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-ß1-42 (Aß1-42) 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 Aß1-42 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.

Losartan May Not Prevent Vestibular Schwannoma Growth or Related Hearing Loss During Observation.

OBJECTIVE: To evaluate the impact of losartan on vestibular schwannoma (VS) growth and related hearing loss during observation. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Sporadic VS patients undergoing initial observation with at least two magnetic resonance imaging and audiologic examinations. INTERVENTION: Losartan. MAIN OUTCOME MEASURES: Endpoints included VS growth, quantitative audiologic changes, survival free of tumor growth, and survival free of nonserviceable hearing. Patient characteristics and endpoints were compared by losartan use. RESULTS: Seventy-nine patients were included, of which 33% were taking losartan. Tumor growth was observed in 50% of patients in the losartan group and 36% in the non-losartan group (p = 0.329). Survival analysis failed to show a significant difference in the hazard rate of VS growth between groups (hazard ratio, 1.38; 95% confidence interval, 0.70-2.70; p = 0.346). Throughout observation, mean decreases in normalized pure-tone average were 5.5 and 9.3 dB in the losartan and non-losartan groups, respectively (p = 0.908). Mean decreases in normalized word recognition score were 11.0 and 16.6% in the losartan and non-losartan groups, respectively (p = 0.757). Nonserviceable hearing developed in 19% of patients in the losartan group and 28% in the non-losartan group (p = 0.734). Survival analysis did not demonstrate a significant difference in the hazard rate of developing nonserviceable hearing between groups (hazard ratio, 1.71; 95% confidence interval, 0.56-5.21; p = 0.337). CONCLUSIONS: Losartan use may not reduce the risk of VS growth or hearing loss during observation. A randomized trial would be ideal to further identify the true effect on growth and hearing.

Preparation of iota-carrageenan@bentonite@4-phenyl-3-thiosemicarbazide ternary hydrogel for adsorption of Losartan potassium and sulfamethoxazole.

A rising quantity of drugs has been discharged into the aquatic environment, posing a substantial hazard to public health. In the current work, a novel hydrogel (i.Carr@Bent@PTC), comprised of iota-carrageenan, bentonite, and 4-phenyl-3-thiosemicarbazide, was successfully prepared. The introduction of 4-phenyl-3-thiosemicarbazide and bentonite in iota-carrageenan significantly increased the mechanical strength of iota-carrageenan hydrogel and improved its degree of swelling, which can be attributed to the hydrophilic properties of PTC and Bent. The recorded contact angle was 70.8°, 59.1°, 53.9°, and 34.6° for pristine i.Carr, i.Carr@Bent, and i.Carr@Bent@PTC, respectively. The low contact angle measurement of the Bent and PTC loaded-i.Carr hydrogel was attributed to the hydrophilic Bent and PTC. The ternary i.Carr@Bent@PTC hydrogel demonstrated broad pH adaptability and excellent adsorption capacities for sulfamethoxazole (SMX) and losartan potassium (LP), i.e., 467.61 mg. g-1 and 274.43 mg. g-1 at 298.15 K, respectively. The pseudo-first-order (PSO) model provided a better fit for the adsorption kinetics. The adsorption of SMX and LP can be better explained by employing the Sips and Langmuir isotherm models. As revealed by XPS and FTIR investigations, π-π stacking, complexation, electrostatic interaction, and hydrogen bonding were primarily involved in the adsorption mechanisms.

Analysis of peri-implant bone tissue between hydrophilic and rough implant surfaces in spontaneously hypertensive rats treated with losartan.

