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Current Metabolomics Sep 2013The presence of elevated glucose concentrations in diabetes is a metabolic change that leads to an increase in the amount of non-enzymatic glycation that occurs for...
The presence of elevated glucose concentrations in diabetes is a metabolic change that leads to an increase in the amount of non-enzymatic glycation that occurs for serum proteins. One protein that is affected by this process is the main serum protein, human serum albumin (HSA), which is also an important carrier agent for many drugs and fatty acids in the circulatory system. Sulfonylureas drugs, used to treat type 2 diabetes, are known to have significant binding to HSA. This study employed ultrafiltration and high-performance affinity chromatography to examine the effects of HSA glycation on the interactions of several sulfonylurea drugs (i.e., acetohexamide, tolbutamide and gliclazide) with fatty acids, whose concentrations in serum are also affected by diabetes. Similar overall changes in binding were noted for these drugs with normal HSA or glycated HSA and in the presence of the fatty acids. For most of the tested drugs, the addition of physiological levels of the fatty acids to normal HSA and glycated HSA produced weaker binding. At low fatty acid concentrations, many of these systems followed a direct competition model while others involved a mixed-mode interaction. In some cases, there was a change in the interaction mechanism between normal HSA and glycated HSA, as seen with linoleic acid. Systems with only direct competition also gave notable changes in the affinities of fatty acids at their sites of drug competition when comparing normal HSA and glycated HSA. This research demonstrated the importance of considering how changes in the concentrations and types of metabolites (e.g., in this case, glucose and fatty acids) can alter the function of a protein such as HSA and its ability to interact with drugs or other agents.
PubMed: 24349966
DOI: 10.2174/2213235x1130100005 -
Biological & Pharmaceutical Bulletin Jan 2005Acetohexamide (AH) is reduced to its alcohol metabolite by carbonyl reductase. We have previously shown that carbonyl reductase present in the liver microsomes of rats... (Comparative Study)
Comparative Study
Acetohexamide (AH) is reduced to its alcohol metabolite by carbonyl reductase. We have previously shown that carbonyl reductase present in the liver microsomes of rats is a male-specific and androgen-dependent enzyme. In the present study, the role of microsomal carbonyl reductase in the pharmacokinetics of AH was examined in male Wistar-Imamichi (WI) and Sprague-Dawley (SD) rats after its intravenous administration. AH was eliminated more slowly from plasma in the WI strain, which lacks most of the microsomal carbonyl reductase, than in the SD strain. Furthermore, several pharmacokinetic parameters were derived from the data for the plasma concentrations of AH. The plasma clearance (CL(p)) of AH (72.8+/-11.2 ml/h/kg) in male WI rats was significantly smaller than that (105.5+/-11.1 ml/h/kg) in male SD rats. Testectomy caused a marked decrease, from 105.5+/-11.1 to 44.3+/-11.8 ml/h/kg, in the CL(p) of AH in male SD rats. These results indicate that microsomal carbonyl reductase plays a critical role in the differential pharmacokinetics of AH in male WI and SD rats.
Topics: Acetohexamide; Alcohol Oxidoreductases; Aldehyde Reductase; Aldo-Keto Reductases; Animals; Female; Male; Microsomes; Rats; Rats, Sprague-Dawley; Rats, Wistar; Species Specificity
PubMed: 15635190
DOI: 10.1248/bpb.28.185 -
PloS One 2023Co-existence of life style disorders, like, Diabetes or Hypertension, increases risk of, treatment failure, deaths and developing drug-resistant TB. Concomitant...
Co-existence of life style disorders, like, Diabetes or Hypertension, increases risk of, treatment failure, deaths and developing drug-resistant TB. Concomitant administration of drugs to treat dual/multi-morbidities may alter their effectiveness, in additive/synergistic or adverse/antagonistic manner. We evaluated interactive effect of 7 anti-hyperglycaemic (HG) and 6 anti-hypertensive (HT) drugs on the inhibitory (MICs) and bactericidal (% killing of intracellular bacilli) activities of anti-TB drugs, Isoniazid (INH), Rifampicin (RFM), Ethambutol (EMB) and Streptomycin (STR) against M. tuberculosis. Five anti-HG drugs, namely, Acarbose, Acetohexamide, Glyburide, Repaglinide and Sitagliptin imparted either 'additive' or 'no effect' on the activities (inhibition or % killing) of all the four anti-TB drugs, as evident by their lower FICs (Fractional Inhibitory concentrations) and higher bacterial killing in combination. Metformin and Rosiglitazone, however, exerted adverse effect on the Ethambutol (FICs >2.0). All the six anti-HT drugs, namely, Atenolol, Hydrochlorothiazide, Ramipril, Valsartan, Nifedipine and Verapamil exerted either 'additive'/'synergistic' or 'no effect' on the activities of anti-TB drugs. These findings may help clinicians to select safe and helpful anti-HG or anti-HT drugs for TB patients, if, suffering with diabetes or hypertension like co-morbidities and receiving DOTs (a set regimen for the treatment of TB based on the WHO guidelines).
