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International Journal of Nanomedicine 2019Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho somes...
INTRODUCTION AND AIM
Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho somes (TEs) for enhancing the transdermal delivery of OLM to avoid its oral problems.
METHODS
TE formulae were prepared utilizing 51.31 full factorial design using various surfactants (SAAs) and different phospholipid-to-SAA ratios. The formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and the amount of drug released after 6 hours (Q6h). Design Expert software was employed to select the optimum formula.
RESULTS
The optimum formula (TE14) had an EE% of 58.50%±1.30%, PS of 222.60±2.50 nm, PDI of 0.11±0.06, ZP of -20.80±0.30 mV, and Q6h of 67.40%±0.20%. In addition, TE14 was compared to transferosomes (TFs) in terms of elasticity and was found to show higher deformability index. Further, evaluation of ex vivo permeation using both rat and shed snake skin showed higher permeability of TE14 compared to TFs and OLM suspension. Confocal laser scanning microscopy confirmed the capability of the fluorolabeled TE14 to penetrate deep within the skin, while the histopathological study confirmed its safety. TE14 successfully maintained normal blood pressure values of rats up to 24 hours. Moreover, TE14 showed superiority in dermatokinetic study when compared with drug suspension.
CONCLUSION
Taken together, the obtained results confirmed the potential of employing TEs as a successful carrier for the transdermal delivery of OLM.
Topics: Administration, Cutaneous; Animals; Antihypertensive Agents; Blood Pressure; Calorimetry, Differential Scanning; Drug Delivery Systems; Drug Stability; Elasticity; Factor Analysis, Statistical; Liposomes; Male; Methylprednisolone; Olmesartan Medoxomil; Rats, Wistar; Skin; Snakes
PubMed: 30936696
DOI: 10.2147/IJN.S196771 -
Current Therapeutic Research, Clinical... Dec 2014Olmesartan is an angiotensin II receptor antagonist and is effective and well tolerated in the treatment of arterial hypertension. Probenecid is a well-established...
BACKGROUND
Olmesartan is an angiotensin II receptor antagonist and is effective and well tolerated in the treatment of arterial hypertension. Probenecid is a well-established hypouricemic agent for the treatment of hyperuricemia and gout.
OBJECTIVE
The goal of this study was to examine the impact of coadministration of probenecid on the pharmacokinetic parameters and tolerability of olmesartan in healthy volunteers.
METHODS
In a randomized, open-label, 2-way crossover study, 12 volunteers received 2 oral treatments (olmesartan alone or olmesartan plus probenecid) separated by 4 days. Blood samples were obtained for a 48-hour pharmacokinetic evaluation after drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests before and after administration of the study drug.
RESULTS
Pharmacokinetic parameters were evaluated in 6 male and 6 female healthy volunteers (mean age, 22 [range, 20-25] years]; weight, 56.0 [range, 51.0-60.0] kg). Probenecid coadministration increased olmesartan Css-av, AUC0→∞, and AUC0-48 by 40%, 50%, and 50%, respectively (P = 0.018, 0.000, 0.000, respectively), but there was no statistical significance for Tmax, t1/2, Css-max, and Css-min between olmesartan plus probenecid and olmesartan alone (P = 0.697, 0.053, 0.521, and 0.734, respectively). No serious adverse event (AE) was reported during the study. The proportion of volunteers with AEs in the olmesartan plus probenecid period (5 of 12 [42%]) was higher than that in the olmesartan-alone period (1 of 12 [8%]). All of the AEs during the olmesartan plus probenecid period were abnormal routine urine test results. The AE in olmesartan-alone period was dizziness. All AEs were classified as mild and considered to be at least possibly related to treatment. All volunteers recovered from the AEs by 2 weeks after the end of the study.
