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International Journal of Pharmaceutics Nov 2022Nasal drug delivery has the potential to improve the systemic bioavailability of drugs with low oral bioavailability. Olmesartan medoxomil (OLM) is one of the most...
Nasal drug delivery has the potential to improve the systemic bioavailability of drugs with low oral bioavailability. Olmesartan medoxomil (OLM) is one of the most popular drugs for the treatment of hypertension with poor oral bioavailability of approximately 26 %. In this context, the goal of this work was to synthesize chitosan nanoparticles (CS NPs) loaded with OLM using the ionotropic gelation method to enhance the bioavailability and decrease oral side effects through nasal route. The particle size (PS), zeta potential (ZP), entrapment efficiency (%EE), and ex-vivo transmucosal permeation study of CS NPs were all evaluated. The pharmacokinetic and pharmacodynamic studies of selected formula compared to oral and nasal OLM suspensions were conducted. Successful formation of spherically shaped OLM CS NPS in the nano-range (240.02-344.45 nm) favorable for the intranasal absorption with high %EE (75.2-83.51 %) was achieved. The ability of OLM CS NPs to permeate efficiently across the nasal mucosa was proven in an ex vivo permeation experiment. Pharmacokinetic study demonstrated that the intranasal administration of OLM CS NPs exhibited improved bioavailability by 11.3-folds relative to oral OLM suspension as indicated by higher AUC value. The superior effect of intranasal OLM CS NPs was also accentuated in l-NAME induced hypertensive rats compared to intranasal and oral OLM suspension by reducing the high blood pressure (BP) and improving the heart rate (HR) of the induced group. Histological examinations revealed no damage occurred to nasal mucosa. In conclusion, OLM CS NPs had the ability to significantly improve the bioavailability of OLM and decrease BP and HR, suggesting the potential application of CS NPs as a promising carrier for the systemic delivery of OLM via intranasal route.
Topics: Animals; Rats; Olmesartan Medoxomil; Chitosan; Administration, Intranasal; Nanoparticles; Biological Availability; Particle Size; Drug Carriers
PubMed: 36243325
DOI: 10.1016/j.ijpharm.2022.122278 -
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 -
The Journal of Surgical Research Nov 2022Sepsis and related complications lead to high morbidity and mortality in humans and animals. Olmesartan medoxomil (OLM), a nonpeptide angiotensin II type 1 receptor...
INTRODUCTION
Sepsis and related complications lead to high morbidity and mortality in humans and animals. Olmesartan medoxomil (OLM), a nonpeptide angiotensin II type 1 receptor blocker, has antiinflammatory and antioxidative effects in various experimental animal models. The present study aimed to investigate whether OLM protects against sepsis in a clinically relevant model of polymicrobial sepsis induced by cecal ligation and puncture (CLP).
METHODS
Sepsis was induced by CLP in anesthetized rats. OLM was administered intraperitoneally 3 h after CLP onset. Hemodynamic, biochemical, and inflammatory parameters were analyzed.
RESULTS
The administration of OLM in CLP rats significantly improved their survival rate. Moreover, OLM mitigated CLP-induced hypotension and organ injury (indicated by biochemical parameters), but not tachycardia. OLM significantly reduced the plasma levels of interleukin-6 and nitric oxide.
CONCLUSIONS
OLM markedly attenuated CLP-induced hypotension and organ injury, and hence improved survival by inhibiting the inflammatory response and nitrosative stress in this clinically relevant model of sepsis.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Cecum; Disease Models, Animal; Humans; Imidazoles; Interleukin-6; Nitric Oxide; Olmesartan Medoxomil; Peritonitis; Rats; Rats, Wistar; Sepsis; Tetrazoles
PubMed: 35868036
DOI: 10.1016/j.jss.2022.05.034 -
Drug Delivery Dec 2022Olmesartan medoxomil (OM) is an angiotensin receptor blocker. This study aimed to investigate the effects of OM self-microemulsifying drug delivery system (OMS) in...