Topics: Humans; Antitubercular Agents; Antihypertensive Agents; Ethambutol; Pharmaceutical Preparations; Mycobacterium tuberculosis; Isoniazid; Microbial Sensitivity Tests; Tuberculosis; Hypertension; Diabetes Mellitus; Hypoglycemic Agents; Tuberculosis, Multidrug-Resistant
PubMed: 38032920
DOI: 10.1371/journal.pone.0292397 -
European Journal of Pharmaceutical... May 2021Cell surface binding immunoglobin protein (csBiP) is predicted to be susceptible to SARS-CoV-2 binding. With a substrate-binding domain (SBD) that binds to polypeptides...
AIMS
Cell surface binding immunoglobin protein (csBiP) is predicted to be susceptible to SARS-CoV-2 binding. With a substrate-binding domain (SBD) that binds to polypeptides and a nucleotide-binding domain (NBD) that can initiate extrinsic caspase-dependent apoptosis, csBiP may be a promising therapeutic target for COVID-19. This study aims to identify FDA-approved drugs that can neutralize viral binding and prevent viral replication by targeting the functional domains of csBiP.
METHODS
In silico screening of 1999 FDA-approved drugs against the functional domains of BiP were performed using three molecular docking programs to avoid bias from individual docking programs. Top ligands were selected by averaging the ligand rankings from three programs. Interactions between top ligands and functional domains of BiP were analyzed.
KEY FINDINGS
The top 10 SBD-binding candidates are velpatasvir, irinotecan, netupitant, lapatinib, doramectin, conivaptan, fenoverine, duvelisib, irbesartan, and pazopanib. The top 10 NBD-binding candidates are nilotinib, eltrombopag, grapiprant, topotecan, acetohexamide, vemurafenib, paritaprevir, pixantrone, azosemide, and piperaquine-phosphate. Among them, Velpatasvir and paritaprevir are antiviral agents that target the protease of hepatitis C virus. Netupitant is an anti-inflammatory drug that inhibits neurokinin-1 receptor, which contributes to acute inflammation. Grapiprant is an anti-inflammatory drug that inhibits the prostaglandin E receptor protein subtype 4, which is expressed on immune cells and triggers inflammation. These predicted SBD-binding drugs could disrupt SARS-CoV-2 binding to csBiP, and NBD-binding drugs may falter viral attachment and replication by locking the SBD in closed conformation and triggering apoptosis in infected cells.
SIGNIFICANCE
csBiP appears to be a novel therapeutic target against COVID-19 by preventing viral attachment and replication. These identified drugs could be repurposed to treat COVID-19 patients.
Topics: Antiviral Agents; Drug Repositioning; Immunoglobulins; Membrane Proteins; Models, Molecular; Molecular Structure; Protein Conformation; SARS-CoV-2; Structure-Activity Relationship; Virus Attachment; Virus Internalization
PubMed: 33617948
DOI: 10.1016/j.ejps.2021.105771 -
Molecular Cell Nov 2017DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within...
DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage. This led to the identification of the clinically approved anti-diabetic drug acetohexamide, which promoted clearance of UV-induced DNA damage without the accumulation of chromosomal aberrations, hence promoting cellular survival. Acetohexamide exerted this protective function by antagonizing expression of the DNA glycosylase, MUTYH. Together, our data reveal the existence of an NER-independent mechanism to remove UV-induced DNA damage and prevent cell death.
Topics: Acetohexamide; Cell Line, Tumor; DNA Damage; DNA Glycosylases; DNA Repair; Gene Expression Regulation, Enzymologic; Humans; Male; Ultraviolet Rays
PubMed: 29149600
DOI: 10.1016/j.molcel.2017.10.021 -
British Medical Journal Jul 1971
Topics: Acetohexamide; Acidosis; Administration, Oral; Anemia; Chlorpropamide; Drug Antagonism; Drug Synergism; England; Ethanol; Female; Fetus; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Metformin; Phenformin; Pregnancy; Scotland; Skin Diseases; Skin Manifestations; Tolazamide; Tolbutamide; Wales
PubMed: 5091891
DOI: 10.1136/bmj.3.5765.29 -
Yakugaku Zasshi : Journal of the... Jan 2001We examined physiological and genetic factors affecting acetohexamide reductase (AHR) and 20 beta-hydroxysteroid dehydrogenase (20 beta-HSD) activities in liver...
