Specific noncovalent drug-polymer interactions were analytically identified using Raman and Fourier transform infrared spectroscopy for amorphous solid dispersions (ASD) formed between either chlorpropamide or tolbutamide and polyvinylpyrrolidone vinyl acetate random copolymer (PVPVA). Spectral changes in the C-Cl stretching vibrations due to changes in the electronic environment of the Cl atom confirmed halogen bond formation in chlorpropamide-PVPVA ASDs, the extent of which was established to be inversely related to the concentration of the drug using 2D correlation spectroscopy analysis. Hydrogen bonding between the secondary amide of each drug and the pyrrolidone carbonyl of the copolymer was also confirmed in all dispersions. Implications of coexistent interactions were investigated for drug-polymer solubility, mixing free energy, and molecular mobility relative to tolbutamide, which only formed hydrogen bonds with PVPVA. Chlorpropamide had a higher solubility, a larger negative mixing free energy, and lower mobility in PVPVA relative to tolbutamide. These thermodynamic and kinetic differences demonstrate the significance of halogen bond formation even when hydrogen bonding is present.

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.[1] 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.[2][3][4][5] 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 the 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 - diphenoxylate + atropine, loperamide. 8. Salicylates/Methyl salicylates - wintergreen oil, bismuth subsalicylate, mentholated balms. 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, ointments, and balms. 13. Non-alkaloid toxic lignan - podophyllin, podofilox. 14. Plant toxin/secondary metabolite - colchicine. 15. Oral acetylcholinesterase inhibitors - rivastigmine, donepezil, 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 (mothballs).

The title compound, C10H13BrN2O3S, 1, contains a sulfonyl urea moiety, which possesses potential therapeutic functions (e.g., anti-diabetic and herbicidal). The geometry of 1 is similar to its closely related analogues, chlorpropamide and tolbutamide. This compound crystallizes in the monoclinic space group C2/c, having one mol-ecule in its asymmetric unit. The crystal structure of 1, recorded at 296 K, shows inter-molecular N-H⋯O and C-H⋯O-type infinite hydrogen-bonded chains involving the sulfonyl urea moiety. Hirshfeld surface analysis and the two-dimensional fingerprint plots confirmed hydrogen bonding as the dominant feature in the crystal packing.

The low solubility of active pharmaceutical ingredients (APIs) is a problem in pharmaceutical development. Several methodologies can be used to improve API solubility, including the use of eutectic systems in which one of the constituents is the API. This class of compounds is commonly called Therapeutic Deep Eutectic Systems (THEDES). THEDES has been gaining attention due to their properties such as non-toxicity, biodegradability, and being non-expensive and easy to prepare. Since the knowledge of the solid liquid diagram of the mixture and the ideal eutectic point is necessary to ascertain if a mixture is a deep eutectic or just a eutectic mixture that is liquid at ambient temperature, the systems studied in this work are called Therapeutic Liquid Eutectic Systems (THELES). Therefore, the strategy proposed in this work is to improve the solubility of chlorpropamide and tolbutamide by preparing THELES. Both APIs are sulfonylurea compounds used for the treatment of type 2 diabetes mellitus and have low solubility in water. To prepare the THELES, several coformers were tested, namely, tromethamine, L(+)-arginine, L-tryptophan, citric acid, malic acid, ascorbic acid, and p-aminobenzoic acid, in molar ratios of 1:1 and 1:2. To improve viscosity, water was added in different molar ratios to all systems. THELES were characterized by mid-infrared spectroscopy (MIR), and differential scanning calorimetry. Their viscosity, solubility, and permeability were also determined. Their stability at room temperature and 40 °C was accessed by MIR. Cytocompatibility was performed by metabolic activity and cell lysis evaluation, according to ISO10993-5:2009, and compared with the crystalline APIs. THELES with TRIS were successfully synthesized for both APIs. Results showed an increased solubility without a decrease in the permeability of the APIs in the THELES when compared with the pure APIs. The THELES were also considered stable for 8 weeks at ambient temperature. The cells studied showed that the THELES were not toxic for the cell lines used.

A 44-year-old man with a history of traumatic brain injury (TBI) presented to the emergency room (ER) with diabetic ketoacidosis (DKA). After resolution of DKA, the patient had persistent polyuria (up to 5.5 L/24 h) associated with low specific gravity (1.002-1.005) and severe hypernatremia (up to 186 mmol/L) that led us to consider the possibility of central diabetes insipidus (DI). Due to the lack of desmopressin availability in our country, we managed the patient using indapamide. Polydipsia and polyuria in a patient with controlled diabetes mellitus (DM) should raise suspicion for alternative etiologies, including DI. Appropriate fluid management during hospitalization is critical to avoid life-threatening complications. TBI is an important cause of central DI and should be treated with desmopressin, an arginine-vasopressin (AVP) analog. In the absence of desmopressin, alternative options can help patients with central DI, including thiazides, carbamazepine, chlorpropamide, among others less studied.

