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European Journal of Preventive... Aug 2023Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, data is missing on patients who had target-achieved (TA). This study aims to show...
Achieved systolic blood pressure and cardiovascular outcomes in 60-80-year-old patients: the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial.
AIMS
Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, data is missing on patients who had target-achieved (TA). This study aims to show the cardiovascular effect of maintaining SBP at intensive levels.
METHODS
The Strategy of Blood Pressure Intervention in Elderly Hypertensive Patients (STEP) trial was a multicentre, randomized, controlled trial which enrolled 8511 young-older (60-80 years) hypertensive patients without prior stroke to compare the cardiovascular prognosis of the intensive treatment (SBP target, 110 to <130 mmHg) vs. the standard treatment (130 to <150 mmHg). This secondary analysis assessed data in patients who achieved a mean SBP within target values. The association of mean achieved SBP and cardiovascular events was examined using a cubic spline function.
RESULTS
In total, 3053 patients (72.0%) in the intensive-treatment group and 3427 (80.3%) in the standard-treatment group had an SBP target achieved, with mean follow-up SBP values of 124.2 mmHg and 137.4 mmHg, respectively. Throughout the median 3.38-year follow-up, the cardiovascular risk was significantly lower in the TA intensive-treatment group than in the TA standard-treatment group [adjusted hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.46-0.80; P < 0.001]. In the intensive-treatment group, patients failing to achieve SBP targets presented higher cardiovascular risk than those TA patients (HR 2.04, 95% CI 1.44-2.88; P < 0.001). A J-shaped relationship was observed between the mean achieved SBP and risk of cardiovascular events, with the lowest risk at an SBP of 126.9 mmHg.
CONCLUSIONS
Maintaining SBP at <130 mmHg offers additional cardiovascular benefits among young-older patients with hypertension.
REGISTRATION
ClinicalTrials.gov: NCT03015311.
PubMed: 37172116
DOI: 10.1093/eurjpc/zwad142 -
ACS Biomaterials Science & Engineering Jun 2023Developing delivery vehicles that achieve drug accumulation in the liver and transferability into hepatic stellate cells (HSCs) across the liver sinusoidal endothelium...
Developing delivery vehicles that achieve drug accumulation in the liver and transferability into hepatic stellate cells (HSCs) across the liver sinusoidal endothelium is essential to establish a treatment for hepatic fibrosis. We previously developed hyaluronic acid (HA)-coated polymeric micelles that exhibited affinity to liver sinusoidal endothelial cells. HA-coated micelles possess a core-shell structure of self-assembled biodegradable poly(l-lysine)--poly(lactic acid) AB-diblock copolymer (PLys--PLLA), and its exterior is coated with HA through polyion complex formation via electrostatic interaction between anionic HAs and cationic PLys segments. In this study, we prepared HA-coated micelles entrapping olmesartan medoxomil (OLM), an anti-fibrotic drug, and evaluated their possibility as drug delivery vehicles. HA-coated micelles exhibited specific cellular uptake into LX-2 cells (human HSC line) in vitro. In vivo imaging analysis after intravenous (.) injection of HA-coated micelles into mice revealed that the micelles exhibited high accumulation in the liver. Observation of mouse liver tissue sections suggested that HA-coated micelles were distributed in liver tissue. Furthermore, . injection of HA-coated micelles entrapping OLM showed a remarkable anti-fibrotic effect against the liver cirrhosis mouse model. Therefore, HA-coated micelles are promising candidates as drug delivery vehicles for the clinical management of liver fibrosis.