[Strain-, sex- and species-related differences of acetohexamide reductase and 20 beta-hydroxysteroid dehydrogenase activities in liver microsomes of experimental animals].
We examined physiological and genetic factors affecting acetohexamide reductase (AHR) and 20 beta-hydroxysteroid dehydrogenase (20 beta-HSD) activities in liver microsomes of experimental animals. Pronounced strain-related differences were found in both activities of AHR and 20 beta-HSD present in liver microsomes of male rats. Among rat strains tested in this study, even though a Wistar-Imamichi (WIM) rat strain was taken to lack AHR activity, it exhibited a significant 20 beta-HSD activity. These findings appeared to be in conflict with our conclusion reported so far, which AHR and 20 beta-HSD present in liver microsomes of male rats are identical enzymes. Thus the reason for this discrepancy was discussed. Furthermore, AHR and 20 beta-HSD activities were little or not observed in liver microsomes of female rats or male experimental animals other than the rat, indicating the existence of sex- and species-related differences in these two enzyme activities.
Topics: 20-Hydroxysteroid Dehydrogenases; Alcohol Oxidoreductases; Animals; Female; Male; Mice; Microsomes, Liver; Rabbits; Rats; Rats, Inbred Strains; Sex Characteristics; Species Specificity
PubMed: 11201165
DOI: 10.1248/yakushi.121.85 -
Journal of Chromatography. A Apr 2011This report examined the use of silica monoliths in affinity microcolumns containing human serum albumin (HSA) to measure the dissociation rates for various drugs from...
This report examined the use of silica monoliths in affinity microcolumns containing human serum albumin (HSA) to measure the dissociation rates for various drugs from this protein. Immobilized HSA and control monolith columns with dimensions of 1 mm × 4.6 mm i.d. were prepared for this work and used with a noncompetitive peak decay method. Several drugs known to bind HSA were examined, such as warfarin, diazepam, imipramine, acetohexamide, and tolbutamide. Items that were studied and optimized in this method included the sample volume, sample concentration, and elution flow rate. It was found that flow rates up to 10 mL/min could be used in this approach. Work with HSA silica monoliths at these high flow rates made it possible to provide dissociation rate constants for drugs such as warfarin in less than 40s. The dissociation rate constants that were measured gave good agreement with values reported in the literature or that had been obtained with other solutes that had similar binding affinities for HSA. This approach is a general one that should be useful in examining the dissociation of other drugs from HSA and in providing a high-throughput method for screening drug-protein interactions.
Topics: Chromatography, Affinity; High-Throughput Screening Assays; Humans; Immobilized Proteins; Kinetics; Pharmaceutical Preparations; Protein Binding; Serum Albumin; Silicon Dioxide
PubMed: 20956006
DOI: 10.1016/j.chroma.2010.09.070 -
British Medical Journal Apr 1964
Topics: Acetohexamide; Blood Chemical Analysis; Chlorpropamide; Diabetes Mellitus; Diet, Diabetic; Gastroenterology; Geriatrics; Glucose Tolerance Test; Hypoglycemic Agents; Leukopenia; Middle Aged; Tolbutamide; Toxicology
PubMed: 14104973
DOI: 10.1136/bmj.1.5387.868 -
Molecules (Basel, Switzerland) Jul 2014Diabetes mellitus is a life threatening disease and scientists are doing their best to find a cost effective and permanent treatment of this malady. The recent trend is...
Diabetes mellitus is a life threatening disease and scientists are doing their best to find a cost effective and permanent treatment of this malady. The recent trend is to control the disease by target base inhibiting of enzymes or proteins. Secreted frizzled-related protein 4 (SFRP4) is found to cause five times more risk of diabetes when expressed above average levels. This study was therefore designed to analyze the SFRP4 and to find its potential inhibitors. SFRP4 was analyzed by bio-informatics tools of sequence tool and structure tool. A total of three potential inhibitors of SFRP4 were found, namely cyclothiazide, clopamide and perindopril. These inhibitors showed significant interactions with SFRP4 as compared to other inhibitors as well as control (acetohexamide). The findings suggest the possible treatment of diabetes mellitus type 2 by inhibiting the SFRP4 using the inhibitors cyclothiazide, clopamide and perindopril.
Topics: Computer Simulation; Diabetes Mellitus; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Proto-Oncogene Proteins
PubMed: 25019556
DOI: 10.3390/molecules190710129