CONCLUSIONS
Probenecid increases the exposure speed of olmesartan by increasing the AUC0-48, AUC0→∞, and Css-av. The combined treatment of olmesartan medoxomil with probenecid may increase the occurrence of genitourinary side effects. ClinicalTrials.gov identifier: NCT01907373.
PubMed: 25067982
DOI: 10.1016/j.curtheres.2013.11.004 -
Journal of the... Dec 2015The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase...
The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling.
HYPOTHESIS/INTRODUCTION
The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22(phox) reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity.
MATERIALS AND METHODS
The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment.
RESULTS
Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001.
CONCLUSIONS
These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials.
Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Cardiovascular System; Densitometry; Diastole; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Myosin-Light-Chain Phosphatase; Olmesartan Medoxomil; Phosphorylation; Receptor, Angiotensin, Type 1; Rho Guanine Nucleotide Exchange Factors; Systole; rho-Associated Kinases; rhoA GTP-Binding Protein
PubMed: 26240115
DOI: 10.1177/1470320315594324 -
International Journal of Molecular... Oct 2022A worldwide crisis with nitrosamine contamination in medical products began in 2018. Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of...
A worldwide crisis with nitrosamine contamination in medical products began in 2018. Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field of quality control. A novel GC-MS method with electron ionization and microextraction was developed and validated for simultaneous determination of nine carcinogenic nitrosamines (NDMA, NMEA, NDEA, NDBA, NMOR, NPYR, NPIP, NDPA, and -methyl-npz) in active pharmaceutical ingredients (APIs): cilostazol, sunitinib malate, and olmesartan medoxomil. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, demonstrating good linearity in the range of LOQ up to 21.6 ng/mL (120% of specification limit). The limits of detection for the nine nitrosamines were determined to be in the range 0.15-1.00 ng/mL. The developed trace level GC-MS method turned out to be specific, accurate, and precise. The accuracy of all the tested APIs ranged from 94.09% to 111.22% and the precision evaluated by repeatability, intermediate precision, and system precision was RSD ≤ 7.65%. Nitrosamines were not detected in cilostazol and sunitinib, whereas in olmesartan medoxomil NDEA was detected at the level of LOQ. The novel protocol was successfully applied for nitrosamines determination in selected APIs and can be used for the routine quality control of APIs under Good Manufacturing Practices rules, ensuring the safety and effectiveness of pharmaceutical products.
Topics: Humans; Nitrosamines; Gas Chromatography-Mass Spectrometry; Sunitinib; Cilostazol; Tandem Mass Spectrometry; DNA Damage; Olmesartan Medoxomil; Pharmaceutical Preparations
PubMed: 36292981
DOI: 10.3390/ijms232012125 -
Journal of Hypertension Apr 2018Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD). (Comparative Study)
Comparative Study Randomized Controlled Trial
A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension.
BACKGROUND
Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD).
OBJECTIVE/METHODS
We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160-190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured.
RESULTS
Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (-37.6 and -38.2 mmHg) versus OLM/HCTZ (-31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (-26.4 and -27.9 versus -20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively.
CONCLUSION
This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ.
Topics: Aged; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Chlorthalidone; Diuretics; Double-Blind Method; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Male; Middle Aged; Oxadiazoles; Tetrazoles
PubMed: 29334491
DOI: 10.1097/HJH.0000000000001647 -
Biological & Pharmaceutical Bulletin 2016The objective of this study was to study the effect of olmesartan medoxomil (OLM), an antihypertensive drug, on intra-articular inflammation induced by zymosan (Zy) in...
