contrast, losartan reduced amygdala response to happy faces early on. In response to fearful faces, the drug prevented habituation, caused sustained amygdala activation, and led to increased activation in other brain areas associated with threat processing, such as the insula and putamen. ConclusionsOur findings suggest two distinct effects of losartan on emotional processing, including an improvement of early discrimination of stimuli as threatening versus safe, and facilitation of threat processing. Both processes are known to be relevant for successful exposure, highlighting two potential pathways by which losartan might exert facilitative effects on psychological treatment.

Ecotoxicological effects of losartan on the brown mussel Perna perna and its occurrence in seawater from Santos Bay (Brazil)

The antihypertensive losartan (LOS) has been detected in wastewater and environmental matrices, however further studies focused on assessing the ecotoxicological effects on aquatic ecosystems are necessary. Considering the intensive use of this pharmaceutical and its discharges into coastal zones, our study aimed to determine the environmental concentrations of LOS in seawater, as well as to assess the biological effects of LOS on the marine bivalve Perna perna. For this purpose, fertilization rate and embryolarval development were evaluated through standardized assays. Phase I (ethoxyresorufin O‑deethylase EROD and dibenzylfluorescein dealkylase DBF) and II (glutathione S-transferase GST) enzymes, glutathione peroxidase (GPx), Cholinesterase (ChE), lipoperoxidation (LPO) and DNA damage were used to analyze sublethal responses in gills and digestive gland of adult individuals. Lysosomal membrane stability was also assessed in hemocytes. Our results showed the occurrence of LOS in 100% of the analyzed water samples located in Santos Bay, Sao Paulo, Brazil, in a range of 0.2 ng/L–8.7 ng/L. Effects on reproductive endpoints were observed after short-term exposure to concentrations up to 75 mg/L. Biomarker responses demonstrated the induction of CYP450 like activity and GST in mussel gills exposed to 300 and 3000 ng/L of LOS, respectively. GPx activity was also increased in concentration of exposure to 3000 ng/L of LOS. Cyto-genotoxic effects were found in gills and hemocytes exposed in concentrations up to 300 ng/L. These results highlighted the concern of introducing this class of contaminants into marine environments, and pointed out the need to include antihypertensive compounds in environmental monitoring programs.