oxadiazoles and Acute-Disease

Topics: Acute Disease; Adult; Aged; Antitussive Agents; Benzhydryl Compounds; Chronic Disease; Clinical Trials as Topic; Codeine; Cough; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines; Propanolamines

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

Topics: Acute Disease; Aminopyridines; Animals; Cell Line, Tumor; Doxycycline; Drug Resistance, Neoplasm; Enzyme Inhibitors; Epigenesis, Genetic; Glycine; HL-60 Cells; Humans; Isocitrate Dehydrogenase; Isoenzymes; Leukemia, Myeloid; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mitochondria; Mutation; Oxadiazoles; Oxidative Phosphorylation; Piperidines; Pyridines; Triazines; Xenograft Model Antitumor Assays

Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide, and both cardiac necroptosis and endoplasmic reticulum stress (ERS) have been involved in the pathophysiology of AMI. ZYZ-803 is a hybrid molecule of a dual donor for gasotransmitters H

Topics: Acute Disease; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiotonic Agents; Down-Regulation; Endoplasmic Reticulum Stress; Humans; Hydrogen Sulfide; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Necroptosis; Nitric Oxide; Nitric Oxide Donors; Oxadiazoles; Random Allocation; Rats; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction; Transfection

Butylaminohydroxypropoxyphenoxymethyl methyloxadiazole was used in prehospital treatment of 40 patients (15 women, 25 men aged 63+/-17.1 years) with complicated hypertensive crises (HC) characterized by acute involvement or high risk of progression of damage of internal organs. The drug was administered as intravenous bolus injection of 10-50 mg (1-5 ml of 1% solution) under control of arterial pressure (AP) and heart rate (HR). The patients noted alleviation of symptoms by 15th min and disappearance of main manifestations of HC by 30th min. Systolic and diastolic AP were significantly lowered from baseline 190.0+/-24.4 and 105.0+/-13.5 mm Hg to 153.3+/-20,1 and 85.0+/-12,6 mm Hg, respectively. Mean dynamics of lowering of systolic and diastolic AP was 19.5 and 19%, respectively. This was accompanied by 15.4% lowering of HR (from 90.3+/-12.0 to 76.4+/-9.4 bpm). Myocardial ischemia in those patients who had it diminished or disappeared. Thus in patients with complicated HC the study drug exerted effective antihypertensive and antiischemic actions. It was well tolerated and did not cause significant side effects.

Topics: Acute Coronary Syndrome; Acute Disease; Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Blood Pressure; Drug Repositioning; Emergency Medical Services; Female; Heart Rate; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Injections, Intravenous; Male; Middle Aged; Oxadiazoles; Therapies, Investigational

Synthesis and biological evaluation of various aroylpropionic acid derivatives containing 1,3,4-Oxadiazole nucleus is reported here. The compounds (3a-w) were synthesized by cyclization of 3-aroylpropionic acids into 1,3,4-oxadiazole nucleus by treating with various aryl acid hydrazides in the presence of POCl(3). The structures of new compounds are supported by IR, (1)H NMR and MS data. These compounds were tested in vivo for their anti-inflammatory activity. All the compounds tested showed anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic and lipid peroxidation activities. Seven (3c, g, i, j, m, o, p) out of 23 new compounds showed very good anti-inflammatory activity in the carrageenan-induced rat paw edema test with very less ulcerogenic action. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA), which is one of the byproducts of lipid peroxidation. Compound 3i and o showed 89.50 and 88.88% of inhibition in paw edema, 69.80 and 66.25% protection against acetic acid induced writhings and 0.7 and 0.65 of severity index respectively, compared to 90.12, 72.50 and 1.95 values of ibuprofen. The study showed that the cyclization of carboxylic group of aroylpropionic acids into an oxadiazole nucleus resulted in compounds having good anti-inflammatory and analgesic effects with reduced gastric irritation.