Olmesartan medoxomil (OM) is an angiotensin receptor blocker. This study aimed to investigate the effects of OM self-microemulsifying drug delivery system (OMS) in trinitrobenzene sulfonic acid (TNBS)-induced acute colitis in rats. Besides two control groups, five TNBS-colitic-treated groups ( = 8) were given orally sulfasalazine (100 mg/kg/day), low and high doses of OM (3.0 and 10.0 mg/kg/day) (OML and OMH) and of OMS (OMSL and OMSH) for seven days. A colitis activity score was calculated. The colon was examined macroscopically. Colonic levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, and reduced glutathione were measured. Plasma and colonic olmesartan levels were measured. Colonic sections were subjected to hematoxylin and eosin staining and immunohistochemical staining for E-cadherin, caspase-3, and matrix metalloproteinase-9 (MMP-9). Protein expression of E-cadherin, Bcl-2 associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 by Western blot was done. TNBS-colitic rats showed increased colonic myeloperoxidase, TNF-α, IL-6, and malondialdehyde, decreased colonic glutathione, histopathological, immunohistochemical, and protein expression alterations. OMS, compared with OM, dose-dependently achieved higher colonic free olmesartan concentration, showed better anti-inflammatory, antioxidant, and anti-apoptotic effects, improved intestinal barrier, and decreased mucolytic activity. OMS more effectively up-regulated the reduced Bcl-2, Bcl-2/Bax ratio, and E-cadherin expression, and down-regulated the overexpressed Bax, cleaved caspase-3, and MMP-9. OMSL exerted effects comparable to OMH. Sulfasalazine exerted maximal colonic protective effects and almost completely reversed colonic damage, and OMSH showed nearly similar effects with non-significant differences in-between or compared with the normal control group. In conclusion, OMS could be a potential additive treatment for Crohn's disease colitis.
Topics: Animals; Apoptosis; Cadherins; Caspase 3; Cell Adhesion; Colitis; Crohn Disease; Drug Delivery Systems; Interleukin-6; Malondialdehyde; Matrix Metalloproteinase 9; Olmesartan Medoxomil; Peroxidase; Rats; Sulfasalazine; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; bcl-2-Associated X Protein
PubMed: 35766160
DOI: 10.1080/10717544.2022.2086939 -
European Journal of Pharmacology Aug 2022Diabetic nephropathy (DN) is one of the most serious consequences of diabetes and the most common reason for end-stage renal disease. The current study was set out to...
Diabetic nephropathy (DN) is one of the most serious consequences of diabetes and the most common reason for end-stage renal disease. The current study was set out to investigate the ability of olmesartan medoxomil (OM) to treat DN by evaluating the reno-protective effects of this drug on fat/fructose/streptozotocin (F/Fr/STZ)-induced diabetic rat model. This model was induced by feeding rats high F/Fr diet for 7 weeks followed by injection of a single sub-diabetogenic dose of STZ (35mg/kg; i.p). The F/Fr/STZ-induced diabetic rats were orally treated with either OM (10 mg/kg) or pioglitazone (10 mg/kg); as a standard drug daily for four consecutive weeks. F/Fr/STZ-induced diabetic rats propagated inflammatory, oxidative, and fibrotic events. OM was able to oppose the injurious effects of diabetes; it significantly reduced the elevated levels of advanced glycated end products (AGEs) and downregulated PKC gene expression, therefore, indicating its antioxidant capacity evidenced by mitigation in GSH, MDA renal content. Moreover, OM impaired the inflammatory cascade by suppressing the elevated level of renal TLR4 as well as diminished the inflammatory profibrotic cytokine TGF-β1. Additionally, OM was able to turn off the MAPK cascade mediated by an upsurge in renal angiotensin 1-7 content and decrease the level of renal tubular injury marker, KIM-1. Furthermore, OM enhanced the autophagic activity pathway by upregulating of gene expression of SIRT-1. The histopathological examination confirmed these results. Finally, OM protected against type 2 diabetes-related nephropathy complications by altering inflammatory pathways, oxidative, fibrotic, and autophagic processes triggered by renal glucose overload. This study shows that OM has a reno-protective effect against DN in rats by inhibiting the AGE/PKC, TLR4/P38-MAPK, and SIRT-1 autophagic signaling pathways.
Topics: Animals; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fructose; Imidazoles; Kidney; Oxidative Stress; Rats; Signal Transduction; Sirtuins; Streptozocin; Tetrazoles; Toll-Like Receptor 4; p38 Mitogen-Activated Protein Kinases
PubMed: 35752350
DOI: 10.1016/j.ejphar.2022.175117 -
Environmental Microbiology Reports Oct 2022Hexavalent chromium resistance and reduction mechanisms of microorganism provide a critical guidance for Cr(VI) bioremediation. However, related researches are limited...
Exploration on the Cr(VI) resistance mechanism of a novel thermophilic Cr(VI)-reducing bacteria Anoxybacillus flavithermus ABF1 isolated from Tengchong geothermal region, China.
