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Scientific Reports May 2023In recent years, the outbreak of infectious disease caused by Zika Virus (ZIKV) has posed a major threat to global public health, calling for the development of...
In recent years, the outbreak of infectious disease caused by Zika Virus (ZIKV) has posed a major threat to global public health, calling for the development of therapeutics to treat ZIKV disease. Several possible druggable targets involved in virus replication have been identified. In search of additional potential inhibitors, we screened 2895 FDA-approved compounds using Non-Structural Protein 5 (NS5) as a target utilizing virtual screening of in-silco methods. The top 28 compounds with the threshold of binding energy -7.2 kcal/mol value were selected and were cross-docked on the three-dimensional structure of NS5 using AutoDock Tools. Of the 2895 compounds screened, five compounds (Ceforanide, Squanavir, Amcinonide, Cefpiramide, and Olmesartan_Medoxomil) ranked highest based on filtering of having the least negative interactions with the NS5 and were selected for Molecular Dynamic Simulations (MDS) studies. Various parameters such as RMSD, RMSF, Rg, SASA, PCA and binding free energy were calculated to validate the binding of compounds to the target, ZIKV-NS5. The binding free energy was found to be -114.53, -182.01, -168.19, -91.16, -122.56, and -150.65 kJ mol for NS5-SFG, NS5-Ceforanide, NS5-Squanavir, NS5-Amcinonide, NS5-Cefpiramide, and NS5-Ol_Me complexes respectively. The binding energy calculations suggested Cefpiramide and Olmesartan_Medoxomil (Ol_Me) as the most stable compounds for binding to NS5, indicating a strong rationale for their use as lead compounds for development of ZIKV inhibitors. As these drugs have been evaluated on pharmacokinetics and pharmacodynamics parameters only, in vitro and in vivo testing and their impact on Zika viral cell culture may suggest their clinical trials on ZIKV patients.
Topics: Humans; Zika Virus; Zika Virus Infection; Protein Binding; Methyltransferases; Drug Repositioning; Viral Nonstructural Proteins; Antiviral Agents
PubMed: 37188743
DOI: 10.1038/s41598-023-33341-6 -
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 -
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 -
Pharmaceutics Mar 2023Olmesartan medoxomil (OLM) is a first-line antihypertensive drug with low oral bioavailability (28.6%). This study aimed to develop oleogel formulations to decrease OLM...
Olmesartan medoxomil (OLM) is a first-line antihypertensive drug with low oral bioavailability (28.6%). This study aimed to develop oleogel formulations to decrease OLM side effects and boost its therapeutic efficacy and bioavailability. OLM oleogel formulations were composed of Tween 20, Aerosil 200, and lavender oil. A central composite response surface design chose the optimized formulation, containing Oil/Surfactant (SAA) ratio of 1:1 and Aerosil % of 10.55%, after showing the lowest firmness and compressibility, and the highest viscosity, adhesiveness, and bioadhesive properties (Fmax and Wad). The optimized oleogel increased OLM release by 4.21 and 4.97 folds than the drug suspension and gel, respectively. The optimized oleogel formulation increased OLM permeation by 5.62 and 7.23 folds than the drug suspension and gel, respectively. The pharmacodynamic study revealed the superiority of the optimized formulation in maintaining normal blood pressure and heart rate for 24 h. The biochemical analysis revealed that the optimized oleogel achieved the best serum electrolyte balance profile, preventing OLM-induced tachycardia. The pharmacokinetic study showed that the optimized oleogel increased OLM's bioavailability by more than 4.5- and 2.5-folds compared to the standard gel and the oral market tablet, respectively. These results confirmed the success of oleogel formulations in the transdermal delivery of OLM.
PubMed: 37111569
DOI: 10.3390/pharmaceutics15041083 -
Turkish Journal of Pharmaceutical... Mar 2023Olmesartan medoxomil (OLM) and metoprolol succinate (MPS) in fixed-dose combination (FDC) tablet formulation prescribed extensively. Stability indicating (SI) method for...
OBJECTIVES
Olmesartan medoxomil (OLM) and metoprolol succinate (MPS) in fixed-dose combination (FDC) tablet formulation prescribed extensively. Stability indicating (SI) method for impurities and related substance (RS) test quantitates the amount of these analytes in formulation; the manuscript presents SI/RS-ultra-high performance liquid chromatography-photodiode array (UHPLC-PDA) method for OLM and MPS and their impurities.
MATERIALS AND METHODS
Well-resolved separation of all analytes was achieved with gradient elution on a Shimadzu on Shimpack GIST-C18 (100 mm x 2.1 mm, 2 µm) column maintained at 25°C. Mobile phase-A consist of 0.1% orthophosphoric acid in water and mobile phase-B was acetonitrile at a flow rate of 0.4 mL/min, data integrated at 225 nm and 16 min of short runtime for satisfactory elution of all peaks.
RESULTS
The proposed SI/RS-UHPLC-PDA method was developed and validated as International Conference on Harmonisation (ICH) of Technical Requirements guidelines. The system suitability test complied by all eluted peaks of the interest with acceptable linearity, recovery, and precision. Specificity, robustness, and method sensitivity parameters were determined; all the parameters were found to be within the limits. All the impurities and stress-degraded peaks were well resolved.
CONCLUSION
The proposed method was found to be simple, fast, linear, and accurate. Further, the method is precise, robust, and specific; suitable for routine IPQC during active pharmaceutical ingredient manufacturing, stability and impurity profiling studies of the titled bulk analytes. Furthermore, the method can be extended to assess the levels of impurities formed during life cycle of new FDCs of titled analytes.
PubMed: 36864594
DOI: 10.4274/tjps.galenos.2022.57384 -
Spectrochimica Acta. Part A, Molecular... Jun 2023For the first time a spectrofluorimetric method had been achieved for the concurrent analysis of metoprolol succinate (MET) and olmesartan medoxomil (OLM). The approach...
Coupling of synchronous fluorescence spectroscopy with derivative amplitude outcomes for simultaneous determination of metoprolol succinate and olmesartan medoxomil in combined pharmaceutical preparation: Application in spiked human plasma.
For the first time a spectrofluorimetric method had been achieved for the concurrent analysis of metoprolol succinate (MET) and olmesartan medoxomil (OLM). The approach depended on assessing the first order derivative (D) of the synchronous fluorescence intensity of the two drugs in aqueous solution at Δλ of 100 nm. The amplitudes of D at 300 nm and 347 nm were measured for MET and OLM, respectively. The linearity ranges were 100-1000 ng/mL and 100-5000 ng/mL for OLM and MET, respectively. This approach is uncomplicated, repetitive, quick, and affordable. The results of analysis had been statistically verified. The validation assessments were carried out following the recommendations of The International Council for Harmonization (ICH). This technique could be employed to assess marketed formulation. The method was sensitive with limits of detection (LOD) of 32 ng/ml and 14 ng/mL for MET and OLM, respectively. Limits of quantitation (LOQ) were 99 ng/ml for MET and 44 ng/mL for OLM. So it can be applied to determine both drugs in spiked human plasma within the linearity ranges of 100-1000 ng/mL for OLM and 100-1500 ng/mL for MET.
Topics: Humans; Olmesartan Medoxomil; Metoprolol; Spectrometry, Fluorescence; Pharmaceutical Preparations
PubMed: 36863080
DOI: 10.1016/j.saa.2023.122549 -
Drug Metabolism and Bioanalysis Letters Feb 2023Angiotensin II type 1 (AT 1) receptor antagonist (angiotensin receptor blocker [ARB]) called Olmesartan medoxomil (OLM) prevents angiotensin II from acting on the...
BACKGROUND
Angiotensin II type 1 (AT 1) receptor antagonist (angiotensin receptor blocker [ARB]) called Olmesartan medoxomil (OLM) prevents angiotensin II from acting on the renin-angiotensin-aldosterone pathway, which is a crucial factor in the development of hypertension. OLM is reported to rapidly hydrolyze into its active metabolite, Olmesartan, in plasma after oral treatment.
OBJECTIVE
The objective of the ongoing study was to develop an easy-to-use, precise, and reliable RP-HPLC method for the determination of Olmesartan in bulk as well as pharmaceutical dosage forms.
METHODS
The stability indicating HPLC method for assay includes the use of Kromasil 100-5-C8 (100 mm × 4.6 mm) column, UV detector 265 nm, and mobile phase composition was a mixture of Acetonitrile: water (70:30) and flow rate of 1.0 mL/min. ICH guidelines were followed in the method's validation. To assess the method's specificity and stability in showing characteristics, stress degradation studies were carried out. The working standard solution of Olmesartan was exposed to 0.1 N HCl at room temperature, 0.1 N NaOH at room temperature, 30 percent hydrogen peroxide by volume, and UV radiation in order to conduct a degradation study.
RESULTS
The retention periods of the drug were found to be 1.36 and 1.47 min for standard and sample solutions, respectively. The degradation behaviour of drug under different conditions was studied. The drug was found susceptible to acidic, alkaline and oxidative conditions while it was found stable in photolytic condition. The developed stability-indicating RP-HPLC method for assay was validated as per ICH Q2 guidelines and the validation parameters such as accuracy, precision and specificity were obtained within the accepted criteria.
CONCLUSION
It may be concluded that this method is stability-indicating and specific and can successfully be applied to analyze tablet dosage form containing Olmesartan.
PubMed: 36843253
DOI: 10.2174/2949681016666230224153822 -
Pakistan Journal of Pharmaceutical... Nov 2022This study aims to formulate Olmesartan medoxomil (OM) into oral fast-dissolving tablets (FDTs) to improve its solubility and bioavailability via two different...
This study aims to formulate Olmesartan medoxomil (OM) into oral fast-dissolving tablets (FDTs) to improve its solubility and bioavailability via two different techniques; The polymer-based surface solid dispersion (SSD) technique and the solidified surfactant (SS) technique. In the first technique, two polymers were used; polyvinylpyrrolidone (PVP K90) and Poloxamer 407 (Pluronic®F127), while in the second technique the liquid Tween 80 was solidified by adsorption onto Aeroperl®300. The pre-compression and post-compression parameters of the obtained formulations were assessed. The best formulations were subjected to a taste masking evaluation and a short-term stability study. The results demonstrated that, in comparison to the pure drug, the proportion of drug released from each of the prepared FDTs considerably increased. Results of the stability studies showed that the chosen drug formulations remained stable throughout the storage period.
Topics: Olmesartan Medoxomil; Surface-Active Agents; Solubility; Polymers; Poloxamer; Pulmonary Surfactants; Biological Availability; Tablets
PubMed: 36789807
DOI: No ID Found -
High Blood Pressure & Cardiovascular... Mar 2023Blood pressure control remains an unmet clinical need. Only about half of patients achieve their blood pressure (BP) targets and of these, the majority require... (Review)
Review
Blood pressure control remains an unmet clinical need. Only about half of patients achieve their blood pressure (BP) targets and of these, the majority require combination and double or triple therapies. International guidelines recommend the association of drugs with complementary mechanisms of action and, in particular, the combination of renin-angiotensin system (RAS) inhibitors, calcium channel blockers (CCBs), and diuretics. Among the various angiotensin receptor blockers, olmesartan (OM) is available as a monotherapy and in dual and triple single-pill combinations (SPCs) with amlodipine (AML) and/or hydrochlorothiazide (HCTZ). Several phase III and IV studies, together with real-world studies, have demonstrated the additional benefits of combining OM either with AML or with HCTZ in terms of BP control and target BP achievements both in the general population and in special subgroups of hypertensive patients, such as the elderly, diabetic, chronic kidney disease or obese patients. Ambulatory BP monitoring studies assessing 24h BP have also demonstrated that dual, as well as triple, OM-based SPCs induce a more sustained and smoother BP reduction than placebo and monotherapy. Furthermore, triple OM-based SPC has been shown to improve therapeutic adherence in hypertensive patients compared to free combinations. The availability of OM combined with HCTZ, AML or both at different dosages makes it a valuable option to customize therapy based on the levels of BP and the clinical characteristics of hypertensive patients.
Topics: Humans; Aged; Antihypertensive Agents; Blood Pressure; Olmesartan Medoxomil; Drug Therapy, Combination; Hypertension; Amlodipine; Hydrochlorothiazide; Leukemia, Myeloid, Acute
PubMed: 36696054
DOI: 10.1007/s40292-023-00563-8