benzofurans and benziodarone

Topics: Adult; Aged; Benzbromarone; Benzofurans; Clinical Trials as Topic; Gout; Humans; Male; Middle Aged; Uric Acid

Topics: Benzofurans; Clinical Trials as Topic; Gout; Humans; Male; Middle Aged; Uric Acid

Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.

Topics: Amyloid; Amyloid Neuropathies, Familial; Benzofurans; Humans; Prealbumin

Applying toxicogenomics to improving the safety profile of drug candidates and crop protection molecules is most useful when it identifies relevant biological and mechanistic information that highlights risks and informs risk mitigation strategies. Pathway-based approaches, such as gene set enrichment analysis, integrate toxicogenomic data with known biological process and pathways. Network methods help define unknown biological processes and offer data reduction advantages. Integrating the 2 approaches would improve interpretation of toxicogenomic information. Barriers to the routine application of these methods in genome-wide transcriptomic studies include a need for "hands-on" computer programming experience, the selection of 1 or more analysis methods (eg pathway analysis methods), the sensitivity of results to algorithm parameters, and challenges in linking differential gene expression to variation in safety outcomes. To facilitate adoption and reproducibility of gene expression analysis in safety studies, we have developed Collaborative Toxicogeomics, an open-access integrated web portal using the Django web framework. The software, developed with the Python programming language, is modular, extensible and implements "best-practice" methods in computational biology. New study results are compared with over 4000 rodent liver experiments from Drug Matrix and open TG-GATEs. A unique feature of the software is the ability to integrate clinical chemistry and histopathology-derived outcomes with results from gene expression studies, leading to relevant mechanistic conclusions. We describe its application by analyzing the effects of several toxicants on liver gene expression and exemplify application to predicting toxicity study outcomes upon chronic treatment from expression changes in acute-duration studies.

Topics: Access to Information; Benzbromarone; Benzofurans; Humans; Internet; Liver; Omeprazole; Phenotype; Toxicogenetics; Transcriptome; Triglycerides

Human toxicity screening is an important stage in the development of safe drug candidates. Hepatotoxicity is one of the major reasons for the withdrawal of drugs from the market because the liver is the major organ involved in drug metabolism, and it can generate toxic metabolites. There is a need to screen molecules for drug-induced hepatotoxicity in humans at an earlier stage. Transcriptomics is a technique widely used to screen molecules for toxicity and to unravel toxicity mechanisms. To date, the majority of such studies were performed using animals or animal cells, with concomitant difficulty in interpretation due to species differences, or in human hepatoma cell lines or cultured hepatocytes, suffering from the lack of physiological expression of enzymes and transporters and lack of nonparenchymal cells. The aim of this study was to classify known hepatotoxicants on their phenotype of toxicity in humans using gene expression profiles ex vivo in human precision-cut liver slices (PCLS). Hepatotoxicants known to induce either necrosis (n = 5) or cholestasis (n = 5) were used at concentrations inducing low (<30%) and medium (30-50%) cytotoxicity, based on ATP content. Random forest and support vector machine algorithms were used to classify hepatotoxicants using a leave-one-compound-out cross-validation method. Optimized biomarker sets were compared to derive a consensus list of markers. Classification correctly predicted the toxicity phenotype with an accuracy of 70-80%. The classification is slightly better for the low than for the medium cytotoxicity. The consensus list of markers includes endoplasmic reticulum stress genes, such as C2ORF30, DNAJB9, DNAJC12, SRP72, TMED7, and UBA5, and a sodium/bile acid cotransporter (SLC10A7). This study shows that human PCLS are a useful model to predict the phenotype of drug-induced hepatotoxicity. Additional compounds should be included to confirm the consensus list of markers, which could then be used to develop a biomarker PCR-array for hepatotoxicity screening.