Hexavalent chromium resistance and reduction mechanisms of microorganism provide a critical guidance for Cr(VI) bioremediation. However, related researches are limited in mesophiles and deficient for thermophiles. In this work, a novel alkaline Cr(VI)-reducing thermophile Anoxybacillus flavithermus ABF1 was isolated from geothermal region. The mechanisms of Cr(VI) resistance and reduction were investigated. The results demonstrated that A. flavithermus ABF1 could survive in a wide temperature range from 50°C to 70°C and in pH range of 7.0-9.0. Strain ABF1 showed excellent growth activity and Cr(VI) removal performance when initial Cr(VI) concentration was lower than 200 mg L . 93.71% of Cr(VI) was removed at initial concentration of 20 mg L after 72 h. The majority of Cr(VI) was found to be reduced extracellularly by enzymes secreted by cells. XPS and Raman analysis further manifested that Cr O was the product of Cr(VI) reduction. Moreover, the Cr(VI) transportation-related gene cysP and Cr(VI) reduction-related gene azoR of A. flavithermus ABF1 played key roles in inhibiting Cr(VI) entering cells and promoting extracellular Cr(VI) reduction respectively. This work provides novel insight into the mechanisms of Cr(VI) resistance and detoxication of thermophiles, which leads to a promising alternative strategy for heavy metal bioremediation in areas with elevated temperature.
Topics: Amlodipine Besylate, Olmesartan Medoxomil Drug Combination; Anoxybacillus; Bacteria; Biodegradation, Environmental; Chromium; Metals, Heavy; Oxidation-Reduction
PubMed: 35701897
DOI: 10.1111/1758-2229.13070 -
Medicine Apr 2022Diabetic nephropathy (DN) is a common microvascular complication of diabetes, which poses a serious threat to the health and life of patients. There is evidence that...
Effects of α lipoic acid combined with olmesartan medoxomil on blood glucose and oxidation indicators in patients with diabetic nephropathy: A protocol for a parallel, randomized, double-blind, controlled clinical trial.
BACKGROUND
Diabetic nephropathy (DN) is a common microvascular complication of diabetes, which poses a serious threat to the health and life of patients. There is evidence that both α lipoic acid and olmesartan medoxomil have positive effects in the treatment of DN, but whether the 2 have synergistic effects and the effects on blood glucose and oxidation indicators are controversial.
METHODS
This is a prospective parallel, randomized, double-blind, placebo-controlled trial to study the effects of α lipoic acid in combination with olmesartan medoxomil on blood glucose and oxidation indicators in patients with DN. Participants will be randomly assigned to a treatment group, which will receive α lipoic acid dispersive tablets combined with olmesartan medoxomil tablets, or a control group, which will receive olmesartan medoxomil tablets combined with placebo for 4 weeks, followed up for 12 weeks. Observation indicators include: glycemic indicators [fasting blood glucose, 2 hours postprandial blood glucose and glycosylated hemoglobin], the oxidation indicators [serum glutathione, superoxide dismutase, malondialdehyde, 8-hydroxydeox-yguanosine], and adverse reactions. Finally, SPASS 22.0 software will be used for statistical analysis of the data.
DISCUSSION
This study will evaluate the effects of α lipoic acid combined with olmesartan medoxomil on blood glucose and oxidation indicators in patients with DN. The results of this study will provide a reference for the clinical use of α lipoic acid combined with olmesartan medoxomil in the treatment of DN.
TRIAL REGISTRATION
OSF Registration number: DOI 10.17605/OSF.IO/VJWXS.
Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Glucose; Blood Pressure; Diabetes Mellitus; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Hypertension; Imidazoles; Male; Olmesartan Medoxomil; Prospective Studies; Randomized Controlled Trials as Topic; Tetrazoles; Thioctic Acid
PubMed: 35512068
DOI: 10.1097/MD.0000000000029080 -
Biophysical Chemistry Jul 2022Microbial decolorization of azo dyes, mediated by an enzymatic mechanism is an intricate cost-effective, and eco-friendly treatment method of genotoxic azo pollutants....