Topics: Acute Disease; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclization; Drug Design; Drug Evaluation, Preclinical; Edema; Ibuprofen; Lipid Peroxidation; Mice; Molecular Structure; Oxadiazoles; Propionates; Rats; Rats, Wistar; Stereoisomerism; Stomach Ulcer

The new glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines, i.e. CEM-VBL10, CEM-VBL100, and U-2 OS/DX580. The mechanism of cell death triggered by NBDHEX has been deeply investigated in leukemia cell lines. Kinetic data indicate a similar NBDHEX membrane permeability between multidrug resistance cells and their sensitive counterpart revealing that NBDHEX is not a substrate of the P-glycoprotein export pump. Unexpectedly, this molecule promotes a caspase-dependent apoptosis that is unusual in the P-glycoprotein-overexpressing cells. The primary event of the apoptotic pathway is the dissociation of glutathione S-transferase P1-1 from the complex with c-Jun N-terminal kinase. Interestingly, leukemia MDR1-expressing cells show lower LC50 values and a higher degree of apoptosis and caspase-3 activity than their drug-sensitive counterparts. The increased susceptibility of the multidrug resistance cells toward the NBDHEX action may be related to a lower content of glutathione S-transferase P1-1. Given the low toxicity of NBDHEX in vivo, this compound may represent an attractive basis for the selective treatment of MDR1 P-glycoprotein-positive tumors.

Topics: Acute Disease; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Caspases; Cell Death; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Glutathione Transferase; Humans; Kinetics; Leukemia, T-Cell; Mitochondria; Oxadiazoles; Phenotype; Piperazines

A distinctive pattern of enterovirus 71 (EV71) infection, characterized by fever, exanthem, acute pulmonary edema (PE), brainstem encephalitis, and flaccid paresis, affects infants and young children. Most die rapidly owing to respiratory failure and fulminant PE.. The authors report short- and long-term outcome of six survivors of the acute illness.. In the context of acute PE and widespread weakness, recognition of the underlying neurologic disorder was facilitated by the distinctive pattern of MRI signal abnormalities in posterior pons and medulla. EV71-specific PCR of clinical samples helped confirm the diagnosis. Acute PE was managed with mechanical ventilation, afterload reduction, and inotrope support, and resolved completely over days. One patient with minimal neurologic recovery died 9 weeks after disease onset. The other patients have residual neurologic dysfunction, varying from subtle monoparesis to severe bulbar dysfunction, central and peripheral respiratory failure, and flaccid quadriparesis. Faster neurologic recovery was associated with less long-term deficit. Long-term outcome was similar in patients treated with and without pleconaril or IV immunoglobulin. Three long-term survivors treated with IV corticosteroids had less severe long-term neurologic disability than two not treated with steroids.. Acute pulmonary edema and encephalomyelitis occurs with EV71 infection in infants. Long-term neurologic outcome varied from minor, focal weakness to profound, global motor dysfunction with respiratory failure.

Topics: Acute Disease; Antiviral Agents; Child, Preschool; Combined Modality Therapy; Disease Outbreaks; Encephalitis, Viral; Enterovirus; Enterovirus Infections; Female; Follow-Up Studies; Humans; Immunoglobulins, Intravenous; Infant; Magnetic Resonance Imaging; Male; New South Wales; Oxadiazoles; Oxazoles; Pulmonary Edema; Survival Analysis; Survivors

