Repositioning of Omarigliptin as a once-weekly intranasal Anti-parkinsonian Agent

Ayoub, Bassam M.; Mowaka, Shereen; Safar, Marwa M.; Ashoush, Nermeen; Arafa, Mona G.; Michel, Haidy E.; Tadros, Mariam M.; Elmazar, Mohamed M.; Mousa, Shaker A.

doi:10.1038/s41598-018-27395-0

Cited by 41 publications

(58 citation statements)

References 77 publications

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“…The diffusion cell method using PBS, pH 7.4, at 37±0.5°C was employed using a digital shaking water bath (WSB-18, Dahan Scientific Co. Ltd., Beijing, China). In brief, 3.3 g of each gel formula with the same amount of polymeric NPs entrapping AT and 3.3 mL drug dispersion F4 29 (equivalent to 10 mg AT) was spread on the membrane, and 1.5 mL of PBS was added to the F1, F2, and F3 tubes. For each sample, and at pre-set timepoints of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hrs, a certain volume was taken and substituted with equal volumes of newly prepared PBS at the same temperature.…”

Section: In Vitro Release Study Of At-plga-cs-nps and At-plga-cs-np Tmentioning

confidence: 99%

<p>Chitosan-Coated PLGA Nanoparticles for Enhanced Ocular Anti-Inflammatory Efficacy of Atorvastatin Calcium</p>

Arafa¹,

Girgis²,

El-Dahan³

2020

IJN

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Background: Atorvastatin calcium (AT) is an ocular anti-inflammatory with limited bioavailability when taken orally due to its low solubility in low pH and extensive first-pass effect. To overcome these problems, AT was entrapped in polymeric nanoparticles (NPs) to improve surface properties and sustained release, in addition to achieving site-specific action. Methods: AT was entrapped in chitosan (CS)-coated polylactic-co-glycolic acid (PLGA) NPs to form AT-PLGA-CS-NPs (F1). F1 and free AT were embedded in thermosensitive Pluronic ® 127-hydroxypropyl methylcellulose (HPMC) to form thermosensitive gels (F2) and (F3) while F4 is AT suspension in water. F1 was assessed for size, surface charge, polydispersity index (PDI), and morphology. F2 and F3 were examined for gelation temperature, gel strength, pH, and viscosity. In vitro release of the four formulations was also investigated. The ocular irritancy and anti-inflammatory efficacy of formulations against prostaglandin E 1-(PGE 1) induced ocular inflammation in rabbits were investigated by counting the polymorphonuclear leukocytes (PMNs) and protein migrated in tears. Results: Oval F1 of 80.0-190.0±21.6 nm exhibited a PDI of 0.331 and zeta potential of 17.4 ±5.62 mV with a positive surface charge. F2 and F3 gelation temperatures were 35.17±0.22°C and 36.93±0.31°C, viscosity 12,243±0.64 and 9759±0.22 cP, gel strength 15.56±0.6 and 12.45 ±0.1 s, and pHs of 7.4±0.02 and 7.4±0.1, respectively. In vitro release of F1, F2, F3, and F4 were 48.21±0.31, 26.48±0.5, 84.76±0.11, and 100% after 24 hrs, respectively. All formulations were non-irritant. F2 significantly inhibited lid closure up to 3 h, PMN counts and proteins in tear fluids up to 5 h compared to other formulations. Conclusion: AT-PLGA-CS-NP thermosensitive gels proved to be successful ocular antiinflammatory drug delivery systems.

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Section: In Vitro Release Study Of At-plga-cs-nps and At-plga-cs-np Tmentioning

confidence: 99%

<p>Chitosan-Coated PLGA Nanoparticles for Enhanced Ocular Anti-Inflammatory Efficacy of Atorvastatin Calcium</p>

Arafa¹,

Girgis²,

El-Dahan³

2020

IJN

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“…However, some glycemia-independent pleiotropic actions of DPP4 inhibitors including antioxidant and neurorestorative effects have been found [24]. Ayoub et al advocated repositioning omarigliptin as a weekly anti-parkinsonian agent because omarigliptin was the first gliptin to cross the blood brain barrier [25]. These findings suggest that omarigliptin confers pleiotropic Hattori Diabetol Metab Syndr (2020) 12:24 pharmacological benefits due to a low molecular weight and lipophilic properties that permit wide organ distribution.…”

Section: Discussionmentioning

confidence: 99%

Omarigliptin decreases inflammation and insulin resistance in a pleiotropic manner in patients with type 2 diabetes

Hattori

2020

Diabetol Metab Syndr

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Background: Omarigliptin is a potent, selective, oral dipeptidyl peptidase 4 (DPP4) inhibitor with a half-life that allows weekly dosing. Inflammation or insulin resistance might be pathological mediators of cardiovascular events in patients with type 2 diabetes. Methods: Whether omarigliptin has anti-inflammatory effects that result in decreased levels of high-sensitivity C-reactive protein (hsCRP) and anti-insulin resistance effects that decrease levels of homeostatic model assessment of insulin resistance (HOMA-IR) were investigated. Patients were allocated to continue with daily DPP4 inhibitors (control, n = 28) or to switch from daily DPP4 inhibitors to weekly omarigliptin (omarigliptin, n = 56). Fasting blood and urine samples were collected before, and every 3 months after intervention for 1 year. Results: Omarigliptin tended to elicit reductions in fasting blood glucose (FBG), LDL-cholesterol, triglyceride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), the urinary albumin-to-creatinine ratio (ACR) with logarithmic transformation (log ACR), and systolic and diastolic blood pressure, but the differences did not reach statistical significance compared with control. Values for HDL-cholesterol tended to increase, but also did not reach statistical significance compared with control. Omarigliptin significantly decreased HOMA-IR, remnant-like particle cholesterol (RLP-C), and hsCRP with logarithmic transformation (log hsCRP) compared with control. However, omarigliptin did not affect hemoglobin A1c (HbA1c), body mass index (BMI), and estimated glomerular filtration rates (eGFR). Conclusion: Omarigliptin decreased inflammation and insulin resistance without affecting HbA1c or BMI. Although how DPP4 inhibitors affect cardiovascular (CV) outcomes remains uncertain, omarigliptin might confer CV benefits at least in part, via pleiotropic anti-inflammatory or anti-insulin resistance effects. Trial registration UMIN Clinical Registry (UMIN000029288). Registered 22 September, 2017, https ://uploa d.umin.ac.jp/ UMIN0 00029 288

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“…Literature review reveals that OTN pharmacokinetics parameters were studied with renal impairment [ 10 ], in repositioning studies [ 11 ] and in healthy Japanese volunteers [ 12 ]. OTN pharmacokinetics were investigating the supra-therapeutic dose of OTN [ 13 ] and the effect of age, sex and obesity [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Clinical studies were also concerned with the effects of multiple and chronic dosage regimens [ 15 , 16 ]. Although, these many articles deal with the pharmacokinetics and/or bio-analysis of OTN [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ], most of the reported studies did not discuss the full details of the validated bio-analytical procedure that may be attributed to using the same methods for many clinical studies by the same common authors [ 12 , 13 , 14 , 15 , 16 , 17 ]. They were emphasizing the findings of the main pharmacokinetic parameters rather than developing or validating a bio-analytical procedure.…”

Section: Introductionmentioning

confidence: 99%

“…One liquid chromatography tandem mass spectrometry (LC-MS/MS) method was discussed in full details for OTN bio-analysis [ 18 ] but that method was related to rats’ plasma only and the authors used only direct precipitation with acetonitrile for the extraction of OTN from spiked and biological rats’ plasma samples. The authors of the current study modified the previously mentioned rats’ plasma method [ 18 ] in another repositioning publication [ 11 ] but with direct precipitation with acetonitrile. The lower limit of quantification (LLOQ) was 50 ng/mL which is very high in comparison to the LLOQ in the current work with the enhanced extraction technique.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Extraction Technique of Omarigliptin from Human Plasma—Applied to Biological Samples from Healthy Human Volunteers

et al. 2020

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Enhancing drug extraction from human plasma is a challenging approach that critically affects pharmacokinetic and any further clinical studies based on the drug Cmin and Cmax values. It also has a serious impact on the sensitivity and the lower limit of quantification (LLOQ) value of the bio-analytical methods. An advanced liquid chromatography tandem mass spectrometry (LC-MS/MS) bio-analytical method of omarigliptin (25–1000 nM) was established in human plasma using one-step liquid-liquid extraction. Alogliptin was used as an internal standard (IS) to attain good recovery and reproducibility while reducing the effects of the matrix. Enhanced plasma extraction of omarigliptin was successfully achieved with tertiary butyl methyl ether—diethyl ether (TBME-DEE) mixture as the extracting solvent, while using acetonitrile as the diluent solvent for the IS to effectively decrease the formed emulsion. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 399.2 to 153.0 for omarigliptin and m/z 340.2 to 116.0 for alogliptin was employed in positive Electro Spray Ionization (ESI) mode. Human plasma samples were collected after 1.5 h (tmax) of Marizev® (12.5 mg) tablets administration to healthy human volunteers showing average concentration of 292.18 nM. Validation results were all satisfactory including successful stability studies with bias below 12%. The proposed study will be valuable for ethnicity comparison studies that will be commenced on omarigliptin in Egypt by the authors in prospective study, following the FDA recommends, to evaluate possible sub-group dissimilarities that include pharmacokinetic parameters.

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Repositioning of Omarigliptin as a once-weekly intranasal Anti-parkinsonian Agent

Cited by 41 publications

References 77 publications

<p>Chitosan-Coated PLGA Nanoparticles for Enhanced Ocular Anti-Inflammatory Efficacy of Atorvastatin Calcium</p>

<p>Chitosan-Coated PLGA Nanoparticles for Enhanced Ocular Anti-Inflammatory Efficacy of Atorvastatin Calcium</p>

Omarigliptin decreases inflammation and insulin resistance in a pleiotropic manner in patients with type 2 diabetes

Enhanced Extraction Technique of Omarigliptin from Human Plasma—Applied to Biological Samples from Healthy Human Volunteers

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