-
Postgraduate Medical Journal Jun 1960
Topics: Chlorothiazide; Humans; Hydrochlorothiazide; Hydroflumethiazide
PubMed: 13847504
DOI: 10.1136/pgmj.36.416.392 -
EBioMedicine Apr 2019Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a...
BACKGROUND
Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment.
METHODS
In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions.
FINDINGS
We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line.
INTERPRETATION
Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.
Topics: Cell Line, Tumor; Cell Survival; Drug Discovery; Drug Repositioning; Gene Expression Profiling; Genes, Reporter; Genome, Human; Genomics; Humans; Male; Metabolic Networks and Pathways; Metabolomics; Piperidines; Prostatic Neoplasms; Proteome; Proteomics
PubMed: 30905848
DOI: 10.1016/j.ebiom.2019.03.009 -
Biochemistry Sep 2009Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission and are therapeutic targets for cognitive enhancement and treatment of...
Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission and are therapeutic targets for cognitive enhancement and treatment of schizophrenia. The binding domains of these tetrameric receptors consist of two dimers, and the dissociation of the dimer interface of the ligand-binding domain leads to desensitization in the continued presence of agonist. Positive allosteric modulators act by strengthening the dimer interface and reducing the level of desensitization, thereby increasing steady-state activation. Removing the desensitized state for simplified analysis of receptor activation is commonly achieved using cyclothiazide (CTZ), the most potent modulator of the benzothiadiazide class, with the flip form of the AMPA receptor subtype. IDRA-21, the first benzothiadiazide to have an effect in behavioral tests, is an important lead compound in clinical trials for cognitive enhancement as it can cross the blood-brain barrier. Intermediate structures between CTZ and IDRA-21 show reduced potency, suggesting that these two compounds have different contact points associated with binding. To understand how benzothiadiazides bind to the pocket bridging the dimer interface, we generated a series of crystal structures of the GluR2 ligand-binding domain complexed with benzothiadiazide derivatives (IDRA-21, hydroflumethiazide, hydrochlorothiazide, chlorothiazide, trichlormethiazide, and althiazide) for comparison with an existing structure for cyclothiazide. The structures detail how changes in the substituents at the 3- and 7-positions of the hydrobenzothiadiazide ring shift the orientation of the drug in the binding site and, in some cases, change the stoichiometry of binding. All derivatives maintain a hydrogen bond with the Ser754 hydroxyl, affirming the partial selectivity of the benzothiadiazides for the flip form of AMPA receptors.
Topics: Allosteric Regulation; Allosteric Site; Animals; Benzothiadiazines; Crystallography, X-Ray; Dimerization; Glutamic Acid; Hydrophobic and Hydrophilic Interactions; Ligands; Protein Structure, Tertiary; Rats; Receptors, AMPA; Structure-Activity Relationship
PubMed: 19673491
DOI: 10.1021/bi901127s -
Postgraduate Medical Journal Oct 1971Two hundred and twenty-seven cases of moderate to severe hypertension were treated with thiazide diuretics alone for periods of up to 12 years. In 80% the hypertension...
Two hundred and twenty-seven cases of moderate to severe hypertension were treated with thiazide diuretics alone for periods of up to 12 years. In 80% the hypertension was adequately controlled without additional antihypertensive agents. Hypokalaemic alkalosis was common despite potassium supplements—but caused no symptoms. The incidence of diabetes and gout was low. It is concluded that thiazide diuretics provide excellent control of hypertension with very few side effects.
Topics: Antihypertensive Agents; Benzothiadiazines; Diabetes Mellitus; Diuretics; Female; Gout; Humans; Hydroflumethiazide; Hypertension; Hypokalemia; Male; Middle Aged; Time Factors
PubMed: 5158836
DOI: 10.1136/pgmj.47.552.639 -
British Medical Journal Nov 1959
Topics: Chlorothiazide; Diuresis; Diuretics; Hydroflumethiazide
PubMed: 14407732
DOI: 10.1136/bmj.2.5157.928 -
Journal of Neurology, Neurosurgery, and... Jul 1976A series of 30 patients (28 females : 2 males) presenting with benign intracranial hypertension is reported. It is shown that the papilloedema may be resolved in as...
Treatment of benign intracranial hypertension by dehydrating agents with particular reference to the measurement of the blind spot area as a means of recording improvement.
A series of 30 patients (28 females : 2 males) presenting with benign intracranial hypertension is reported. It is shown that the papilloedema may be resolved in as little as six weeks by the use of dehydration therapy. Evidence is presented that this method can restore to normal a visual acuity which is as low as 6/24 or even 6/36. It is concluded that surgery is never required in the management of this condition. It is strongly recommended that serial blind-spot measurements should be used routinely to assess the effectiveness of therapy. Fluorescein angiography has a place in diagnosis among a small proportion of these patients.
Topics: Adolescent; Adult; Chlorthalidone; Female; Glycerol; Humans; Hydroflumethiazide; Intracranial Pressure; Male; Methods; Optic Disk; Papilledema; Pregnancy; Time Factors; Urea
PubMed: 993795
DOI: 10.1136/jnnp.39.7.627 -
British Medical Journal Jul 1974Renal lithium clearances were determined after the administration of a small test dose of lithium carbonate in 22 patients when they were on long-term treatment with...
Renal lithium clearances were determined after the administration of a small test dose of lithium carbonate in 22 patients when they were on long-term treatment with thiazides and when they were not on such treatment. Thiazide administration led to a 24% reduction in the lithium clearance. Diuretic drugs should be used with caution in patients given lithium treatment, and lithium should be used with caution in patients receiving diuretic treatment.
Topics: Bendroflumethiazide; Creatinine; Diuretics; Drug Interactions; Edema; Female; Humans; Hydroflumethiazide; Kidney; Kidney Function Tests; Lithium; Male; Sodium; Sodium Chloride Symporter Inhibitors
PubMed: 4846274
DOI: 10.1136/bmj.3.5924.143 -
Quarterly Journal of Experimental... Oct 1966
Topics: Absorption; Animals; Bendroflumethiazide; Chlorides; Chlorothiazide; Diazoxide; Hydrochlorothiazide; Hydroflumethiazide; Kidney Tubules; Natriuresis; Potassium; Sheep; Vasopressins; Water-Electrolyte Balance
PubMed: 5182361
DOI: 10.1113/expphysiol.1966.sp001864 -
Quarterly Journal of Experimental... Jul 1963
Topics: Benzothiadiazines; Diabetes Insipidus; Diabetes Mellitus; Diuresis; Electrolytes; Humans; Hydroflumethiazide; Spironolactone; Water-Electrolyte Balance
PubMed: 14031943
DOI: 10.1113/expphysiol.1963.sp001661