Sulfonylureas are widely used oral anti-diabetic drugs. However, its long-term usage effects on patients' lifespan remain controversial, with no reports of influence on animal longevity. Hence, the anti-aging effects of chlorpropamide along with glimepiride, glibenclamide, and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+ (mitoK-ATP) channels and mitochondrial complex II. Chlorpropamide delayed aging in Caenorhabditis elegans, human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice. In addition, the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms, which is consistent with the function of its reported targets, mitoK-ATP channels. Increased levels of mitochondrial reactive oxygen species (mtROS) were observed in chlorpropamide-treated worms. Moreover, the lifespan extension by chlorpropamide required complex II and increased mtROS levels, indicating that chlorpropamide acts on complex II directly or indirectly via mitoK-ATP to increase the production of mtROS as a pro-longevity signal. This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C. elegans.

Hyponatremia is frequently encountered in clinical practice and usually induced by renal water retention. Many medications are considered to be among the various causes of hyponatremia, because they either stimulate the release of arginine vasopressin (AVP) or potentiate its action in the kidney. Antidepressants, anticonvulsants, antipsychotics, diuretics, and cytotoxic agents are the major causes of drug-induced hyponatremia. However, studies addressing the potential of these drugs to increase AVP release from the posterior pituitary gland or enhance urine concentration through intrarenal mechanisms are lacking. We previously showed that in the absence of AVP, sertraline, carbamazepine, haloperidol, and cyclophosphamide each increased vasopressin V2 receptor (V2R) mRNA and aquaporin-2 (AQP2) protein and mRNA expression in primary cultured inner medullary collecting duct cells. The upregulation of AQP2 was blocked by the V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors. These findings led us to conclude that the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the main mechanism of drug-induced hyponatremia. Previous studies have also shown that the V2R has a role in chlorpropamide-induced hyponatremia. Several other agents, including metformin and statins, have been found to induce antidiuresis and AQP2 upregulation through various V2R-independent pathways in animal experiments but are not associated with hyponatremia despite being frequently used clinically. In brief, drug-induced hyponatremia can be largely explained by AQP2 upregulation from V2R-cAMP-PKA signaling in the absence of AVP stimulation. This paper reviews the central and nephrogenic mechanisms of drug-induced hyponatremia and discusses the importance of the canonical pathway of AQP2 upregulation in drug-induced NSIAD.

Contemporary literature documents extensive research on common causative mechanisms, pathogenic pathways and dual effective remedies for Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM). Tolbutamide (TBM), chlorpropamide (CPM), and glyburide (GLY) are three sulfonylurea antidiabetic drugs of different generations. All these drugs were found to exhibit moderate to strong inhibitory efficiency on the neurotransmitter degrading enzyme acetylcholinesterase (AChE) with GLY (IC50 = 0.74 ± 0.02 μM) being the most potent, followed by CPM (IC50 = 5.72 ± 0.24 μM) and TBM (IC50 = 28.9 ± 1.60 μM). Notably, the inhibition efficiency of GLY is even comparable with the FDA approved AD drug, donepezil (DON). The larger size of GLY spans almost the full gorge of AChE ranging from catalytic active site (CAS) to the peripheral active site (PAS) with relatively strong binding affinity (6.0 × 105 M-1) and acts as a competitive inhibitor for AChE. On the other hand, while they show relatively weak binding ((2-6) × 104 M-1), both CPM and TBM act as noncompetitive binders. While these two drugs can bind to PAS, MD simulation results predict an alternative noncompetitive inhibition mechanism for CPM. These results open the possibility of repurposing the antidiabetic drugs, particularly GLY, in the treatment of AD. The consequential side effect of excess acetylcholine production, due to the administration of these drugs to AD-unaffected patients, can be rectified by using colloidal gold and silver nanofluids as potential AChE activity boosters.