The objective of this study was to study the effect of olmesartan medoxomil (OLM), an antihypertensive drug, on intra-articular inflammation induced by zymosan (Zy) in Wistar rats. Intra-articular inflammation was induced in the right knees of rats by 1 mg Zy dissolved in saline. The animals were divided into the following groups: saline only (oral saline and intra-articular saline); Zy only (intra-articular Zy and oral saline), and intra-articular Zy and oral OLM (5, 15, or 30 mg/kg) or diclofenac sodium (SD; 100 mg/kg). Twenty-four hours after Zy injection, synovial fluid was collected for total leukocyte counts, blood was collected for biochemical measurements, and synovial tissue was collected for histopathology, immunohistochemistry, immunofluorescence and myeloperoxidase (MPO), malonaldehyde (MDA), and non-protein sulphydryl (NPSH) assays. OLM doses of 15 and 30 mg/kg had protective effects, as evidenced by improved histopathological parameters of synovium, reduced total leukocyte counts, reduced MPO and MDA levels, and increased NPSH group levels compared with the Zy group. OLM reduced immunostaining for cyclooxygenase 2, tumour necrosis factor and interleukin 17 and increased immunostaining for superoxide dismutase and glutathione peroxidase. SD produced similar results. The drugs studied caused no change in biochemical parameters of the animals. OLM showed protective effects in this model of Zy-induced intra-articular inflammation.
Topics: Alanine Transaminase; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Arthritis, Experimental; Aspartate Aminotransferases; Creatinine; Cyclooxygenase 2; Glutathione; Glutathione Peroxidase; Imidazoles; Interleukin-17; Leukocyte Count; Male; Malondialdehyde; Peroxidase; Rats, Wistar; Superoxide Dismutase; Synovial Membrane; Tetrazoles; Tumor Necrosis Factor-alpha; Urea; Zymosan
PubMed: 27803450
DOI: 10.1248/bpb.b16-00296 -
Journal of Hypertension Apr 2016Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent ARB for the treatment of stages 1-2 hypertension. We compared the efficacy, safety, and metabolic effects of AZL-M to both valsartan (VAL) and olmesartan (OLM), separately in patients with impaired fasting glucose (prediabetes mellitus) and T2DM.
METHODS
A pooled analysis of 3821 patients from three separate randomized placebo-controlled trials comparing the effects of AZL-M (40 and 80 mg), OLM (40 mg), VAL (320 mg), and placebo on changes in ambulatory and clinic blood pressure (BP) among patients with hypertension and prediabetes mellitus or T2DM was performed. Two analysis pools were created to facilitate comparisons: Pool A included patients who received placebo, AZL-M or OLM and Pool B included those who received AZL-M or VAL. Within each pool, patients were stratified by glycemic subgroups (normoglycemic, prediabetes mellitus, or T2DM) based on hemoglobin A1c values. Changes from baseline in both 24-h and clinic SBP were the primary efficacy assessments.
RESULTS
Baseline 24-h mean SBPs were approximately 145 and 146 mmHg in the prediabetes mellitus and T2DM subgroups, respectively; corresponding clinic SBPs were approximately 158 and 159 mmHg. Baseline hemoglobin A1c values for each subgroup (both pools) were normoglycemic, 5.3%; prediabetes mellitus, 6.0%; and T2DM, 6.9%. Changes from baseline in 24-h or clinic SBP were significantly greater with AZL-M, 80 mg compared with either OLM 40 mg or VAL 320 mg in all subgroups in each pool. Safety and tolerability were similar among the active treatment and placebo subgroups.
CONCLUSION
These analyses indicate that AZL-M, 80 mg/day lowers SBP by a greater magnitude than OLM or VAL at maximally approved doses in patients with prediabetes mellitus and T2DM. These findings have important clinical implications for this high-risk patient group.
Topics: Adult; Aged; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Imidazoles; Male; Middle Aged; Oxadiazoles; Prediabetic State; Tetrazoles; Valsartan
PubMed: 26766564
DOI: 10.1097/HJH.0000000000000839 -
Pharmaceutics Jun 2016The main purpose of this study was to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of Olmesartan (OLM) for enhancement of its solubility and...
Novel Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Oral Delivery of Olmesartan Medoxomil: Design, Formulation, Pharmacokinetic and Bioavailability Evaluation.