Microbial decolorization of azo dyes, mediated by an enzymatic mechanism is an intricate cost-effective, and eco-friendly treatment method of genotoxic azo pollutants. Scientists are on the constant lookout for microbes, enzymes, and mechanisms that could aid remediation of the environment at a fast pace. Alcaligenes faecalis subsp. phenolicus MB207 is one such bacteria, consisting of azoreductase (AzoR) and laccase/multicopper oxidase enzyme responsible for sulphonated mono-azo dye (Methyl orange) and di-azo dye (Congo red) degradation. AzoR degrades dyes by a ping-pong setup while multicopper oxidase achieves this through a non-specified radical approach. We have coupled experimental analysis with bioinformatics for deciphering intricacies of this procedure in tiny scale enzymatic machines of this biotope. The degradation assays were followed by molecular docking of the enzyme-substrate complexes. Key anchoring bonds were detected and mapped H-bonding, electron exchange, ionic interactions, as well as hydrophobic interactions, provided insights into dye-enzyme and NADH-enzyme binding. This study establishes a foundation of the molecular basis of dye interaction with azoR and multicopper oxidase in A. facealis subsp. phenolicus MB207.
Topics: Alcaligenes; Amlodipine Besylate, Olmesartan Medoxomil Drug Combination; Azo Compounds; Biodegradation, Environmental; Coloring Agents; Molecular Docking Simulation
PubMed: 35397247
DOI: 10.1016/j.bpc.2022.106806 -
Journal of Mass Spectrometry : JMS Apr 2022Two unknown solution degradants were found during the dissolution testing in 0.1-M HCl for olmesartan medoxomil (OLM) tablets. The structure of the degradants was...
Two unknown solution degradants were found during the dissolution testing in 0.1-M HCl for olmesartan medoxomil (OLM) tablets. The structure of the degradants was identified and characterized by liquid chromatography-ultraviolet (LC-UV), liquid chromatography with tandem mass spectrometry (LC-MS/MS), and nuclear magnetic resonance (NMR) and demonstrated to be cyclization of tetrazole and benzene in the olmesartan (OL) and OLM structures. A series of studies including stress studies, simulation studies, and mechanism-based studies were performed to reveal the potential mechanisms that lead to the formation of the unknown degradants. The study results demonstrated that the degradation was catalyzed with radicals that originated from the metal ions leached from the inner surface of high-performance liquid chromatography (HPLC) glass vials with dissolved oxygen under acidic condition. Prerinsing the glass vials with acidic solution dissolved with EDTA can effectively avoid the generation of such oxidative impurities. The present work provides new insights into the understanding of degradation pathways of OLM, which might support the development of OLM tablets.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Ions; Olmesartan Medoxomil; Tandem Mass Spectrometry
PubMed: 35347807
DOI: 10.1002/jms.4821 -
Clinical Pharmacology in Drug... Jun 2022Combined antihypertensive drugs have become the basic method of treating hypertension. Olmesartan and amlodipine, as representative drugs of angiotensin receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetics and Bioequivalence Evaluation of 2 Olmesartan Medoxomil and Amlodipine Besylate Fixed-Dose Combination Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions.
Combined antihypertensive drugs have become the basic method of treating hypertension. Olmesartan and amlodipine, as representative drugs of angiotensin receptor blockers and calcium channel blockers, were developed as a compound formulation for antihypertensive treatment. The purpose of this study was to evaluate the bioequivalence of olmesartan medoxomil/amlodipine besylate tablet (20 mg/5 mg) under fasting and fed conditions in healthy Chinese volunteers. A phase 1 randomized, open-label, 2-period, single-dose crossover study (n = 56) was designed, with subjects under fasting (n = 28) or fed (n = 28) conditions. Of the 56 enrolled participants, 55 healthy volunteers completed the study. Blood samples for pharmacokinetic analysis were collected from 1.5 hours before dosing to 168 hours after dosing. The 90%CIs for the geometric mean ratios of maximum plasma drug concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration and AUC from time 0 to infinity of the test/reference were all within the acceptance range for bioequivalence (80%-125%). The data showed that the absorption of amlodipine is not affected by food, but the exposure of olmesartan (both AUC from time 0 to the last measurable concentration and AUC from time 0 to infinity were P < .05) reduced significantly after consuming a high-fat meal, which indicates that the effects of food on olmesartan exposure in healthy Chinese were clinically relevant. During the study, there were no suspected serious adverse reactions or serious adverse events. All adverse events were determined to be mild after Common Terminology Criteria for Adverse Events 5.0 evaluation. These results indicated that both the test and reference formulations were bioequivalent with similar safety profiles.
Topics: Amlodipine; Antihypertensive Agents; China; Cross-Over Studies; Fasting; Healthy Volunteers; Humans; Olmesartan Medoxomil; Tablets; Therapeutic Equivalency
PubMed: 35289500
DOI: 10.1002/cpdd.1086