OBJECTIVES: to evaluate the morphological and functional characteristics of the peri-implant bone tissue that was formed during the healing process by the placement implants using two different surface treatments: hydrophilic Acqua™ (ACQ) and rough NeoPoros™ (NEO), in spontaneously hypertensive (SHR) and normotensive rats (Wistar) whether or not treated with losartan. METHODOLOGY: In total, 96 male rats (48 Wistar and 48 SHR) were divided into eight subgroups: absolute control rough (COA NEO), absolute control hydrophilic (COA ACQ), losartan control rough (COL NEO), losartan control hydrophilic (COL ACQ), SHR absolute rough (SHR NEO), SHR absolute hydrophilic (SHR ACQ), SHR losartan rough (SHRL NEO), and SHR losartan hydrophilic (SHRL ACQ). The rats medicated with losartan received daily doses of the medication. NeoPoros™ and Acqua™ implants were installed in the tibiae of the rats. After 14 and 42 days of the surgery, the fluorochromes calcein and alizarin were injected in the rats. The animals were euthanized 67 days after treatment. The collected samples were analyzed by immunohistochemistry, biomechanics, microcomputerized tomography, and laser confocal scanning microscopy analysis. RESULTS: The osteocalcin (OC) and vascular endothelium growth factor (VEGF) proteins had moderate expression in the SHRL ACQ subgroup. The same subgroup also had the highest implant removal torque. Regarding microarchitectural characteristics, a greater number of trabeculae was noted in the control animals that were treated with losartan. In the bone mineralization activity, it was observed that the Acqua™ surface triggered higher values of MAR (mineral apposition rate) in the COA, COL, and SHRL groups (p<0.05). CONCLUSION: the two implant surface types showed similar responses regarding the characteristics of the peri-implant bone tissue, even though the ACQ surface seems to improve the early stages of osseointegration.

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.

Novel benzimidazole angiotensin receptor blockers with anti-SARS-CoV-2 activity equipotent to that of nirmatrelvir: computational and enzymatic studies.

BACKGROUND: Hypertension worsens outcomes in SARS-CoV-2 patients. Sartans, a type of antihypertensive angiotensin receptor blocker-(ARB), reduce COVID-19 morbidity and mortality by targeting angiotensin-converting enzyme-2 (ACE2). This study aimed to evaluate the antiviral and antihypertensive effects of nirmatrelvir, commercial sartans (candesartan, losartan, and losartan carboxylic (Exp3174)), and newly synthesized sartans (benzimidazole-N-biphenyl carboxyl (ACC519C) and benzimidazole-N-biphenyl tetrazole (ACC519T)), compared to nirmatrelvir, the antiviral component of Paxlovid. RESEARCH DESIGN AND METHODS: Surface plasmon resonance (SPR) and enzymatic studies assessed drug effects on ACE2. Antiviral abilities were tested with SARS-CoV-2-infected Vero E6 cells, and antihypertensive effects were evaluated using angiotensin II-contracted rabbit iliac arteries. RESULTS: Benzimidazole-based candesartan and ACC519C showed antiviral activity comparable to nirmatrelvir (95% inhibition). Imidazole-based losartan, Exp3174, and ACC519T were less potent (75%-80% and 50%, respectively), with Exp3174 being the least effective. SPR analysis indicated high sartans-ACE2 binding affinity. Candesartan and nirmatrelvir combined had greater inhibitory and cytopathic effects (3.96%) than individually (6.10% and 5.08%). ACE2 enzymatic assays showed varying effects of novel sartans on ACE2. ACC519T significantly reduced angiotensin II-mediated contraction, unlike nirmatrelvir and ACC519T(2). CONCLUSION: This study reports the discovery of a new class of benzimidazole-based sartans that significantly inhibit SARS-CoV-2, likely due to their interaction with ACE2.

Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1.

Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1.

Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome.

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.

Losartan and metabolite EXP3179 activate endothelial function without lowering blood pressure in AT2 receptor KO mice.

BACKGROUND: We have documented profound release of nitric oxide (NO) and endothelium-derived hyperpolarization factor (EDHF) by angiotensin II (ANGII) receptor 1 (AT1) blocker (ARB) losartan and its unique metabolite EXP3179, a pleiotropic effect that may help rationalize the protective properties of ARBs. Since blood pressure (BP) lowering by ARBs likely require an ANGII-dependent switch from AT1 to ANGII receptor 2 (AT2) signaling, a receptor known to stimulate endothelial NO release, we investigated the contribution of AT1 and AT2 to losartan and EXP3179's endothelial function-activating properties. EXPERIMENTAL APPROACH: Two AT1 ligands were used in an attempt to block the AT1-dependent endothelium-enhancing effects of EXP3179. AT2-null mice were used to evaluate the acute ex vivo and chronic in vivo effects of EXP3179 (20µM) and losartan (0.6 g/l), respectively, on endothelial function, BP and aortic stiffness. KEY RESULTS: Ex vivo blockade of AT1 receptors did not attenuate EXP3179's effects on NO and EDHF-dependent endothelial function activation. We observed significant reductions in PE-induced contractility with EXP3179 in both WT and AT2 knockout (KO) aortic rings. In vivo, a 1-month chronic treatment with losartan did not affect pulse wave velocity (PWV) but decreased PE-induced contraction by 74.9 % in WT (p < 0.0001) and 47.3 % in AT2 KO (p < 0.05). Presence of AT2 was critical to losartan's BP lowering activity. CONCLUSION: In contrast to BP lowering, the endothelial function-enhancing effects of losartan and EXP3179 are mostly independent of the classic ANGII/AT1/AT2 pathway, which sheds light on ARB pleiotropism.