Equine neuroaxonal dystrophy/degenerative myeloencephalopathy (eNAD/EDM) is a hereditary, deteriorating central nervous disease in horses. Currently, the only way to confirm eNAD/EDM is through a postmortem histological evaluation of the central nervous system. Vitamin E, specifically the isoform alpha-tocopherol (α-TP), is known to protect eNAD/EDM susceptible horses from developing the clinical phenotype. While vitamin E is an essential nutrient in the diet of horses, there are no diagnostic tests able to quantitate vitamin E and its metabolites in urine. An ultra-performance liquid chromatography-atmospheric-pressure chemical ionization mass spectrometry (UPLC-APCI-MS/MS) method was developed and validated following acidic hydrolysis and solid phase extraction to quantitate vitamin E and its metabolites in equine urine. A blank control horse urine matrix was used and spiked with different concentrations of analytes to form a standard curve using either alpha-tocopherol-d6 or chlorpropamide as the internal standard. Inter-day and intra-day statistics were performed to evaluate the method for accuracy (90% to 116%) and precision (0.75% to 14%). Matrix effects, percent recovery, and stability were also assessed. The method successfully analyzed alpha-carboxyethyl hydroxychroman (α-CEHC), alpha-carboxymethylbutyl hydroxychromans (α-CMBHC), gamma-carboxyethyl hydroxychroman γ-CEHC, and α-TP concentrations in urine to determine a baseline levels of analytes in healthy horses, and can be used to determine concentrations of vitamin E metabolites in equine urine allowing for its evaluation as a diagnostic approach in the treatment of eNAD/EDM.

The effective concentration of a drug in the blood, i.e. the concentration of a free drug in the blood, is influenced by the strength of drug binding onto plasma proteins. Besides its efficacy, these interactions subsequently influence the liberation, absorption, distribution, metabolism, excretion, and toxicological properties of the drug. It is important to not only determine the binding strength and stoichiometry, but also the binding site of a drug on the plasma protein molecule, because the co-administration of drugs with the same binding site can affect the above-mentioned concentration and as a result the pharmacological behavior of the drugs and lead to side effects caused by the change in free drug concentration, its toxicity. In this study, the binding characteristics of six drugs with human serum albumin, the most abundant protein in human plasma, were determined by capillary electrophoresis-frontal analysis, and the obtained values of binding parameters were compared with the literature data. The effect of several drugs and site markers on the binding of l-tryptophan and lidocaine to human serum albumin was investigated in subsequent displacement studies which thus demonstrated the usability of capillary electrophoresis as an automated high-throughput screening method for drug-protein binding studies.

The objective of this study is to achieve a fundamental understanding of polymorphic interconversion during the tableting process, including during compaction, dwell, decompression/unloading, and ejection using an in situ mechanical Raman spectroscopy. The fit-for-purpose in situ mechanical Raman spectroscopy developed herein can provide simultaneous measurement of Raman spectra and densification for the powder compacts. Chlorpropamide (CPA), an antidiabetic drug, was selected as a model pharmaceutical compound because of its mechanical shear-induced polymorphic conversions. The results confirm that CPA polymorph A (CPA-A) was transformed to CPA polymorph C (CPA-C) under different compaction stresses. We also observed that the converted polymorph CPA-C could be reverted to the CPA-A due to the elastic recovery of powder compacts as detected during dwelling and unloading. This study is the first depiction of the dynamics of CPA polymorphic interconversion during compression, dwell, unloading, and ejection. Mechanistically, this study illustrates a correlation between the change in the powder compact's relative density and polymorphic interconversion of the drug substance in different solid-state forms. The present research suggests that the process-induced polymorph conversion is a complicated dynamic process, which could be affected by the compaction pressure, the elasticity/plasticity of the material, the level of elastic recovery, and the dissipation of residual stress. In summary, this study demonstrates that the in situ mechanical Raman spectroscopy approach enables the simultaneous detection of mechanical and chemical information of the powder compact throughout the tableting process.

As a potential drug for treating inflammatory, autoimmune diseases and cancers, triptolide (TP) is greatly limited in clinical practice due to its severe toxicity, particularly for liver injury. Recently, metabolic homeostasis was vitally linked to drug-induced liver injury and gut microbiota was established to play an important role. In this study, we aimed to investigate the functions of gut microbiota on TP-induced hepatotoxicity using metabolomics in mice. Here, predepletion of gut microbiota by antibiotic treatment strikingly aggravated liver injury and caused mortality after treated with a relatively safe dosage of TP at 0.5 mg/kg, which could be reversed by gut microbial transplantation. The loss of gut microbiota prior to TP treatment dramatically elevated long chain fatty acids and bile acids in plasma and liver. Further study suggested that gut microbiota-derived propionate contributed to the protective effect of gut microbiota against TP evidenced by ameliorative inflammatory level (Tnfa, Il6 and Cox2), ATP, malondialdehyde and hepatic histology. Supplementing with propionate significantly decreased the mRNA levels of genes involved in fatty acid biosynthesis (Srebp1c, Fasn and Elovl6), resulting in the decreased long chain fatty acids in liver. Moreover, TP restricted the growth of Firmicutes and led to the deficiency of short chain fatty acids in cecum content. In conclusion, our study warns the risk for TP and its preparations when antibiotics are co-administrated. Intervening by foods, prebiotics and probiotics toward gut microbiota or supplementing with propionate may be a clinical strategy to improve toxicity induced by TP.