To investigate whether the retina of the rat exerts a vasodilatory influence by the release of a relaxing factor and to characterize the retinal relaxing factor (RRF).. The relaxing influence of the rat retina was investigated by placing the retina in close proximity with a precontracted isolated rat carotid artery ring segment, mounted for isometric tension measurements.. Application of rat retina relaxed the artery in a reliable and reproducible way. The nitric oxide (NO)-synthase inhibitor N(omega)-nitro-L-arginine (L-NA), the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and the removal of the endothelium of the artery all failed to affect the RRF response. The RRF response was not decreased; in contrast, it increased after treatment with a cyclooxygenase (COX) inhibitor (indomethacin or sodium diclofenac). Acute hypoxia largely enhanced retina-induced relaxation. Several potential mediators of hypoxia-induced vasodilation were excluded as candidates for the RRF or for mediating the enhanced response to RRF in hypoxia. Inhibition of the plasma membrane Ca(2+)-adenosine triphosphatase (ATPase) with vanadate significantly affected the RRF response.. The release of an as yet unidentified relaxing factor(s) from the rat retina was demonstrated. Acute hypoxia profoundly enhances the RRF response. None of the known mediators of hypoxia-induced vasodilation nor NO, prostanoids, or endothelial factors mediate the RRF response. Activation of the plasma membrane Ca(2+)-ATPase seems to be involved in the RRF response.

Topics: Acute Disease; Animals; Calcium-Transporting ATPases; Carotid Arteries; Cyclooxygenase Inhibitors; Diclofenac; Endothelium, Vascular; Enzyme Inhibitors; Female; Guanylate Cyclase; Hypoxia; In Vitro Techniques; Indomethacin; Isometric Contraction; Nitroarginine; Oxadiazoles; Quinoxalines; Rats; Rats, Wistar; Retina; Sarcoplasmic Reticulum; Thapsigargin; Vasodilation; Vasodilator Agents

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Anti-Inflammatory Agents; Antitussive Agents; Bronchitis; Female; Humans; Male; Oxadiazoles; Tracheitis

The hemodynamic effects and duration of action of 4 mg of intravenous molsidomine (M), a new peripheral vasodilator antianginal agent, were evaluated and compared to those of 10 mg sublingual isosorbide dinitrate (ISDN) in 12 patients with uncomplicated acute myocardial infarction (AMI). Both M and ISDN produced marked decreases in mean right atrial pressure (RAP), mean pulmonary capillary wedge pressure (WP), and mean pulmonary arterial pressure. The maximal decreases in RAP (-56%) and WP (-35%) with intravenous M intended to be more pronounced than with sublingual ISDN (RAP-35% and WP-29%). Physiologic modest declines in systemic vascular resistance, cardiac output, and arterial pressure were similar with the both drugs. The duration of action of M was longer (average 5 hours) than that of ISDN (2 hours). No patient experienced hypotension, tachycardia, or other adverse responses following M, suggesting that M is well isolated by patients with normotensive AMI.

Topics: Acute Disease; Adult; Aged; Blood Pressure; Cardiac Output; Female; Heart Rate; Hemodynamics; Humans; Isosorbide Dinitrate; Male; Middle Aged; Molsidomine; Morpholines; Myocardial Infarction; Oxadiazoles; Sydnones; Vasodilator Agents

Increased resistance of the heart to acute transitory coronary insufficiency under conditions of prophylactic use of molsidomin was demonstrated in experiments on dogs and rats. The agent prevents electric destabilization of the heart. Reduction of pre- and postexertion of the heart is one of the main factors of the protective action of molsidomin. It is suggested that the drug may be included in the complex of measures used in the treatment of patients suffering from anginal and anginal-arrhythmic forms of stable and unstable angina pectoris.

Topics: Acute Disease; Animals; Coronary Disease; Dogs; Drug Evaluation, Preclinical; Female; Heart; Male; Molsidomine; Morpholines; Myocardial Contraction; Oxadiazoles; Rats; Sydnones; Time Factors

Topics: Acute Disease; Adult; Aged; Female; Humans; Male; Middle Aged; Myocardial Infarction; Oxadiazoles; Vasodilator Agents

Topics: Acute Disease; Adult; Anti-Inflammatory Agents; Bronchitis; Chronic Disease; Female; Humans; Male; Middle Aged; Oxadiazoles; Tetracycline

Topics: Acute Disease; Adult; Anti-Inflammatory Agents; Bronchitis; Chronic Disease; Drug Combinations; Female; Humans; Male; Middle Aged; Oxadiazoles; Tetracycline