- Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies. [Journal Article]
- JPJ Pharm Sci 2018 Sep 21
- Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model dr...
Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation.
- Chromatographic studies of chlorpropamide interactions with normal and glycated human serum albumin based on affinity microcolumns. [Journal Article]
- JCJ Chromatogr B Analyt Technol Biomed Life Sci 2018 Oct 15; 1097-1098:64-73
- Sulfonylurea drugs have significant binding to proteins in blood, with most of this binding believed to occur with human serum albumin (HSA). High performance affinity chromatography and affinity mic...
Sulfonylurea drugs have significant binding to proteins in blood, with most of this binding believed to occur with human serum albumin (HSA). High performance affinity chromatography and affinity microcolumns containing immobilized HSA were used to investigate binding by the sulfonylurea drug chlorpropamide to normal HSA and glycated HSA, which is a modified form of HSA that has an increased serum concentration in diabetes. Experiments employing frontal analysis indicated that the binding by chlorpropamide gave a good fit to a two-site model for both normal HSA and glycated HSA samples that were representative of controlled or advanced diabetes. These interactions involved a set of moderate-to-high affinity sites and a set of lower affinity sites, with binding constants in the range of 6.2-9.9 × 104 M-1 and 0.18-0.57 × 104 M-1, respectively, at pH 7.4 and 37 °C. Competition studies utilizing a zonal elution format demonstrated that chlorpropamide could interact at both Sudlow sites I and II of HSA, with affinities in the range expected for the moderate-to-high affinity sites of this drug. The affinity of chlorpropamide at Sudlow site I had a small increase of up to 1.2-fold when comparing the normal HSA and glycated HSA samples. Chlorpropamide gave a larger 1.4- to over 1.5-fold increase at Sudlow site II when the affinity of this drug was compared between normal HSA and the same samples of glycated HSA. These results were compared to those obtained previously with other sulfonylurea drugs to help determine how glycation can change the overall and site-selective binding strength of these drugs with HSA at levels of protein modification that are seen in patients with diabetes.
- Interaction of chlorpropamide with serum albumin: Effect on advanced glycated end (AGE) product fluorescence. [Journal Article]
- SASpectrochim Acta A Mol Biomol Spectrosc 2019 Jan 05; 206:569-577
- Carrier proteins like bovine or human serum albumin (BSA and HSA, respectively) are prone to glycation as compared to the other available proteins. In this study, reducing sugars such as l-arabinose ...
Carrier proteins like bovine or human serum albumin (BSA and HSA, respectively) are prone to glycation as compared to the other available proteins. In this study, reducing sugars such as l-arabinose (ara), d-(-) galactose (gal) and d-(-) fructose (fru) were used to create model glycated serum albumins and binding ability of these with well-known antidiabetic drug chlorpropamide (CPM) was monitored. Fluorescence quenching experiment revealed that interaction of CPM with native as well as glycated albumins undergoes through a ground state complex formation. CPM binds strongly to glycated HSA with arabinose (gHSAara) as compared to other glycated systems and to the native proteins. CPM interacts through Van der Waals and hydrogen bonding interaction to glycated BSA by d-(-) fructose (gBSAfru) and also with native HSA; whereas, it's interaction with BSA and others glycated systems like gBSAara, gBSAgal and gHSAara occurs primarily through hydrophobic interaction. CPM showed an enhancement in the production of the advanced glycated end products (AGE) in all the glycated proteins. The difference in the binding capability of CPM to differently glycated albumins could be a major model to understand the drug carrying capacity of the glycated serum albumins.
- StatPearls [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- This class of medications represents a group of anti-hyperglycemic agents mainly used in the treatment of type 2 diabetes mellitus. Sulfonylureas, commonly divided into first and second generations, ...
This class of medications represents a group of anti-hyperglycemic agents mainly used in the treatment of type 2 diabetes mellitus. Sulfonylureas, commonly divided into first and second generations, can be utilized as adjuvant therapy with metformin in patients not at target hemoglobin A1c after 3 months on biguanides. If a patient’s hemoglobin A1c initially is greater than 9.0%, providers can consider combination therapy with metformin and a sulfonylurea or other anti-hyperglycemic agent. Additionally, sulfonylurea monotherapy can be considered in patients intolerant to metformin or in those who have a contraindication to this medication. Sulfonylureas can be used in combination with any other class of oral diabetic medications besides meglitinides. Infants with permanent neonatal diabetes also tend to respond well to sulfonylurea treatment. Examples of first-generation sulfonylureas include chlorpropamide, tolazamide, and tolbutamide, while second-generation sulfonylureas include glipizide, gliclazide, and glyburide. Glimepiride occasionally is referred to as a third-generation medication, though it commonly is classified as second-generation. Furthermore, chlorpropamide, glyburide, and glimepiride have a prolonged duration of action when compared to short-acting medications such as gliclazide and tolbutamide. Due to their low cost, wide availability, and effectiveness, sulfonylureas have remained a frequently prescribed medication despite potential hypoglycemic risks.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- Limited data indicate that amounts of chlorpropamide in breastmilk are unlikely to affect a breastfed infant. Short-acting drugs are generally preferred while breastfeeding a neonate to avoid drug ac...
Limited data indicate that amounts of chlorpropamide in breastmilk are unlikely to affect a breastfed infant. Short-acting drugs are generally preferred while breastfeeding a neonate to avoid drug accumulation. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with hypoglycemic agents.
- Prescription of high-risk medications among patients with chronic kidney disease: a cross-sectional study from the Washington, Wyoming, Alaska, Montana and Idaho region Practice and Research Network. [Journal Article]
- FPFam Pract 2018 Sep 18; 35(5):589-594
- CONCLUSIONS: Primary care patients with stage III/IV CKD were frequently prescribed or had documented use of relatively contraindicated drugs and thus were at risk of adverse drug events. Given the significant number of individuals with CKD in the USA, research that examines rates of adverse events related to these prescriptions and that tests primary care-based interventions to decrease inappropriate prescribing of relatively contraindicated medications to these patients is needed.
- 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; 39(3):135-142
- 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 in 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 catalysed 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 C18 column (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).
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- 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.