The main purpose of this study was to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of Olmesartan (OLM) for enhancement of its solubility and dissolution rate. In this study, liquid SNEDDS containing Olmesartan was formulated and further developed into a solid form by the spray drying technique using Aerosil 200 as a solid carrier. Based on the preliminary screening of different unloaded SNEDDS formulae, eight formulae of OLM loaded SNEEDS were prepared using Capryol 90, Cremophor RH40 and Transcutol HP as oil, surfactant and cosurfactant, respectively. Results showed that the mean droplet size of all reconstituted SNEDDS was found to be in the nanometric range (14.91-22.97 nm) with optimum PDI values (0.036-0.241). All formulae also showed rapid emulsification time (15.46 ± 1.34-24.17 ± 1.47 s), good optical clarity (98.33% ± 0.16%-99.87% ± 0.31%) and high drug loading efficiency (96.41% ± 1.20%-99.65% ± 1.11%). TEM analysis revealed the formation of spherical and homogeneous droplets with a size smaller than 50 nm. In vitro release of OLM from SNEDDS formulae showed that more than 90% of OLM released in approximately 90 min. Optimized SNEDDS formulae were selected to be developed into S-SNEDDS using the spray drying technique. The prepared S-SNEDDS formulae were evaluated for flow properties, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), reconstitution properties, drug content and in vitro dissolution study. It was found that S-SNEDDS formulae showed good flow properties and high drug content. Reconstitution properties of S-SNEDDS showed spontaneous self-nanoemulsification and no sign of phase separation. DSC thermograms revealed that OLM was in solubilized form and FTIR supported these findings. SEM photographs showed smooth uniform surface of S-SNEDDS with less aggregation. Results of the in vitro drug release showed that there was great enhancement in the dissolution rate of OLM. To clarify the possible improvement in pharmacokinetic behavior of OLM S-SNEDDS, plasma concentration-time curve profiles of OLM after the oral administration of optimized S-SNEDDS formula (F3) were compared to marketed product and pure drug in suspension. At all time points, it was observed that OLM plasma concentrations in rats treated with S-SNEDDS were significantly higher than those treated with the drug in suspension and marketed product.
PubMed: 27355963
DOI: 10.3390/pharmaceutics8030020 -
Scientia Pharmaceutica 2015Drug product purity and potency are of most significance in the regulatory market as we notice many recalled batches worldwide, particularly in the US and Japan....
Drug product purity and potency are of most significance in the regulatory market as we notice many recalled batches worldwide, particularly in the US and Japan. Olmesartan Medoxomil is an anti-hypertensive drug. The present invention relates to a process for the preparation of Olmesartan Medoxomil with 99.9% purity in an overall 62% yield. The synthesis includes three isolations and one purification with easy plant operations. This process describes the formation and control of each individual impurity in all stages. This process for Olmesartan Medoxomil and its intermediates is competent for industrial production in very short reaction time intervals with an appreciable yield and high purity.
PubMed: 26839831
DOI: 10.3797/scipharm.1502-04 -
Annals of Gastroenterology 2017Sprue-like enteropathy associated with treatment with olmesartan medoxomil, an angiotensin II receptor blocker, has been described recently. Herein, we report two...
Sprue-like enteropathy associated with treatment with olmesartan medoxomil, an angiotensin II receptor blocker, has been described recently. Herein, we report two patients who developed chronic severe non-bloody diarrhea, weight loss, and muscle wasting after prolonged use of olmesartan. Histologic and immunohistochemical examination of multiple duodenal biopsies revealed severe villous atrophy. Clinical signs ceased upon drug discontinuation. Physicians should be aware of this enteropathy even if olmesartan has been taken for months or years. Whether this adverse event is specific for olmesartan or is a class effect of angiotensin II receptor blockers is currently unknown. To the best of our knowledge, these case reports are the first reported in Greece.
PubMed: 28042253
DOI: 10.20524/aog.2016.0052