Angiotensin II Type 1 receptor blockade attenuates the neuropathological changes in the spinal cords of diabetic rats with modulation of nuclear factor erythroid 2-related factor 2/ heme oxygenase 1 system.

Peripheral and central neuropathies frequently complicate worldwide diabetes. Compared to peripheral neuropathy, central neuropathy didn`t gain a major research interest. Angiotensin II is reported to be involved in diabetic neuropathic pain but its role in the central pathological changes in the spinal cord is not clear. Here, we study the role of Losartan; an Angiotensin II receptor 1 (AT1) antagonist in suppression of the diabetes-induced changes in the spinal cord. Three groups of rats were applied; a negative control group, a streptozotocin (STZ) diabetic group, and a group receiving STZ and Losartan. After two months, the pathological alteration in the spinal cord was investigated, and an immunohistochemical study was performed for neuronal, astrocytic, and microglial markers; nuclear protein (NeuN), Glial fibrillary acidic protein (GFAP), and Ionized calcium-binding adaptor molecule 1 (Iba1), respectively, and for an apoptosis marker; caspase-3, and the inflammatory marker; nuclear factor kappa B (NF-kB) signaling, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2); physiological antioxidant system. The results showed that Losartan caused recovery of spinal cord changes, by inhibiting the microglial and astrocytic activation, suppressing neuronal apoptosis and NF-kB expression with activation of Nrf2/HO-1 (P<0.0005). It is suggested, herein, that Losartan can suppress diabetes-induced glial activation, inflammation, neuronal apoptosis, and oxidative stress in the spinal cord; the mechanisms that may underlie the role of AT1 antagonism in suppressing diabetic neuropathic pain.

Resolution of overlapping spectra using chemometric manipulations of UV-spectrophotometric data for the determination of Atenolol, Losartan, and Hydrochlorothiazide in pharmaceutical dosage form.

Simultaneous determination of atenolol (ATN), losartan potassium (LOS), and hydrochlorothiazide (HCZ) in presence of HCZ impurity B was conducted by chemometric approaches and radial basis function network (RBFN) using UV-spectrophotometry without preliminary separation. Three chemometric models namely, classical least-squares (CLS), principal component regression (PCR), and partial least-squares (PLS) along with RBFN were utilized using the ternary mixtures of the three drugs. The multivariate calibrations were obtained by measuring the zero-order absorbance of the mixtures from 250 to 270 nm at the interval of 0.2 nm. The models were built covering the concentration range of (4.0 to 20.0), (3.8 to 20.2), and (0.9 to 50.1) µg mL-1 for ATN, LOS, and HCZ, respectively. The regression coefficient was calculated between the actual and predicted concentrations of the 3 drugs using CLS, PCR, PLS and RBFN. The accuracy of the developed models was evaluated using the root mean square error of prediction (RMSEP) giving satisfactory results. The proposed methods were simple, accurate, precise and were applied efficiently for the quantitation of the three components in laboratory-prepared mixtures, and in dosage form showing good recovery values. In addition, the obtained results were compared statistically with each other using ANOVA test showing non-significant difference between them.

Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness. CASE PRESENTATION: A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels. CONCLUSION: Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Tackling Losartan Contamination: The Promise of Peroxymonosulfate/Fe(II) Advanced Oxidation Processes.