This communication is an interesting and off-beat take on the concept of theranostics, as applied to diabetes care. It proposes the use of the term diabeto-theranostics, to define the combined use of diagnostic and therapeutic modalities, so as to create individualized or personalized treatment strategies in persons with diabetes. Historical examples such as the chlorpropamide challenge test and modern innovations such as genotyping are described. The rubrics of gluco-phenotype, endo-phenotype, metabolic phenotype, glucagon: insulin ratio, and adenosine monophosphate activated protein kinase (AMPK) status in planning glucose lowering therapy are explained. Novel concepts such as psycho-theranostics and electro-theranostics in diabetes are discussed.

Binding strength of the anti-diabetic drugs chlorpropamide (CPM) and tolbutamide (TBM) with model protein bovine serum albumin (BSA) shows strong modulation in presence of colloidal gold nanoparticles (AuNP). Intrinsic tryptophan fluorescence of both the native BSA and BSA-AuNP conjugate quenched in presence of the drugs. Stern-Volmer quenching constant (KSV) of CPM binding to BSA-AuNP conjugate at different temperatures is almost twice (6.76~14.76 × 103 M-1) than the corresponding values in native BSA (3.21~5.72 × 103 M-1). However, the calculated KSV values with TBM show certain degree of reduction in presence of AuNP (6.46× 103 M-1), while comparing with native BSA (8.83 × 103 M-1). The binding mode of CPM towards BSA-AuNP conjugate is mainly through hydrophobic forces; whereas, TBM binding is identified to be Van der Waal's and hydrogen bonding type of interaction. Fluorescence lifetime analysis confirms static type of quenching for the intrinsic tryptophan fluorescence of BSA as well as BSA-AuNP conjugate with addition of CPM and TBM at different concentrations. The α-helical content in the secondary structure of BSA is decreased to 48.32% and 45. 28% in presence of AuNP, when the concentration of CPM is 0.08 mM and 0.16 mM in comparison with that of native protein (50.13%). On the other hand, the intensity of sugar induced advanced glycated end (AGE) product fluorescence is decreased by 55% and 80% at 0.13 nM and 0.68 nM AuNP, respectively. Change in the binding strength of the drugs with transport protein and reduced AGE product formation in presence of AuNP could lead to a major development in the field of nanomedicine and associated drug delivery techniques. Graphical Abstract Modulated drug binding ability and AGE product formation of serum proteins in presence of AuNP.

A procedure was established and fully validated for the screening and quantification of fourteen synthetic antidiabetic adulterants in herbal pharmaceuticals and health foods, including metformin (MF), buformin (BF), phenformin (PHF), rosiglitazone (RGZ), pioglitazone (PGZ), chlorpropamide (CPM), glipizide (GPZ), tolbutamide (TBM), gliclazide (GCZ), glibenclamide (GBM), glimepiride (GMR), repaglinide (RGN), gliquidone (GQD) and nateglinide (NGN). The samples were extracted by methanol and separated by HPLC. Retention times and ultraviolet spectra were used for the preliminary screening, and the suspected adulterants were then confirmed by liquid chromatography-quadrupole-time of flight mass spectrometry (LC-Q-TOF-MS/MS) and quantified by HPLC. The developed procedure was successfully applied to assess twenty-four herbal samples, and PHF, GCZ, GBM, MF, GPZ and BF were found in many. To the best of our knowledge, this is the first report of simultaneous screening and quantification of these fourteen synthetic antidiabetic adulterants from any matrix.

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.

