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Medicine Mar 1998The relationship of long-term and heavy exposure of nonnarcotic analgesics to the risk of chronic renal disease (CRD) has been the object of intensive clinical,... (Review)
Review
The relationship of long-term and heavy exposure of nonnarcotic analgesics to the risk of chronic renal disease (CRD) has been the object of intensive clinical, pharmacologic, toxicologic, and epidemiologic research for 4 decades. The clinical evidence of an increased risk has been suggestive but inconclusive. The experimental evidence in animal models has been inconsistent, and in any case it cannot be generalized to humans. The epidemiologic evidence has been unsatisfactory for the most part: most of the early studies had severe methodologic limitations; moreover, they related mainly to phenacetin-containing drugs and did not have useful information on other analgesics. Since 1980, 9 analytical epidemiologic studies have attempted to confirm that a causal relationship exists between phenacetin or other analgesics and CRD. In the aggregate, despite methodologic flaws, this work suggests that excessive use of phenacetin-containing analgesics probably causes renal papillary necrosis and interstitial nephritis. In contrast, there is no convincing epidemiologic evidence that nonphenacetin-containing analgesics (including acetaminophen, aspirin, and mixtures of these two compounds) or that nonsteroidal antiinflammatory drugs cause CRD. Moreover, the nature of dose-response relationships, the types of renal disease possibly caused by analgesics, and the cofactors that might be related both to analgesic use and to the development of CRD in humans are still uncertain, and the pathologic mechanisms of analgesic-induced CRD in humans remain unclear. It may take many years before all the outstanding issues are settled. Until they are, as a matter of good clinical judgment it would be prudent to consider all analgesics as potentially nephrotoxic and, as much as possible, to avoid excessive, protracted use.
Topics: Adult; Aged; Analgesics; Belgium; Bias; Case-Control Studies; Confounding Factors, Epidemiologic; Dose-Response Relationship, Drug; Epidemiologic Methods; Follow-Up Studies; Humans; Kidney Failure, Chronic; Middle Aged; Risk Assessment; Substance-Related Disorders; United States
PubMed: 9556702
DOI: 10.1097/00005792-199803000-00003 -
Pharmaceutics Dec 2022The solubility of active pharmaceutical ingredients is a mandatory physicochemical characteristic in pharmaceutical practice. However, the number of potential solvents...
Solubility Characteristics of Acetaminophen and Phenacetin in Binary Mixtures of Aqueous Organic Solvents: Experimental and Deep Machine Learning Screening of Green Dissolution Media.
The solubility of active pharmaceutical ingredients is a mandatory physicochemical characteristic in pharmaceutical practice. However, the number of potential solvents and their mixtures prevents direct measurements of all possible combinations for finding environmentally friendly, operational and cost-effective solubilizers. That is why support from theoretical screening seems to be valuable. Here, a collection of acetaminophen and phenacetin solubility data in neat and binary solvent mixtures was used for the development of a nonlinear deep machine learning model using new intuitive molecular descriptors derived from COSMO-RS computations. The literature dataset was augmented with results of new measurements in aqueous binary mixtures of 4-formylmorpholine, DMSO and DMF. The solubility values back-computed with the developed ensemble of neural networks are in perfect agreement with the experimental data, which enables the extensive screening of many combinations of solvents not studied experimentally within the applicability domain of the trained model. The final predictions were presented not only in the form of the set of optimal hyperparameters but also in a more intuitive way by the set of parameters of the Jouyban-Acree equation often used in the co-solvency domain. This new and effective approach is easily extendible to other systems, enabling the fast and reliable selection of candidates for new solvents and directing the experimental solubility screening of active pharmaceutical ingredients.
PubMed: 36559321
DOI: 10.3390/pharmaceutics14122828 -
Frontiers in Oncology 2021Melanoma is the most aggressive form of skin cancer and the most rapidly expanding cancer in terms of worldwide incidence. If primary cutaneous melanoma is mostly...