Losartan, an angiotensin II receptor antagonist frequently detected in wastewater effluents, poses considerable risks to both aquatic ecosystems and human health. Seeking to address this challenge, advanced oxidation processes (AOPs) emerge as robust methodologies for the efficient elimination of such contaminants. In this study, the degradation of Losartan was investigated in the presence of activated peroxymonosulfate (PMS), leveraging ferrous iron as a catalyst to enhance the oxidation process. Utilizing advanced analytical techniques such as NMR and mass spectrometry, nine distinct byproducts were characterized. Notably, seven of these byproducts were identified for the first time, providing novel insights into the degradation pathway of Losartan. The study delved into the kinetics of the degradation process, assessing the degradation efficiency attained when employing the catalyst alone versus when using it in combination with PMS. The results revealed that Losartan degradation reached a significant level of 64%, underscoring the efficacy of PMS/Fe(II) AOP techniques as promising strategies for the removal of Losartan from water systems. This research not only enriches our understanding of pollutant degradation mechanisms, but also paves the way for the development of sustainable water treatment technologies, specifically targeting the removal of pharmaceutical contaminants from aquatic environments.

Losartan ameliorates renal fibrosis by inhibiting tumor necrosis factor signal pathway.

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-ß1 (TGF-ß1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.

Assembly of In-Situ Gel Containing Nano-Spanlastics of an Angiotensin II Inhibitor as a Novel Epitome for Hypertension Management: Factorial Design Optimization, In-vitro Gauging, Pharmacokinetics, and Pharmacodynamics Appraisal.

More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.

Unraveling the role of natriuretic peptide clearance receptor (NPR3) in glomerular diseases.

Natriuretic peptides (NPs) are cardio-derived hormones that have a crucial role in maintaining cardiovascular homeostasis. Physiological effects of NPs are mediated by binding to natriuretic peptide receptors 1 and 2 (NPR1/2), whereas natriuretic peptide receptor 3 (NPR3) acts as a clearance receptor that removes NPs from the circulation. Mouse studies have shown that local NP-signaling in the kidney glomerulus is important for the maintenance of renal homeostasis. In this study we examined the expression of NPR3 in kidney tissue and explored its involvement in renal physiology and disease by generating podocyte-specific knockout mice (NPR3podKO) as well as by using an NPR3 inhibitor (NPR3i) in rodent models of kidney disease. NPR3 was highly expressed by podocytes. NPR3podKO animals showed no renal abnormalities under healthy conditions and responded similarly to nephrotoxic serum (NTS) induced glomerular injury. However, NPR3i showed reno-protective effects in the NTS-induced model evidenced by decreased glomerulosclerosis and reduced podocyte loss. In a ZSF1 rat model of diabetic kidney injury, therapy alone with NPR3i did not have beneficial effects on renal function/histology, but when combined with losartan (angiotensin receptor blocker), NPR3i potentiated its ameliorative effects on albuminuria. In conclusion, these results suggest that NPR3 may contribute to kidney disease progression.

Effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve-related aortopathy.

AIMS: The aim of this study is to evaluate the effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve (BAV)-related aortopathy and ascending phenotype. METHODS: Consecutive paediatric patients (≤16 years) with BAV and ascending aorta (AsAo) dilation (z-score > 3) were enrolled in this observational retrospective cohort study. Patients receiving prophylactic treatment with either atenolol (0.5 to 1.0 mg/kg/daily) or losartan (0.7 to 1.4 mg/kg/daily) were compared with those who did not receive medical prophylaxis (control group). The primary outcome of interest was the annual rate of change in maximal AsAo diameter z-score in the treatment and control groups. RESULTS: From a cohort of 1005 patients, 120 (mean age 11.3 ± 4.5 years, 82% males) fulfilled the inclusion criteria and were included in the study. Patients in the treatment and control group had similar age, sex, family history of BAV, BAV morphology, and baseline AsAo diameter. During a median follow-up of 7.1 years (interquartile range 3.8-10.2), no differences were observed in the annual growth rate of aortic diameter z-score between patients on treatment and controls. The prevalence of aortic diameter progression was similar in the treatment and control groups, and treatment with atenolol or losartan was not associated with a lower rate of aortic disease progression. CONCLUSIONS: The findings revealed no significant difference in the annual aortic growth rate between treated and untreated patients. Larger cohort studies or, ideally, randomized clinical controlled trials are needed to validate these findings.

Development of Losartan Orally Disintegrating Tablets by Direct Compression: a Cost-Effective Approach to Improve Paediatric Patient's Compliance.

