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The class III effect of azimilide is not associated with reverse use-dependence in open-chest dogs.

Certain class III antiarrhythmic agents manifest loss of effect at short cycle lengths (CLs). This effect may limit their efficacy in the presence of tachycardia. We studied the frequency-dependent effect of azimilide (NE-10064), a new class III agent, on the right ventricular monophasic action potential (APD90) in 12 open-chest dogs. The monophasic action-potential duration at different pacing CLs (140-400 ms), during sinus rhythm, and ventricular fibrillation CL (VFCL) from left epicardial electrograms were recorded before and after increasing doses of intravenous azimilide. At pacing CL of

Expression of a human P-450IIC gene in yeast cells using galactose-inducible expression system.

A cDNA of a human liver cytochrome P-450, corresponding to P-450 human-2, was expressed in Saccharomyces cerevisiae cells by the use of a galactose-inducible expression vector containing the GAL7 promoter and terminator. In Western blots using anti-P-450 human-2 IgG, a single band, which exhibited mobility identical to that of authentic P-450 human-2 purified from human liver, was detected in microsomes of the yeast cells. The amount synthesized in yeast was estimated to be approximately 1% of the total cell protein, and approximately 25% of the cytochrome existed in the holoenzyme state. Micr

A Triazaspirane Derivative Inhibits Migration and Invasion in PC3 Prostate Cancer Cells.

Cancer is a serious health problem due to the complexity of establishing an effective treatment. The purpose of this work was to evaluate the activity of a triazaspirane as a migration and invasion inhibitor in PC3 prostatic tumor cells through a possible negative regulation of the FAK/Src signal transduction pathway and decreased secretion of metalloproteinases 2 and 9. Molecular docking analysis was performed using Moe 2008.10 software. Migration (wound-healing assay) and invasion (Boyden chamber assay) assays were performed. In addition, the Western blot technique was used to quantify prote

The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice.

UNLABELLED: Fibrogenesis encompasses the deposition of matrix proteins, such as collagen I, by hepatic stellate cells (HSCs) that culminates in cirrhosis. Fibrogenic signals drive transcription of procollagen I, which enters the endoplasmic reticulum (ER), is trafficked through the secretory pathway, and released to generate extracellular matrix. Alternatively, disruption of procollagen I ER export could activate the unfolded protein response (UPR) and drive HSC apoptosis. Using a small interfering RNA screen, we identified Transport and Golgi organization 1 (TANGO1) as a potential participant

Rapid determination of fungicides in fruit juices by micellar electrokinetic chromatography: use of organic modifiers to enhance selectivity and on-column high-salt stacking to improve sensitivity.

A rapid, reliable method for the multiresidue analysis of eight commonly used fungicides by micellar electrokinetic chromatography (MEKC) was developed. Excellent separation of the eight fungicides (carbendazim, metalaxyl, captan, procymidone, folpet, captafol, vinclozolin and iprodione) is achieved within about 10 min by using optimized electrophoretic conditions that include the addition of a mixture of organic modifiers to the running buffer for improved resolution. The sensitivity of the method is enhanced by using an enrichment step that involves on-column high-salt stacking. Limits of de

National scientific medical meeting 1996 abstracts

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Cytotoxicity and transcriptional activation of stress genes in human liver carcinoma (HepG2) cells exposed to iprodione.

Iprodione (C13H13Cl2N3O3) is a broad spectrum dicarboximide fungicide used on a wide variety of crop diseases. It is used on vegetables, ornamentals, pome and stone fruit, root crops, cotton and sunflowers, to control a variety of fungal pests. Iprodione inhibits the germination of spores and the growth of the fungal mycelium. Experimental studies with mice have indicated that exposure to iprodione at dose levels 5 to 15 folds greater than the LOAEL for liver injury, induces microsomal enzyme activities, hepatocyte proliferation, hepatomegaly, centrilobular hypertrophy, diffuse hypertrophy, an

Drug Repurposing for the Management of Depression: Where Do We Stand Currently?