Topics: Acetaminophen; Aged; Benzofurans; Bile Acids and Salts; Chloramphenicol; Chlorpromazine; Cholestasis; Colchicine; Cyclosporine; Diethylnitrosamine; Drug-Related Side Effects and Adverse Reactions; Ethinyl Estradiol; Female; Gene Expression Profiling; Hepatocytes; Humans; Liver; Male; Methyltestosterone; Middle Aged; Necrosis; Phenotype; Toxicogenetics; Young Adult

Topics: Aged; Anti-Arrhythmia Agents; Benzofurans; Drug Interactions; Female; Flecainide; Heart Block; Humans; Kidney Transplantation; Vasodilator Agents

Topics: Acute Kidney Injury; Adult; Benzofurans; Humans; Kidney Transplantation; Male; Uric Acid; Uricosuric Agents

Hyperuricemia is associated with hypertension and vascular disease, but whether this represents a causal relationship or an epiphenomenon remains unknown. We recently reported a model of mild hyperuricemia in rats that results in increased blood pressure and mild renal fibrosis. In this study, we examined the effect of hyperuricemia on the renal vasculature. Rats fed 2% oxonic acid and a low-salt diet for 7 wk developed mild hyperuricemia (1.8 vs. 1.4 mg/dl, P < 0.05), hypertension [147 vs. 127 mmHg systolic blood pressure (SBP), P < 0.05], and afferent arteriolar thickening, with a 35% increase in medial area (P < 0.05). Allopurinol or benziodarone prevented the hyperuricemia, hypertension, and arteriolopathy. Hydrochlorothiazide treatment did not prevent the hyperuricemia or arteriolopathy despite controlling blood pressure. In contrast, the arteriolopathy and hypertension were prevented by both enalapril and losartan. Uric acid also directly stimulated vascular smooth muscle cell proliferation in vitro, and this was partially inhibited by losartan. Thus hyperuricemia induces a renal arteriolopathy in rats that is blood pressure independent and involves the renin-angiotensin system.

Topics: Administration, Oral; Allopurinol; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Benzofurans; Blood Pressure; Diuretics; Enalapril; Hydrochlorothiazide; Hypertension; Kidney; Losartan; Male; Muscle, Smooth, Vascular; Oxonic Acid; Rats; Rats, Sprague-Dawley; Sodium Chloride Symporter Inhibitors; Sodium Chloride, Dietary; Uric Acid; Uricosuric Agents; Vascular Diseases

The prevalence of hyperuricemia was investigated in 214 kidney allograft recipients, 81 were on azathioprine and steroids and 133 on cyclosprine (CyA) and low-dose steroids or on triple therapy. All had stable renal function, serum creatinine < 2.5 mg/dl, and a follow-up between 12 and 120 months. At the time of the study, blood and urine samples were obtained to perform tests of renal function. The renal handling of urate was evaluated by a combined pyrazinamide and probenecid test in 35 selected patients (12 normouricemic on azathioprine, 9 normouricemic on CyA and 14 hyperuricemic on CyA). The prevalence of hyperuricemia was higher in the group of patients on CyA (19.7 vs. 66.9%, p < 0.001), as well as the concentration of serum urate (6.1 +/- 1.9 vs. 7.6 +/- 1.7, p < 0.001), and serum creatinine (1.2 +/- 0.3 vs. 1.4 +/- 0.4, p < 0.001). In patients on CyA, multivariate analysis showed that the most important predictive variables of hyperuricemia were: serum creatinine, FEurate, diuretic use and CyA blood levels (r = 0.73, p < 0.0001). Thirteen patients on CyA (9.9%) had at least one episode of gouty arthritis. Those patients were older than the hyperuricemic patients without gout (45.7 +/- 6.7 vs. 37.1 +/- 13.5 years, p < 0.01), had worse renal function (serum creatinine 1.9 +/- 0.4 vs. 1.5 +/- 0.4 mg/dl, p < 0.01), and higher prevalence of hypertension (100 vs. 63.1%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Benzofurans; Cyclosporine; Female; Humans; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Prevalence; Probenecid; Pyrazinamide; Retrospective Studies; Uric Acid; Uricosuric Agents

Benzofuran derivatives: amiodarone, benziodarone, benzbromarone and benzarone, extracted from plasma, were separated by TLC method on silica gel by ascending and horizontal developments, using suitable mobile phases. The substances were identified by reaction with potassium permanganate solution, either by Dragendorff (modified after Amelink) or Sonnenschein reagents (up to the amounts of 250 ng of amiodarone and benzarone and 500 ng of benziodarone and benzbromarone).