Melanoma is the most aggressive form of skin cancer and the most rapidly expanding cancer in terms of worldwide incidence. If primary cutaneous melanoma is mostly treated with a curative wide local excision, malignant melanoma has a poor prognosis and needs other therapeutic approaches. Angiogenesis is a normal physiological process essential in growth and development, but it also plays a crucial role in crossing from benign to advanced state in cancer. In melanoma progression, angiogenesis is widely involved during the vertical growth phase. Currently, no anti-angiogenic agents are efficient on their own, and combination of treatments will probably be the key to success. In the past, phenacetin was used as an analgesic to relieve pain, causing side effects at large dose and tumor-inducing in humans and animals. By contrast, low-dilution is often used in skin febrile exanthema, patches profusely scattered on limbs, headache, or flushed face without side effects. Herein are described the , , and anti-angiogenic and anti-tumoral potentials of low-dilution in a B16F1 tumor model and endothelial cells. We demonstrate that low-diluted inhibits tumor growth and tumor vascularization and thus increases the survival time of B16F1 melanoma induced-C57BL/6 mice. Moreover, modulates the lung metastasis in a B16F10 induced model. and , we evidence that low-diluted inhibits the migration and the recruitment of endothelial cells and leads to an imbalance in the pro-tumoral macrophages and to a structural malformation of the vascular network. All together these results demonstrate highly hopeful anti-tumoral, anti-metastatic, and anti-angiogenic effects of low-dilution on melanoma. Continued studies are needed to preclinically validate low-dilution as a complementary or therapeutic strategy for melanoma treatment.
PubMed: 33747916
DOI: 10.3389/fonc.2021.597503 -
International Journal of Hepatology 2018Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents. Part of phenacetin therapeutic activity is attributed to its metabolism into paracetamol....
Comparative Protective Effects of N-Acetylcysteine, N-Acetyl Methionine, and N-Acetyl Glucosamine against Paracetamol and Phenacetin Therapeutic Doses-Induced Hepatotoxicity in Rats.
BACKGROUND AND AIMS
Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents. Part of phenacetin therapeutic activity is attributed to its metabolism into paracetamol. Paracetamol causes direct hepatic oxidative stress damage. The present study aimed to investigate the possible damaging effects of both PA and PH, when used in therapeutic doses, on rat liver and to compare the antioxidant and hepatoprotective effects of N-acetylcysteine (NAC), N-acetyl-methionine (NAM), and N-acetylglucosamine (NAG) against PA- or PH-induced hepatic damage.
METHODS
90 male Wistar albino rats (120-140 gm) were undertaken, categorized randomly into 9 groups of 10 rats each, and administered by gavage for 2 weeks with DMSO 1% (controls), PA, PA+NAC, PA+NAM, PA+NAG, PH, PH+NAC, PH+NAM, and PH+NAG. Biochemical assays of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), total thiols, and alpha-fetoprotein (AFP) in liver homogenates and serum assays of ALT, AST, 8-hydroxy guanine (8-OH-Gua), and AFP were done. Also histopathological examinations of liver tissues in various groups were done.
RESULTS
PA and PH cause significant increase in hepatic levels of MDA, NO, and AFP and serum ALT, AST, and 8-OH-Gua levels, with significant decrease in hepatic GSH and total thiols. NAG and NAC significantly improve the PA- and PH-induced hepatic and blood, biochemical, and histopathological disturbances, respectively.
CONCLUSIONS
Both PA and PH induce oxidative stress in rat liver within their therapeutic doses. NAG and NAC in pharmacological doses can antagonize the oxidative damaging effect of both PA and PH.