Topics: Mice; Humans; Animals; Micelles; Hyaluronic Acid; Endothelial Cells; Drug Delivery Systems; Polymers; Liver Cirrhosis
PubMed: 37159164
DOI: 10.1021/acsbiomaterials.3c00327 -
The Journal of the Association of... Mar 2024For >3 decades now, angiotensin receptor blockers (ARB) have been used in the management of hypertension (HTN) and HTN-related cardiovascular (CV) diseases. Olmesartan... (Review)
Review
For >3 decades now, angiotensin receptor blockers (ARB) have been used in the management of hypertension (HTN) and HTN-related cardiovascular (CV) diseases. Olmesartan medoxomil (OLM) is an angiotensin II type 1 (AT1) receptor antagonist (or blocker) that binds tightly to the AT1 receptor with long-lasting efficacy over the 24-hour period and safety demonstrated in several trials. It is well tolerated and effective in reducing blood pressure (BP) in mono and combination therapy with thiazide diuretics or calcium channel blockers across a wide range of patient subgroups. The effectiveness and safety of OLM-based combination therapies have good and tolerable profiles with high adherence in the fixed single-pill formulation. Consistent antihypertensive efficacy and good tolerability when used as monotherapy or as a combined therapy make OLM a valuable treatment option for adults with HTN. In this review, we discuss the important clinical implications of OLM as an optimal choice as monotherapy and combination therapy in managing patients with HTN.
Topics: Humans; Hypertension; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Drug Therapy, Combination; Imidazoles; Tetrazoles; Olmesartan Medoxomil
PubMed: 38736121
DOI: 10.59556/japi.72.0480 -
Internal Medicine Journal May 2020Duodenal villous atrophy with olmesartan was described in 2012, 10 years following registration of olmesartan. Clinical features are severe watery diarrhoea, usually...
Duodenal villous atrophy with olmesartan was described in 2012, 10 years following registration of olmesartan. Clinical features are severe watery diarrhoea, usually occurring in association with weight loss. Onset is delayed, with a mean duration of prior exposure to olmesartan of 3 years. Diagnosis may be delayed. Symptoms resolve over weeks following cessation of olmesartan. Epidemiological studies suggest increased risk with olmesartan, rather than a class effect of all angiotensin receptor blockers. Post-marketing surveillance for drug safety remains important.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrophy; Humans; Hypertension; Imidazoles; Olmesartan Medoxomil; Tetrazoles
PubMed: 32431039
DOI: 10.1111/imj.14834 -
Spectrochimica Acta. Part A, Molecular... Feb 2021Versatile, extraction-free univariate spectrophotometric methods have been modified to get effective spectral resolution of mixtures in accordance with their feature...
Versatile, extraction-free univariate spectrophotometric methods have been modified to get effective spectral resolution of mixtures in accordance with their feature challenges. The proposed methods have been applied and validated for analyzing some antihypertensive medicines in their co-formulated medicinal products. Two mixtures have been used: the first one [Mix I ] is composed of Olmesartan medoxomil (OLM) and Amlodipine besylate (ADB) with partly-overlapped spectra while the second [Mix II ] is made up Telmisartan (TEL) and Hydrochlorothiazide (HCT) with total-overlapped spectra. Induced dual wavelength, absorbance correction and ratio subtraction coupled with constant multiplication methods were applied to Mix I , while dual wavelength, advanced absorbance subtraction and constant center coupled with spectrum subtraction methods were applied to Mix II Calibration graphs were established with good correlation coefficients. The methods exhibit significant advantages as simplicity, sensitivity, minimal data manipulation besides optimum robustness. Selectivity was inspected using lab-mixtures with diverse ratios. Accuracy, precision and repeatability were found to be within the acceptable limits. The proposed methods are good enough to be used for co-assay of analytes in combined forms without any interfering from excipients. Moreover, all results were estimated in accordance with ICH criteria and successfully compared with those of the reported methods applying t-test and F-test at 95% confidence level. Generally, these methods can be used efficiently for routine quality control testing.
Topics: Amlodipine; Antihypertensive Agents; Spectrophotometry; Tablets
PubMed: 33126135
DOI: 10.1016/j.saa.2020.119080 -
Drug Development and Industrial Pharmacy May 2020This study aims to detect the enhancement in the oral bioavailability of a poorly water-soluble antihypertensive drug Olmesartan Medoxomil (OM) due to the formulation...