Topics: Amiodarone; Benzbromarone; Benzofurans; Chromatography, Thin Layer; Fibrinolytic Agents; Humans; Uricosuric Agents; Vasodilator Agents

Topics: Benzofurans; Cyclosporine; Humans; Kidney Transplantation; Kidney Tubules; Uric Acid; Uricosuric Agents

The authors pay attention to benziodarone, a representative of the category of benzofurans. They test its effect on the uric acid serum level in normouraemic subjects as well as in hyperuricaemic syndrome and gouty arthritis. The hypouricaemic action of benziodarone (Amplivex-Labaz) is prompt. The maximum drop of uricaemia after Amplivex administration (2 tablets/day) occurs during the first three days. The uric acid level declines by as much as 80% of the baseline value. For long-term treatment 1 tablet per day is sufficient, in some instances even 1 tablet twice a week. The tolerance of the preparation is satisfactory. The authors deal also with the mechanism of action of benziodarone. Amplivex is not only a uricostatic but also a uricosuric agent.

Topics: Arthritis, Gouty; Benzofurans; Female; Humans; Male; Uric Acid; Uricosuric Agents

Amiodarone.HCl (I), 2-butyl-3-benzofuranyl 4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride, C25H30I2NO3+.Cl-, Mr = 680.78, monoclinic, P2(1)/c, a = 17.124 (2), b = 17.079 (2), c = 9.162 (1) A, beta = 98.37 degrees, V = 2651.2 A3, Z = 4, Dx = 1.71 g cm-3, lambda(Mo K alpha) = 0.7107 A, mu = 24.73 cm-1, F(000) = 1332, T = 294 K, R = 6.6% for 5515 data; desethyl-amiodarone.HCl (II), 2-butyl-3-benzofuranyl 4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride, C23H26I2NO3+.Cl-, Mr = 654.74, monoclonic, P2(1)/c, a = 23.867 (2), b = 10.134 (1), c = 10.287 (2) A, beta = 93.91 (2) degrees, V = 2482.5 A3, Z = 4, Dx = 1.75 g cm-3, lambda(Mo K alpha) = 0.07107 A, mu = 26.37 cm-1, F(000) = 1276, T = 294 K, R = 5.7% for 5916 data; benziodarone (III), 2-ethyl-3-benzofuranyl 4-hydroxy-3,5-diiodophenyl ketone, C17H12I2O3, Mr = 518.09, monoclinic, P2(1)/n, a = 17.564 (2), b = 8.294 (1), c = 11.587 (2) A, beta = 93.20 (2) degrees, V = 1685.55 A3, Z = 4, Dx = 2.04 g cm-3, lambda(Mo K alpha) = 0.7101 A, mu = 36.99 cm-1, F(000) = 976, T = 294 K, R = 6.2% for 4311 data.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Molecular Conformation; Stereoisomerism; Structure-Activity Relationship; Thyroxine

This study examined whether or not the electrophysiological effect of amiodarone on the heart is mediated through its action on thyroxine metabolism. Serum thyroid hormones and ECG were evaluated before and serially during amiodarone (15 subjects) and benziodarone (15 subjects) administration. Both amiodarone and benziodarone shifted the peripheral conversion of thyroxine (P less than 0.001 for amiodarone and P less than 0.001 for benziodarone) towards reverse triiodothyronine and away from triiodothyronine, whilst TSH levels initially fell and then rose with both drugs. After amiodarone the heart rate decreased (P less than 0.025), whilst the PR (P less than 0.005) and the QT interval (P less than 0.005) corrected for the heart rate increased. By contrast with benziodarone only the PR interval decreased (P less than 0.05). Since both drugs had roughly similar effects on thyroid hormone metabolism but different ones on the ECG, our results provide indirect evidence against the hypothesis that the antiarrhythmic effects of amiodarone are mediated through a decrease in the serum T3 presented to the peripheral tissues.

Topics: Adolescent; Adult; Aged; Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Electrocardiography; Female; Humans; Middle Aged; Thyrotropin; Thyroxine; Triiodothyronine

The effect of benziodarone on the levels of thyroid hormones in the serum has not attracted interest, in spite of the prolific literature on the related drug amiodarone. It is shown here that benziodarone administration has several effects, mainly similar to amiodarone, but some possibly opposite and inappropriate. Nine normal volunteers received benziodarone, 100 mg three times daily for 14 days. Before and 1, 3, 7 and 14 days after continuous administration the following estimates were obtained: serum T4, T3, rT3 and TSH, both basal (TSH0) and 30 min after iv administration of TRH (TSH30), the difference being calculated as delta TSH. Serum T4 remained relatively constant. Serum T3 decreased significantly from the 1st to the 14th day (eg. before 2.15 +/- 0.12 nmol/l, at 3 days 1.45 +/- 0.07). Serum rT3 increased significantly from the 1st to the 14th day (eg. before 0.71 +/- 0.16 nmol/l, at 7 days 2.61 +/- 0.19). Serum TSH0 and TSH30 decreased significantly on the 1st and 3rd day. Later they increased, and TSH0 at 14 days was significantly higher than the pre-treatment value. Our results suggest that benziodarone has an amiodarone-like action in diverting the peripheral metabolism of T4 towards rT3 rather than T3. However, the effects on the pituitary-thyroid axis are not similar to those previously reported by others and ourselves about amiodarone, and these merit further research.