A slow rate of new drug discovery and higher costs of new drug development attracted the attention of scientists and physicians for the repurposing and repositioning of old medications. Experimental studies and off-label use of drugs have helped drive data for further studies of approving these medications. A deeper understanding of the pathogenesis of depression encourages novel discoveries through drug repurposing and drug repositioning to treat depression. In addition to reducing neurotransmitters like epinephrine and serotonin, other mechanisms such as inflammation, insufficient blood supp

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… the formulation, NYHA class III/IV heart failure Phenytoin Dilantin ® , Phenytek ® [ 84 ] | Seizures (non-emergent use), status epilepticus | Stabilizes neuronal membranes and decreases seizure activity by modulating efflux or influx of sodium, shortens action potential in the heart/Anticonvulsant, hydantoin … | NA | Nystagmus, ataxia, slurred speech, decreased coordination, somnolence, mental confusion | Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation, concurrent use of delavirdine, history of prior acute hepatotoxicity attributable to phenytoin Pramipexole Mirapex ® …

NTP Toxicology and Carcinogenesis Studies of Nitrofurantoin (CAS No. 67-20-9) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Nitrofurantoin was studied and evaluated because of its widespread use as a drug for treating urinary tract infections in humans, its structural relationship to known carcinogenic 5-nitrofuran compounds, and the lack of adequate studies to assess its carcinogenicity. Toxicology and carcinogenesis studies of nitrofurantoin were conducted by administering nitrofurantoin (greater than 99% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: None of the rats (at dietary concentrations up to 20,000 ppm) died be

Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis.

Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to a subset of resistant plasma cells that continue to secrete misfolding-prone light chains. These light chains are susceptible to the proteolytic cleavage that may enable light chain aggregation. We propose that small molecules that preferentially bind to the nativ

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… Yan NL; Santos-Martins D; Rennella E; Sanchez BB; Chen JS; Kay LE; Wilson IA; Morgan GJ; Forli S; Kelly JW Structural basis for the stabilization of amyloidogenic immunoglobulin light chains by hydantoins. Bioorganic Med. Chem. Lett 2020, 30, 127356. 85. …

Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs.

ObjectiveTo determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties.Material and methodsA review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it w

Next-Generation HDAC Inhibitors: Advancing Zinc-Binding Group Design for Enhanced Cancer Therapy.

Histone deacetylases (HDACs) are pivotal epigenetic regulators that control gene expression, cell proliferation, and differentiation, and their dysregulation is closely associated with the onset and progression of multiple cancers. The therapeutic importance of these enzymes is reflected by FDA approval of HDAC inhibitors for oncology indications. Despite this clinical success, most FDA-approved agents employ conventional zinc-binding groups (ZBGs) such as hydroxamic acid and 2-aminoanilide, which are frequently linked to metabolic instability, genotoxicity, and poor pharmacokinetic behavior.

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy.

Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reacti

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… RO-2443 and its chemically optimized analog RO-5963 are indolyl hydantoins which appeared to be MDM2/X antagonists with promising preclinical results ( 36 , 210 ). …

DNA Damaging Drugs

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What is the Reason That the Pharmacological Future of Chemotherapeutics in the Treatment of Lung Cancer Could Be Most Closely Related to Nanostructures? Platinum Drugs in Therapy of Non-Small and Small Cell Lung Cancer and Their Unexpected, Possible Interactions. The Review.

Over the course of several decades, anticancer treatment with chemotherapy drugs for lung cancer has not changed significantly. Unfortunately, this treatment prolongs the patient's life only by a few months, causing many side effects in the human body. It has also been proven that drugs such as Cisplatin, Carboplatin, Oxaliplatin and others can react with other substances containing an aromatic ring in which the nitrogen atom has a free electron group in its structure. Thus, such structures may have a competitive effect on the nucleobases of DNA. Therefore, scientists are looking not only for

Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies.

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase