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Drug Design, Development and Therapy 2019Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an...
BACKGROUND
Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) and also a major cause of end-stage renal disease (ESRD). Olmesartan medoxomil (OM) is an angiotensin II receptor blocker (ARB) and has been shown to exhibit renoprotective effects on a streptozotocin (STZ)-induced diabetic rat model. Yet, whether OM affects DN progression and renal injury in db/db mice, a type 2 diabetic murine model, has not been established.
METHODS
Wild-type (n = 15) and db/db mice (n = 15) were treated with control saline or OM via oral gavage. The physiological and biochemical parameters were evaluated and histological examinations of kidney specimens were performed.
RESULTS
Compared with saline-treated db/db mice, db/db mice administered with OM showed ameliorated diabetic physiological and biochemical parameters. In addition, OM decreased urinary albumin excretion and plasma creatinine level in db/db mice. Moreover, histologically, OM reduced glomerular hypertrophy and injury, and also ameliorated tubular injury, thus suggesting that OM improves renal function and minimizes renal pathological deterioration in db/db mice.
CONCLUSION
Our study reveals a beneficial role of OM in ameliorating DN in db/db mice, which is associated with its renoprotective function.
Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Animals; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Male; Mice; Olmesartan Medoxomil
PubMed: 31695333
DOI: 10.2147/DDDT.S217826 -
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 -
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 -
Regulatory Toxicology and Pharmacology... Dec 2016Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of... (Comparative Study)
Comparative Study
Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients.
Topics: Administration, Oral; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Biomarkers; Body Weight; Brain; Chromatography, Liquid; Drinking; Drug Carriers; Drug Compounding; Eating; Emulsions; Male; Nanomedicine; Nanoparticles; Oils; Olmesartan Medoxomil; Organ Size; Permeability; Rats, Wistar; Reproducibility of Results; Risk Assessment; Tandem Mass Spectrometry; Tissue Distribution; Toxicity Tests, Subchronic; Water
PubMed: 27815174
DOI: 10.1016/j.yrtph.2016.10.020 -
Biological & Pharmaceutical Bulletin Feb 2018Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and hydrolyzes compounds at both sites. Although the hydrolytic interaction of ester-type... (Comparative Study)
Comparative Study
Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and hydrolyzes compounds at both sites. Although the hydrolytic interaction of ester-type drugs with other drugs by HSA has been reported, there are only a few studies concerning the effect of pharmaceutical excipients on the hydrolysis of ester-type drugs by HSA. In the present study, we investigated the effect of ethanol (2 vol%; 345 mM) on the hydrolysis of aspirin, p-nitrophenyl acetate, and olmesartan medoxomil, which are ester-type drugs, with 4 different lots of HSA preparations. The hydrolysis activities of HSA toward aspirin, p-nitrophenyl acetate, and olmesartan medoxomil were measured from the pseudo-first-order degradation rate constant (k) of salicylic acid, p-nitrophenol, and olmesartan, respectively, which are the HSA-hydrolyzed products. Ethanol inhibited hydrolysis of aspirin by HSA containing low levels of fatty acids, but not by fatty acid-free HSA. Ethanol inhibited hydrolysis of p-nitrophenyl acetate by both fatty acid-free HSA and HSA containing low levels of fatty acids. In contrast, the hydrolysis of olmesartan medoxomil by HSA was insignificantly inhibited by ethanol, but inhibited not only by warfarin and indomethacin but also by naproxen, which are site I binding drugs and a site II binding drug, respectively. These results suggest that the inhibitory action of ethanol on the hydrolysis of ester-type drugs by HSA differs between site I binding drugs and site II binding drugs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Antihypertensive Agents; Aspirin; Binding Sites; Drug Stability; Ethanol; Excipients; Fatty Acids, Nonesterified; Humans; Hydrolysis; Indomethacin; Kinetics; Ligands; Naproxen; Nitrophenols; Olmesartan Medoxomil; Preservatives, Pharmaceutical; Serum Albumin, Human; Warfarin
PubMed: 29176265
DOI: 10.1248/bpb.b17-00680 -
Journal of AOAC International Mar 2022Few spectrophotometric methods have been developed for the simultaneous determination of atorvastatin calcium (ATO) and olmesartan medoxomil (OLM).
BACKGROUND
Few spectrophotometric methods have been developed for the simultaneous determination of atorvastatin calcium (ATO) and olmesartan medoxomil (OLM).
OBJECTIVE
This work aimed to develop and validate five simple spectrophotometric methods for the simultaneous estimation of ATO and OLM in their tablet form.
METHODS
Method I applied the area under curve (AUC) based on the measurement of areas between 241 and 261 nm for ATO, and 248 and 263 nm for OLM. Method II applied second derivative spectrophotometry where the analytical amplitudes at 246.5 and 235 nm were chosen for the estimation of ATO and OLM, respectively. Method III applied the ratio difference (RD) method based on the measurement of amplitude difference (ΔP) within ratio spectra; ΔP (240-260 nm) was directly related to ATO concentration, and ΔP (262-240 nm) was directly related to OLM concentration. Method IV depended on the absorbance ratio method in which the wavelength at the iso-absorptive point (λISP) and the maximum absorbance wavelength (λmax), 277 and 255.5 nm, respectively, were used to calculate OLM concentration, while ATO concentration was determined from the zero-order UV spectra at 300 nm. Method V utilized a dual wavelength (DW) technique where ΔA between 247.5 and 262 nm was directly related to ATO concentration, and ΔA between 216 and 238 nm was directly related to OLM concentration.
RESULTS
The results of the assays indicated good mean % recovery ± SD as well as good agreement with the reported method.
CONCLUSION
Five simple and rapid spectrophotometric methods were developed, validated, and successfully applied for simultaneous estimation of ATO and OLM tablets.
HIGHLIGHTS
None of the developed methods has previously been reported for simultaneous determination of ATO and OLM.
Topics: Atorvastatin; Drug Compounding; Olmesartan Medoxomil; Spectrophotometry; Tablets
PubMed: 34850012
DOI: 10.1093/jaoacint/qsab151 -
Pharmaceutical Research May 2024Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human...
PURPOSE
Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1.
METHODS
Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry.
RESULTS
Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration-time curve of olmesartan to 76.9%.
CONCLUSION
Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.
Topics: Animals; Humans; Intestinal Absorption; Olmesartan Medoxomil; Prodrugs; HEK293 Cells; Tetrazoles; Organic Anion Transporters; Male; Imidazoles; Rats; Rats, Sprague-Dawley; Jejunum; Angiotensin II Type 1 Receptor Blockers; Permeability; Caco-2 Cells
PubMed: 38485855
DOI: 10.1007/s11095-024-03687-1 -
AAPS PharmSciTech Sep 2020Olmesartan medoxomil (OLM) an antihypertensive molecule with poor solubility and poor bioavailability (26% when taken orally) was selected as a model drug. Herein,...
Olmesartan medoxomil (OLM) an antihypertensive molecule with poor solubility and poor bioavailability (26% when taken orally) was selected as a model drug. Herein, rationale development of amorphous solid dispersion with hot-melt extrusion of poorly bioavailable OLM was carried out with the aid of quality by design (QbD), in-silico, in-vitro, and in-vivo evaluations. Polymer selection commenced with the selection of thermoplastic water-soluble polymers with the compatible processing temperature window as per the thermal behavior of OLM. Molecular dynamics (MD) simulations as well assisted in the selection of a carrier. Promising dissolution enhancement was observed with the help of Kollidon VA-64 (VA-64) as a carrier. Optimization of the formulation was executed using the QbD approach with design of experiment as a statistical optimization tool. Interactions between VA-64 and OLM on the atomic level were studied with the help of atomistic MD simulations. Characterization of the optimized extrudates were carried out with scanning electron microscopy, atomic force microscopy, differential scanning calorimetry, thermogravimetric analysis, Fourier transforms infrared spectroscopy, powder X-ray diffraction, in-vitro dissolution study, and in-vivo pharmacokinetic studies. Molecular-level mixing of OLM with VA-64 resulted into glass solution formation which rapidly dissolves (28 times in-vitro dissolution enhancement) in GI tract fluids and instantly gets absorbed into blood circulation. In-vivo pharmacokinetic studies performed in Sprague-Dawley rats reflected superior bioavailability (201.60%) with a significant increase in the C with short T through amorphization of OLM. The in-silico results were in agreement with the observed results of in-vitro dissolution studies and in-vivo pharmacokinetic study.
Topics: Administration, Oral; Animals; Antihypertensive Agents; Biological Availability; Calorimetry, Differential Scanning; Computer Simulation; Hot Melt Extrusion Technology; In Vitro Techniques; Olmesartan Medoxomil; Rats; Rats, Sprague-Dawley; Solubility; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction
PubMed: 32888102
DOI: 10.1208/s12249-020-01780-3 -
Pharmaceutical Development and... Jul 2022Hexadecane membrane-parallel artificial membrane permeability assay (HDM-PAMPA) is based on an artificial HDM that separates the two compartments (donor and acceptor...
Hexadecane membrane-parallel artificial membrane permeability assay (HDM-PAMPA) is based on an artificial HDM that separates the two compartments (donor and acceptor compartment). This model is used to predict the permeability of drugs in gastrointestinal tract and to simulate the passive absorption. behavior of the drugs can be estimated with these systems in drug development studies. In our study, we optimized HDM-PAMPA model to determine permeability of olmesartan medoxomil (OM) lipid based drug delivery system (OM-LBDDS). In order to prove that LBDDS formulation facilitates the weak permeability of OM, permeation rates were compared with the OM suspension formula (containing 0.25% carboxymethylcellulose). The experiment was performed on a 96-well MultiScreen® PAMPA filter plate (MAIPN4510). The permeability of olmesartan formulations from the donor to acceptor compartment separated by a HDM membrane were determined by the previous validated HPLC method. We created positive control series without coating HDM to present the LBDDS and suspension formulation permeability from uncoated plates. The effective permeability constant () was calculated by the formula and improvement of permeability of OM-LBDDS formulation from HDM was confirmed. On the contrary there was no permeation of OM-Suspension in the hexadecane coated plates. As a result, the intestinal permeability of OM-LBDDS was calculated to be at least 100 times more than the suspension. OM-Suspension permeation was only observed in the hexadecane uncoated positive control plates. This was also manifestation of HDM-PAMPA mimicking permeability of intestines because of its lipidic construction.
Topics: Alkanes; Carboxymethylcellulose Sodium; Lipids; Membranes, Artificial; Olmesartan Medoxomil; Permeability; Suspensions
PubMed: 35972198
DOI: 10.1080/10837450.2022.2114495 -
Computational and Mathematical Methods... 2021Ischemic stroke combined with hypertension can increase risks of stroke recurrence and death.
The Clinical Efficacy of Clopidogrel Bisulfate Tablets Combined with Olmesartan Medoxomil for Ischemic Stroke with Hypertension and the Effect of Angiotensin II Type 1 Receptor Level on Prognosis.
BACKGROUND
Ischemic stroke combined with hypertension can increase risks of stroke recurrence and death.
AIM
The aim of this study is to investigate the clinical efficacy of clopidogrel bisulfate tablets combined with olmesartan medoxomil in the treatment of ischemic stroke patients with hypertension and the effect of angiotensin II type 1 receptor (ATR) level on prognosis.
METHODS
Ninety ischemic stroke patients with hypertension were chosen for continuous treatment with clopidogrel bisulfate tablets and olmesartan medoxomil for 12 months. The Modified Edinburgh Scandinavian Stroke Scale (MESSS) score, Brunnstrom score, Barthel score, death, recurrence, and progression of cerebrovascular residual lesions were observed and recorded during the treatment period. According to the plasma ATR expression of the patients before treatment, the patients were divided into a high-ATR group and low-ATR group. Then, survival analysis was performed.
RESULTS
Compared with pretreatment, the MESSS scores of the patients at the first, second, third, sixth, ninth, and twelfth months after treatment were reduced ( < 0.01) while the Brunnstrom score and Barthel score were prominently boosted ( < 0.01). Compared with the low-ATR group, patients in the high-ATR group had higher rates of stroke recurrence and progression of residual cerebrovascular lesions ( < 0.05).
CONCLUSION
Clopidogrel bisulfate tablets combined with olmesartan medoxomil has prominent clinical effects in the treatment of ischemic stroke patients with hypertension, evidently improving the prognosis. In addition, the level of ATR may be a vital factor affecting the prognosis.
Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Clopidogrel; Computational Biology; Drug Therapy, Combination; Female; Humans; Hypertension; Ischemic Stroke; Male; Middle Aged; Olmesartan Medoxomil; Platelet Aggregation Inhibitors; Prognosis; Receptor, Angiotensin, Type 1; Treatment Outcome
PubMed: 34745325
DOI: 10.1155/2021/4487393