- Inhibitory Effects of Sulfonylureas and Non-Steroidal Anti-Inflammatory Drugs on In-Vitro Metabolism of Canagliflozin in Human Liver Microsomes. [Journal Article]
- BDBiopharm Drug Dispos 2018 Jan 10
- Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co-administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulf...
Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co-administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non-steroidal anti-inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride, and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC50 value of 88 μM, compared to chlorpropamide and gliclazide with IC50 values of more than 500 μM. Diclofenac inhibited M5 metabolite formation more than M7, with IC50 values of 32 μM for M5 and 80 μM for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalyzed by UGT1A9, with an IC50 value of 1.9 μM and an inhibition constant value of 0.8 μM. A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified.
- Quantitative determination of carfilzomib in mouse plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. [Journal Article]
- JPJ Pharm Biomed Anal 2017 Nov 30; 146:341-346
- A highly sensitive and rapid LC-MS/MS method was developed and validated to determine the levels of carfilzomib in mice plasma by using chlorpropamide as an internal standard. Carfilzomib and chlorpr...
A highly sensitive and rapid LC-MS/MS method was developed and validated to determine the levels of carfilzomib in mice plasma by using chlorpropamide as an internal standard. Carfilzomib and chlorpropamide were extracted from 5 μL of plasma after protein precipitation with acetonitrile. Chromatographic separation was performed on Phenomenex Luna C18column (50×2.0mm id, 3μm). The mobile phase consisted of 0.1% formic acid in acetonitrile -0.1% formic acid in water (1:1v/v) and the flow rate was 0.3mL/min. The total chromatographic run time was 2.5min. Detection was performed on a triple quadrupole mass spectrometer equipped with positive-ion electrospray ionization by selected reaction monitoring of the transitions at m/z 720.20>100.15 (for carfilzomib) and m/z 277.05>111.05 (for the internal standard). The lower limit of quantification was 0.075ng/mL and the linear range was 0.075-1250ng/mL (r≥0.9974). All validation data, including selectivity, precision, accuracy, matrix effect, recovery, dilution integrity, stability, and incurred sample reanalysis, were well within acceptance limits. This newly developed bioanalytical method was simple, highly sensitive, required only a small volume of plasma, and was suitable for application in pharmacokinetic studies in mice that used serial blood sampling.
- StatPearls [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- Although the basics of evaluating and treating most unknown ingestants are well known, many overdoses require very specific treatment if the patient is to have any chance of survival. Countless studi...
Although the basics of evaluating and treating most unknown ingestants are well known, many overdoses require very specific treatment if the patient is to have any chance of survival. Countless studies have been published supporting Dr. Gideon Koren's 1993 landmark article “Medications Which can Kill a Toddler with One Tablet or Teaspoonful” in the Journal of Toxicology. While each has its own merits, most focus solely on pediatric overdoses and relatively few of them provide an exhaustive list or act as a “quick-reference” when dealing with real-time ingestions. Despite widespread public education, childproof containers, and other safety measures, accidental overdoses continue to occur. In the United States, poison control centers receive over 2.2 million calls each year, 47% of which concern children less than six years of age. Most pediatric accidental ingestions involve cosmetics and personal care products, followed by cleaning products, and then analgesics and prescription medications. Adult overdoses usually are due to intentional ingestion of analgesics and sedative hypnotics. Following are the list of toxic drugs (in decreasing severity/difficulty of treatment) included in this summary: 1. Alpha-2 Adrenergic Agonists - Clonidine, Naphazoline, Oxymetazoline, Tetrahydrozoline. 2. Sulfonylureas - Chlorpropamide, Glyburide, Glipizide, Glimepiride. 3. Calcium Channel Blockers - Nifedipine, Verapamil, Diltiazem, Amlodipine, Nicardipine. 4. Beta Blockers - Metoprolol, Labetalol. 5. Tricyclic Antidepressants - Imipramine, Desipramine, Amitriptyline, Nortriptyline. 6. Opioids - Codeine, Hydrocodone, Methadone, Morphine, Heroin. 7. Anti-diarrheals - Lomotil (Diphenoxylate + Atropine), Loperamide. 8. Salicylates/Methyl salicylates - Bengay, Wintergreen Oil, Peptobismol, Tiger Balm. 9. Antipsychotics - Loxapine, Thioridazine, Chlorpromazine. 10. Antimalarials - Chloroquine, Hydroxychloroquine, Quinine. 11. Antiarrhythmics - Quinidine, Disopyramide, Procainamide, Flecainide. 12. Terpenoid (Camphor) - Analgesic, Anti-itch, and Cooling Gels, Vicks, Tiger Balm. 13. Non-alkaloidToxic Lignan - Podophyllin, Condylox. 14. Plant Toxin / Secondary metabolite - Colchicine. 15. Oral Acetylcholinesterase Inhibitors - Rivastigmine, Donepezil, Tacrine, Galantamine. 16. Methylxanthine - Theophylline: 1,3-dimethylxanthine. 17. Partial Opioid Agonist / Synthetics - Buprenorphine / Fentanyl. 18. Toxic Alcohols - Methanol, Ethylene Glycol. 19. Caustics / Household Products - Acidic or Alkaline household products, hydrofluoric acid, selenious acid, ammonia fluoride, Methacrylic acid (cosmetic glue), Naphthalene (moth balls).