This study aims to detect the enhancement in the oral bioavailability of a poorly water-soluble antihypertensive drug Olmesartan Medoxomil (OM) due to the formulation of lyophilized oily-core nanocapsules. A comparative pharmacokinetic study in rats was conducted for oily-core polymeric nanocapsules (ONC) after formulation and lyophilization against market tablet products to show the significant improvement in oral absorption of OM. OM loaded ONC were prepared using poly-Ɛ-caprolactone (0.5% w/v) as a polymer and an oily core of Labrafac PG by applying a well-controlled nanoprecipitation technique in terms of injection rate (80 mL/h) and magnetic stirring rate (300 rpm). The prepared lyophilized ONC were characterized after reconstitution and evaluated for oral bioavailability after a single OM oral dose (20 mg/kg) of reconstituted lyophilized ONC dispersion was administered to rats. The prepared lyophilized ONC containing 10% w/v mannitol showed an average particle size of 158 nm, polydispersity index of 0.37, negative zeta potential value equals 33.9 and entrapment efficiency of 90%. The dissolution profile for OM from lyophilized ONC powder filled into hard gelatin capsules (HGC) showed a 1.8-fold increase in dissolution rate as compared to the pure drug. pharmacokinetic study in rats revealed a significant enhancement in the oral bioavailability of OM with 1.6-fold increase for AUC and a 1.9-fold increase for as compared to marketed product. It is concluded that the formulation of lyophilized ONC for OM can significantly enhance its oral bioavailability and consequently, its therapeutic efficacy and patient compliance.
Topics: Administration, Oral; Animals; Biological Availability; Caproates; Drug Compounding; Freeze Drying; Lactones; Male; Nanocapsules; Oils; Olmesartan Medoxomil; Rats; Rats, Wistar
PubMed: 32275456
DOI: 10.1080/03639045.2020.1753763 -
The Journal of Antimicrobial... Aug 2021The SmeVWX efflux pump of Stenotrophomonas maltophilia contributes to menadione (MD) tolerance and resistance to chloramphenicol, quinolones and tetracycline. The...
BACKGROUND
The SmeVWX efflux pump of Stenotrophomonas maltophilia contributes to menadione (MD) tolerance and resistance to chloramphenicol, quinolones and tetracycline. The components of the SmeVWX efflux pump are encoded by a five-gene operon, smeU1VWU2X. We have previously demonstrated that the smeU1VWU2X operon is intrinsically unexpressed and inducibly expressed by MD via a SoxR- and SmeRv-involved regulatory circuit in S. maltophilia KJ. We also inferred that there should be other regulator(s) involved in MD-mediated smeU1VWU2X expression in addition to SoxR and SmeRv.
OBJECTIVES
To identify novel regulator(s) involved in the regulation of MD-mediated smeU1VWU2X expression and elucidate the regulatory circuit.
METHODS
A possible regulator candidate involved in the regulation of MD-mediated smeU1VWU2X expression was identified by a homologue search using the helix-turn-helix domain of SmeRv as a query. Gene expression was assessed using the promoter-xylE transcriptional fusion assay and quantitative RT-PCR. The impact of the regulator on SmeVWX pump-mediated functions was investigated via mutant construction and functional tests (antibiotic susceptibility and MD tolerance).
RESULTS
AzoR (Smlt3089), a LysR-type transcriptional regulator, was investigated. In unstressed logarithmically grown cells, AzoR was abundantly expressed and functioned as a repressor, inhibiting the expression of the smeU1VWU2X operon. MD challenge attenuated azoR expression, thus derepressing the expression of the smeU1VWU2X operon in S. maltophilia KJ. AzoR down-regulation-mediated smeU1VWU2X expression was observed in quinolone-resistant and SmeVWX-overexpressing S. maltophilia clinical isolates.
CONCLUSIONS
AzoR negatively regulates the expression of the smeU1VWU2X operon and SmeVWX pump-mediated antibiotic resistance in S. maltophilia.
Topics: Amlodipine Besylate, Olmesartan Medoxomil Drug Combination; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Membrane Transport Proteins; Microbial Sensitivity Tests; Stenotrophomonas maltophilia
PubMed: 34151959
DOI: 10.1093/jac/dkab203 -
AAPS PharmSciTech Oct 2020During production, the supplemental file "Trajectory analysis of 5ns MD simulation of VA-64 and OLM.mpeg", as well as the "RunNo and Serial numbers", for Table III and...