Topics: Adult; Benzofurans; Female; Humans; Male; Middle Aged; Pituitary Gland; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The biliary secretion of methylmercury was investigated in male rats which were given i.p. 400 mumoles/kg azathioprine or 96 mumoles/kg benziodarone 2 hr after the i.v. injection of 5 mumoles/kg MeHgCl. A group of rats were given 400 mg/kg trans-stilbene oxide (TSO) for 4 days before treatment with 10 mumoles/kg MeHgCl. A common link between these three compounds is their interference with ligandin. Azathioprine is a competitive inhibitor of glutathione S-transferase, benziodarone is covalently bound to ligandin and TSO is an inducer of liver ligandin. Although only azathioprine depletes liver GSH stores, both azathioprine and benziodarone inhibited the biliary secretion of methylmercury. As there is published proof that the reaction of MeHg+ with GSH does not require enzymatic help, the inhibitory effect of azathioprine and benziodarone confirms the role of ligandin in the transport of methylmercury or its GSH complex. However, the biliary secretion of methylmercury was increased only slightly by TSO pretreatment, but when 2 hr after the injection of MeHgCl animals received 2 mmoles/kg GSH, secretion increased twice as much in TWO pretreated than in control rats. This indicates the dual dependance of biliary methylmercury secretion on liver GSH and ligandin.

Topics: Animals; Azathioprine; Benzofurans; Bile; Biliary Tract; Glutathione; Glutathione Transferase; Liver; Male; Methylmercury Compounds; Rats; Rats, Inbred Strains; Stilbenes; Time Factors

Topics: Administration, Oral; Adult; Aged; Allopurinol; Benzofurans; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Uric Acid

Topics: Allopurinol; Animals; Benzofurans; Rats; Rats, Inbred Strains; Xanthine Oxidase

Topics: Angina Pectoris; Benzofurans; Drug Therapy; Furans; Hypothyroidism; Intermittent Claudication; Iodides; Iodine; Toxicology; Vascular Diseases; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Furans; Humans; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Geriatrics; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Electrocardiography; Furans; Geriatrics; Humans; Physical Exertion; Vasodilator Agents

Topics: Benzofurans; Chemical and Drug Induced Liver Injury; Furans; Hepatitis; Jaundice; Toxicology; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Drug Therapy; Furans; Humans; Injections, Intravenous; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Drug Tolerance; Electrocardiography; Furans; Geriatrics; Placebos; Vasodilator Agents

Topics: Animals; Benzofurans; Furans; Myocardium; Rabbits; Vasodilator Agents

Topics: Anticoagulants; Benzofurans; Coronary Disease; Furans; Humans; Vasodilator Agents

Topics: Adenosine Triphosphatases; Benzofurans; In Vitro Techniques; Kidney; Liver; Muscles; Myocardium; Succinate Dehydrogenase; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Double-Blind Method; Furans; Humans; Vasodilator Agents

Topics: Benzofurans; Coronary Artery Disease; Coronary Disease; Furans; Humans; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Furans

Topics: Angina Pectoris; Benzofurans; Cardiovascular Agents; Electrocardiography; Furans; Humans; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Biomedical Research; Cardiovascular Agents; Furans; Humans; Pentaerythritol Tetranitrate; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Double-Blind Method; Furans

Topics: Angina Pectoris; Benzofurans; Furans; Humans

Topics: Anti-Arrhythmia Agents; Benzofurans; Coronary Disease; Enzyme Inhibitors; Furans; Humans; Vasodilator Agents

Topics: Benzofurans; Furans; Iodides; Iodine; Research; Thyroid Gland

Topics: Anti-Arrhythmia Agents; Benzofurans; Cardiotonic Agents; Coronary Disease; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Furans; Humans; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Furans; Syndrome; Vasodilator Agents

Topics: Angina Pectoris; Benzofurans; Coumarins