- Quantification and modeling of nanomechanical properties of chlorpropamide α, β, and γ conformational polymorphs. [Journal Article]
- EJEur J Pharm Sci 2017 Dec 15; 110:109-116
- The nanomechanical properties of the α-, β-, and γ- conformational polymorphs of chlorpropamide were determined by the dynamic contact module continuous stiffness measurement at nanoindenter. The mec...
The nanomechanical properties of the α-, β-, and γ- conformational polymorphs of chlorpropamide were determined by the dynamic contact module continuous stiffness measurement at nanoindenter. The mechanical anisotropy of the α-polymorph was confirmed by indenting different faces, and its deformational behavior was assigned as ductile. Based on the nanoindentation results, the β and γ forms are moderately hard with plastic flow at contact points. The results revealed a correlation between Young's modulus and inter-planar interaction energy with regard to crystal orientation. Interpretation of the measurements was assisted by two- and three-dimensional periodic density functional theory (DFT) calculations, yielding inter-planar energies of polymorphs along the cell vectors and exhibiting a very good match with the experimental observations. The results suggest that the inter-planar interaction energy could serve as a first-order indicator for ranking the mechanical propensity of crystalline active ingredients. The study confirms the practical aspect of using the α- form for preparing chlorpropamide tablets with a direct compression procedure due to its substantial level of ductility.
- Rapid Simultaneous Separation of Four Oral Antidiabetic Drugs and Quantitative Determination of Glibenclamide Using Conventional and Fused-Core Silica Columns. [Journal Article]
- JAJ AOAC Int 2017 Sep 01; 100(5):1420-1427
- Diabetes mellitus is a chronic disease with high and growing prevalence worldwide. Therefore, the development of fast and efficient methods for the QC of antidiabetic drugs is of fundamental importan...
Diabetes mellitus is a chronic disease with high and growing prevalence worldwide. Therefore, the development of fast and efficient methods for the QC of antidiabetic drugs is of fundamental importance. Two ultra-fast methods, using a conventional (C18 100 × 2.1 mm, 5 μm fully porous particle) column or a fused-core (C18 100 × 2.1 mm, 2.7 μm fused-core particle) column, were developed for the simultaneous determination of four antidiabetic drugs (chlorpropamide, glibenclamide, gliclazide, and glimepiride). The developed methods were compared in terms of efficiency, speed of analysis, resolution, and peak symmetry. Both methods were validated with respect to selectivity, system suitability, linearity, precision, accuracy, LOD, LOQ, and robustness, using glibenclamide as model. Conventional and fused-core methods were shown to be appropriate for the determination of glibenclamide in tablets; however, the fused-core column presented higher efficiency, detectability, and resolution. Also, it enabled faster analysis, with separation of the four drugs in less than 1 min.
- Potentially inappropriate prescribing and associated factors in elderly patients at hospital discharge in Brazil: a cross-sectional study. [Journal Article]
- IJInt J Clin Pharm 2017; 39(2):386-393
- Background The Screening Tool of Older Persons' Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) criteria is used to identify instances of potentially inappropriate pres...
Background The Screening Tool of Older Persons' Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) criteria is used to identify instances of potentially inappropriate prescribing in a patient's medication regimen. Objective To determine the prevalence and predictors of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) among elderly patients at hospital discharge. Setting A university hospital medical clinic in Brazil. Method Discharge prescriptions were examined using the STOPP/START criteria. Subjects were inpatients aged ≥60 years receiving at least one medication prior to hospitalization and with a history of cardiovascular disease. The prevalence of PIMs and PPOs was determined and a multivariable binary regression analysis was performed to identify independent predictors associated with PIMs or PPOs. Main outcome measure Prevalence of PIMs and PPOs. Results Of the 230 subjects, 13.9% were prescribed at least one PIM. The most frequently prescribed PIMs were glibenclamide or chlorpropamide prescribed for type 2 diabetes mellitus (31.0%), and aspirin at doses >150 mg/day (14.3%). Ninety patients had at least one PPO (39.1%). The most prevalent PPOs were statins (29.8%) and antiplatelet therapy (13.7%) for diabetes mellitus when coexisting major cardiovascular risk factors were present. No predictors for PIMs were found. In contrast, diabetes was a risk factor while dyslipidaemia was a protective factor for PPOs. Conclusion PIMs and PPOs commonly occur with elderly people at hospital discharge. Diabetes and dyslipidaemia were significantly associated with PPOs. Our findings show the need for interventions to reduce potentially inappropriate prescribing, such as a pharmacist medication review process at hospital discharge.
- Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice. [Journal Article]
- MCMol Cell Endocrinol 2017 Mar 15; 444:26-37
- Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevat...
Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis.
- Simultaneous Quantification of Antidiabetic Agents in Human Plasma by a UPLC-QToF-MS Method. [Journal Article]
- PlosPLoS One 2016; 11(12):e0167107
- An ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry method for the simultaneous quantification of chlorpropamide, glibenclamide, gliclazide, glimepiride, metformin,...
An ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry method for the simultaneous quantification of chlorpropamide, glibenclamide, gliclazide, glimepiride, metformin, nateglinide, pioglitazone, rosiglitazone, and vildagliptin in human plasma was developed and validated, using isoniazid and sulfaquinoxaline as internal standards. Following plasma protein precipitation using acetonitrile with 1% formic acid, chromatographic separation was performed on a cyano column using gradient elution with water and acetonitrile, both containing 0.1% formic acid. Detection was performed in a quadrupole time-of-flight analyzer, using electrospray ionization operated in the positive mode. Data from validation studies demonstrated that the new method is highly sensitive, selective, precise (RSD < 10%), accurate (RE < 12%), linear (r > 0.99), free of matrix and has no residual effects. The developed method was successfully applied to volunteers' plasma samples. Hence, this method was demonstrated to be appropriate for clinical monitoring of antidiabetic agents.
- A simple and sensitive liquid chromatography-tandem mass spectrometry method for trans-ε-viniferin quantification in mouse plasma and its application to a pharmacokinetic study in mice. [Journal Article]
- JPJ Pharm Biomed Anal 2017 Feb 05; 134:116-121
- In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of trans-ε-viniferin in small volumes (10μl) of mouse plasma using chlorp...
In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of trans-ε-viniferin in small volumes (10μl) of mouse plasma using chlorpropamide as an internal standard was developed and validated. Plasma samples were precipitated with acetonitrile and separated using an Eclipse Plus C18 column (100×4.6mm, 1.8-μm) with a mobile phase consisting of 0.1% formic acid in acetonitrile and 0.1% formic acid in water (60:40v/v) at a flow rate of 0.5ml/min. A triple quadrupole mass spectrometer operating in positive ion mode with selected reaction-monitoring mode was used to determine trans-ε-viniferin and chlorpropamide transitions of 455.10→215.05 and 277.00→111.00, respectively. The lower limit of quantification was 5ng/ml with a linear range of 5-2500ng/ml (r≥0.9949). All validation data, including the selectivity, precision, accuracy, recovery, dilution integrity, and stability, conformed to the acceptance requirements. No matrix effects were observed. The developed method was successfully applied to pharmacokinetic studies of trans-ε-viniferin following intravenous (2.5mg/kg), intraperitoneal (2.5, 5 and 10mg/kg), and oral (40mg/kg) administration in mice. This is the first report on the pharmacokinetic properties of trans-ε-viniferin. The results provide a meaningful basis for evaluating the pre-clinical or clinical applications of trans-ε-viniferin.
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- Study on the interactions of sulfonylurea antidiabetic drugs with normal and glycated human serum albumin by capillary electrophoresis-frontal analysis. [Journal Article]
- JSJ Sep Sci 2016; 39(18):3631-7
- Diabetes is one of the most widespread diseases characterized by a deficiency in the production of insulin or its ineffectiveness. As a result, the increased concentrations of glucose in the blood le...
Diabetes is one of the most widespread diseases characterized by a deficiency in the production of insulin or its ineffectiveness. As a result, the increased concentrations of glucose in the blood lead not only to damage to many of the body's systems but also cause the nonenzymatic glycation of plasma proteins affecting their drug binding. Since the binding ability influences its pharmacokinetics and pharmacodynamics, this is a very important issue in the development of new drugs and personalized medicine. In this study, capillary electrophoresis-frontal analysis was used to evaluate the affinities between human serum albumin or its glycated form and the first generation of sulfonylurea antidiabetics, since their inadequate concentration may induce hypoglycaemia or on the contrary hyperglycaemia. The binding constants decrease in the sequence acetohexamide > tolbutamide > chlorpropamide > carbutamide both for normal and glycated human serum albumins, with glycated giving lower values. These results provide a more quantitative picture of how these drugs bind with normal and modified human serum albumin and indicate capillary electrophoresis-frontal analysis to be another tool for examining the changes arising from modifications of albumin, or any other protein, with all its benefits like short analysis time, small sample requirement, and automation.