During production, the supplemental file "Trajectory analysis of 5ns MD simulation of VA-64 and OLM.mpeg", as well as the "RunNo and Serial numbers", for Table III and Table VII respectively, were inadvertently omitted from the published article.
PubMed: 33006687
DOI: 10.1208/s12249-020-01820-y -
Gut Microbes 2023Prodrugs reliant on microbial activation are widely used but exhibit a range of efficacies that remain poorly understood. The anti-inflammatory compound 5-aminosalicylic...
Prodrugs reliant on microbial activation are widely used but exhibit a range of efficacies that remain poorly understood. The anti-inflammatory compound 5-aminosalicylic acid (5-ASA), which is packaged in a variety of azo-linked prodrugs provided to most Ulcerative Colitis (UC) patients, shows confounding inter-individual variabilities in response. Such prodrugs must be activated by azo-bond reduction to form 5-ASA, a process that has been attributed to both enzymatic and non-enzymatic catalysis. Gut microbial azoreductases (AzoRs) are the first catalysts shown to activate azo-linked drugs and to metabolize toxic azo-chemicals. Here, we chart the scope of the structural and functional diversity of AzoRs in health and in patients with the inflammatory bowel diseases (IBDs) UC and Crohn's Disease (CD). Using structural metagenomics, we define the landscape of gut microbial AzoRs in 413 healthy donor and 1059 IBD patient fecal samples. Firmicutes encode a significantly higher number of unique AzoRs compared to other phyla. However, structural and biochemical analyses of distinct AzoRs from the human microbiome reveal significant differences between prevalent orthologs in the processing of toxic azo-dyes, and their generally poor activation of IBD prodrugs. Furthermore, while individuals with IBD show higher abundances of AzoR-encoding gut microbial taxa than healthy controls, the overall abundance of AzoR-encoding microbes is markedly low in both disease and health. Together, these results establish that gut microbial AzoRs are functionally diverse but sparse in both health and disease, factors that may contribute to non-optimal processing of azo-linked prodrugs and idiopathic IBD drug responses.
Topics: Humans; Gastrointestinal Microbiome; Prodrugs; Amlodipine Besylate, Olmesartan Medoxomil Drug Combination; Crohn Disease; Colitis, Ulcerative; Mesalamine; Inflammatory Bowel Diseases
PubMed: 37122075
DOI: 10.1080/19490976.2023.2203963 -
Drug Metabolism and Pharmacokinetics Feb 2021In the present study, the biodistribution of self-microemulsifying drug delivery system of hydrophobic olmesartan medoxomil (OM-SMEDDS) was determined by labeling with a...
In the present study, the biodistribution of self-microemulsifying drug delivery system of hydrophobic olmesartan medoxomil (OM-SMEDDS) was determined by labeling with a fluorescent dye VivoTag®680 XL and Xenolight® DiR. Labeled OM-SMEDDS and control dye solution administered orally to mice; real-time dynamic biodistributions over 7 h were determined by 2D-fluorescent imaging to verify their anatomic location. Fluorescent Emissions by Vivotag 680® XL and Xenolight® DiR labeled OM-SMEDDS emitted 2 to 24 times stronger emission than control dye administered group. To further confirm the results, organs were removed and examined using the same technique at the end of 7 h. VivoTag®680XL and Xenolight® DiR emitted 4 and 1.7 times stronger emission respectively than control dye administered mice in ex-vivo organ imaging studies. This study showed that OM-SMEDDS can be succesfully labeled with fluorescent dye and tracked with optical imaging method for the visualisation of biodistribution of drugs and is also useful for enhanced bioavailability.
Topics: Administration, Oral; Animals; Drug Delivery Systems; Emulsifying Agents; Fluorescent Dyes; Male; Mice; Olmesartan Medoxomil; Optical Imaging; Solubility; Tissue Distribution
PubMed: 33191089
DOI: 10.1016/j.dmpk.2020.10.004