Aim: A revised method of preparing the mimetic tissue model for quantitative imaging mass spectrometry (IMS) is evaluated. Concepts of assessing detection capability are adapted from other imaging or mass spectrometry (MS)-based technologies to improve upon the reliability of IMS quantification. Materials & methods: The mimetic tissue model is prepared by serially freezing spiked-tissue homogenates into a cylindrical mold to create a plug of tissue with a stepped concentration gradient of matrix-matched standards. Weighted least squares (WLS) linear regression is applied due to the heteroscedastisity (change in variance with intensity) of most MS data. Results & conclusions: Imaging poses several caveats for quantification which are unique compared with other MS-based methods. Aspects of the design, construction, application, and evaluation of the matrix-matched standard curve for the mimetic tissue model are discussed. In addition, the criticality of the ion distribution in the design of a purposeful liquid chromatography coupled to mass spectrometry (LC-MS) validation is reviewed.

Previously, we proposed 12 marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb4b) to discriminate mouse genotoxic hepatocarcinogens (GTHC) from non-genotoxic hepatocarcinogens (NGTHC). This was determined by qPCR and principal component analysis (PCA), as the aim of an in vivo short-term screening for genotoxic hepatocarcinogens. For this paper, we conducted an application study of the 12 mouse marker genes to rat data, Open TG-GATEs (public data). We analyzed five typical rat GTHC (2-acetamodofluorene, aflatoxin B1, 2-nitrofluorene, N-nitrosodiethylamine and N-nitrosomorpholine), and not only seven typical rat NGTHC (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital and WY-14643) but also 11 non-genotoxic non-hepatocarcinogens (NGTNHC; allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline and tolbutamide) from Open TG-GATEs. The analysis was performed at 3, 6, 9 and 24 h after a single administration and 4, 8, 15 and 29 days after repeated administrations. We transferred Open TG-GATEs DNA microarray data into log2 data using the "R Project for Statistical Computing". GTHC-specific dose-dependent gene expression changes were observed and significance assessed with the Williams test. Similar significant changes were observed during 3-24 h and 4-29 days, assessed with Welch's t-test, except not for NGTHC or NGTNHC. Significant differential changes in gene expression were observed between GTHC and NGTHC in 11 genes (except not Tubb4b) and between GTHC and NGTNHC in all 12 genes at 24 h and 10 genes (except Ccnf and Mbd1) at 29 days, per Tukey's test. PCA successfully discriminated GTHC from NGTHC and NGTNHC at 24 h and 29 days. The results demonstrate that 12 previously proposed mouse marker genes are useful for discriminating rat GTHC from NGTHC and NGTNHC from Open TG-GATEs.

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.[1][2]

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.

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.

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.

The first generation sulfonylureas include acetohexamide, chlorpropamide, tolazamide and tolbutamide, oral hypoglycemic agents that are used in therapy of type 2 diabetes. They are well known, but rare causes of clinically apparent liver injury.

The sulfonylureas are a class of agents that lower blood sugar as a result of increasing release of insulin from the pancreas. The sulfonylureas are used for the therapy of mild-to-moderate type 2 diabetes in conjunction with diet, and can be used alone or in combination with metformin, thiazolidinediones or other hypoglycemic agents. The sulfonylureas have been associated with rare cases of idiosyncratic drug induced liver disease with somewhat similar pattern of onset, injury and outcome. While the sulfonylureas are derivatives of sulfonamides, they have no intrinsic antibacterial activity. They are believed to lower blood glucose levels by stimulating insulin release from pancreatic beta cells. However, their effects on blood glucose with chronic therapy are more complex, and the sulfonylureas may have extra-pancreatic actions that affect blood sugar, reducing hepatic clearance of insulin or increasing insulin sensitivity. The sulfonylureas have little effect in type 1 diabetes, in which there is a deficiency in insulin producing pancreatic beta cells. The sulfonylureas are widely used and are generally considered a first line of medication therapy for type 2 diabetes. The sulfonylureas are divided into first and second generation agents, based upon their relative potency. All sulfonylureas share a similar structure, being substituted arylsulfonylureas. They differ on the basis of substitutions at the para positions at the two ends of the arylsulfonylurea molecule. The first generation sulfonylureas include chlorpropamide, tolazamide and tolbutamide. These agents are now rarely used although still available in the United States. The second generation sulfonylureas include gliclazide, glimepiride, glipizide and glyburide (known as glibenclamide outside of the United States) which are active in lower concentrations, are effective when taken once daily and have fewer of the troublesome dose related side effects of the first generation sulfonylureas, such as headache, nausea, anorexia, fatigue and paresthesias. The sulfonylureas (particularly the first generation agents) can also cause alcohol intolerance (flushing) through inhibition of alcohol dehydrogenase. The sulfonylureas are all labelled with a warning of increased risk of cardiovascular mortality with long term use.