The development of suitable dosage forms is essential for an effective pharmacological treatment in children. Orally disintegrating tablets (ODTs) are attractive dosage forms that avoid swallowing problems, ensure dosage accuracy and are easy to administer as they disintegrate in the oral cavity. This study aimed to develop ODTs containing losartan potassium (LP) for the treatment of arterial hypertension in children. The ODTs, produced by the cost-effective manufacturing process of direct compression, consisted of a mixture of diluent, superdisintegrant, glidant and lubricant. Five superdisintegrants (croscarmellose sodium, two grades of crospovidone, sodium starch glycolate and pregelatinized starch) were tested (at two concentrations), and combined with three diluents (mannitol, lactose and sorbitol). Thus, thirty formulations were evaluated based on disintegration time, hardness and friability. Two formulations, exhibiting the best results concerning disintegration time (< 30 s), hardness and friability (≤ 1.0%), were selected as the most promising ones for further evaluation. These ODTs presented favourable drug-excipient compatibility, tabletability and flow properties. The in vitro dissolution studies demonstrated 'very rapid' drug release. Preliminary stability studies highlighted the requirement of a protective packaging. All quality properties retained appropriate results after 12 months of storage in airtight containers. In conclusion, the ODTs were successfully developed and characterised, suggesting a potential means to accomplish a final prototype that enables an improvement in childhood arterial hypertension treatment.

[Economic evaluation of Annao Pills combined with antihypertensive drugs in treatment of primary hypertension: a study based on decision tree model].

The purpose of this study was to evaluate the economics of Annao Pills combined with antihypertensive drugs in the treatment of primary hypertension in the Chinese medical setting. TreeAge pro 2018 was used for cost-effect analysis and sensitivity analysis of the two treatment regimens. The intervention time of the simulation model was 2 weeks. The cost parameters were derived from Yaozhi.com, and the effect parameters were based on Meta-analysis of randomized controlled trial(RCT) involving Annao Pills. The experimental group was treated with Annao Pills combined with anti-hypertensive drugs(nifedipine controlled-release tablets + losartan potassium tablets), and the control group was treated with anti-hypertensive drugs(nifedipine controlled-release tablets + losartan potassium tablets). The basic analysis showed that the incremental cost-effect ratio(ICER) of the two groups was 2 678.67 yuan, which was less than 7.26% of the per capita disposable income in 2022. That is, compared with anti-hypertensive drugs alone, Annao Pills combined with antihypertensive drugs cost 2 678.67 yuan more for each additional patient with primary hypertension. The results of sensitivity analysis verified the robustness of the basic analysis results. The probability sensitivity results showed that when the patient's personal willingness to pay the price was higher than 2 650 yuan, the probability of the regimen in the experimental group was higher, which was consistent with the results of the basic analysis. In conclusion, when the price was higher than 2 650 yuan, Annao Pills combined with anti-hypertensive drugs was more economical than anti-hypertensive drugs alone in terms of improving the response rate of the patients with primary hypertension.

Role of angiotensin pathway and its target therapy to rescue from experimental cerebral malaria.

Cerebral malaria (CM) induced by Plasmodium falciparum is a devastating neurological complication that may lead the patient to coma and death. This study aimed to protect Plasmodium-infected C57BL6 mice from CM by targeting the angiotensin II type 1 (AT1) receptor, which is considered the common connecting link between hypertension and CM. In CM, AT-1 mediates blood-brain barrier (BBB) damage through the overexpression of ß-catenin. The AT-1-inhibiting drugs, such as irbesartan and losartan, were evaluated for the prevention of CM. The effectiveness of these drugs was determined by the down regulation of ß-catenin, TCF, LEF, ICAM-1, and VCAM-1 in the drug-treated groups. The expression levels of VE-cadherin and vinculin, essential for the maintenance of BBB integrity, were found to be restored in the drug-treated groups. The pro-inflammatory cytokine levels were decreased, and the anti-inflammatory cytokine levels increased with the treatment. As a major highlight, the mean survival time of treated mice was found to be increased even in the absence of treatment with an anti-malarial agent. The combination of irbesartan or losartan with the anti-malarial agent α/ß-arteether has contributed to an 80% cure rate, which is higher than the 60% cure rate observed with α/ß-arteether alone treatment.