PubMed: 30245889
DOI: 10.1155/2018/7603437 -
Genes and Environment : the Official... 2016Toxicogenomics is a rapidly developing discipline focused on the elucidation of the molecular and cellular effects of chemicals on biological systems. As a collaborative... (Review)
Review
Toxicogenomics is a rapidly developing discipline focused on the elucidation of the molecular and cellular effects of chemicals on biological systems. As a collaborative study group of Toxicogenomics/JEMS·MMS, we conducted studies on hepatocarcinogens in rodent liver in which 100 candidate marker genes were selected to discriminate genotoxic hepatocarcinogens from non-genotoxic hepatocarcinogens. Differential gene expression induced by 13 chemicals were examined using DNA microarray and quantitative real-time PCR (qPCR), including eight genotoxic hepatocarcinogens [o-aminoazotoluene, chrysene, dibenzo[a,l]pyrene, diethylnitrosamine (DEN), 7,12-dimethylbenz[a]anthracene, dimethylnitrosamine, dipropylnitrosamine and ethylnitrosourea (ENU)], four non-genotoxic hepatocarcinogens [carbon tetrachloride, di(2-ethylhexyl)phthalate (DEHP), phenobarbital and trichloroethylene] and a non-genotoxic non-hepatocarcinogen [ethanol]. Using qPCR, 30 key genes were extracted from mouse livers at 4 h and 28 days following dose-dependent gene expression alteration induced by DEN and ENU: the most significant changes in gene expression were observed at 4 h. Next, we selected key point times at 4 and 48 h from changes in time-dependent gene expression during the acute phase following administration of chrysene by qPCR. We successfully showed discrimination of eight genotoxic hepatocarcinogens [2-acetylaminofluorene, 2,4-diaminotoluene, diisopropanolnitrosamine, 4-dimethylaminoazobenzene, 4-(methylnitsosamino)-1-(3-pyridyl)-1-butanone, N-nitrosomorpholine, quinoline and urethane] from four non-genotoxic hepatocarcinogens [1,4-dichlorobenzene, dichlorodiphenyltrichloroethane, DEHP and furan] using qPCR and principal component analysis. Additionally, we successfully identified two rat genotoxic hepatocarcinogens [DEN and 2,6-dinitrotoluene] from a nongenotoxic-hepatocarcinogen [DEHP] and a non-genotoxic non-hepatocarcinogen [phenacetin] at 4 and 48 h. The subsequent gene pathway analysis by Ingenuity Pathway Analysis extracted the DNA damage response, resulting from the signal transduction of a p53-class mediator leading to the induction of apoptosis. The present review of these studies suggests that application of principal component analysis on the gene expression profile in rodent liver during the acute phase is useful to predict genotoxic hepatocarcinogens in comparison to non-genotoxic hepatocarcinogens and/or non-carcinogenic hepatotoxins.
PubMed: 27482301
DOI: 10.1186/s41021-016-0041-0 -
BioMed Research International 2014Hydrogen sulfide (H2S) is the second leading cause of toxin related death (after carbon monoxide) in the workplace. H2S is absorbed by the upper respiratory tract...
Hydrogen sulfide (H2S) is the second leading cause of toxin related death (after carbon monoxide) in the workplace. H2S is absorbed by the upper respiratory tract mucosa, and it causes histotoxic hypoxemia and respiratory depression. Cocktail method was used to evaluate the influences of acute H2S poisoning on the activities of cytochrome P450 isoforms CYP2B6, CYP2D6, CYP3A4, CYP1A2, CYP2C19, and CYP2C9, which were reflected by the changes of pharmacokinetic parameters of six specific probe drugs, bupropion, metoprolol, midazolam, phenacetin, omeprazole, and tolbutamide, respectively. The experimental rats were randomly divided into two groups, control group and acute H2S poisoning group (inhaling 300 ppm for 2 h). The mixture of six probes was given to rats by oral administration and the blood samples were obtained at a series of time points through the caudal vein. The concentrations of probe drugs in rat plasma were measured by LC-MS. The results for acute H2S poisoning and control groups were as follows: there was a statistically significant difference in the AUC and C max for bupropion, metoprolol, phenacetin, and tolbutamide, while there was no statistical pharmacokinetic difference for midazolam and omeprazole. Acute H2S poisoning could inhibit the activity of CYP2B6, CYP2D6, CYP1A2, and CYP2C9 in rats.
Topics: Animals; Cytochrome P-450 Enzyme System; Enzyme Activation; Enzyme Inhibitors; Hydrogen Sulfide; Isoenzymes; Liver; Male; Metabolic Clearance Rate; Pharmacokinetics; Rats; Rats, Sprague-Dawley
PubMed: 24790991
DOI: 10.1155/2014/209393 -
Canadian Medical Association Journal Sep 1964
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthritis, Rheumatoid; Aspirin; Biomedical Research; Chloroquine; Codeine; Drug Therapy; Gold; Leukocyte Count; Oxyphenbutazone; Phenacetin; Phenylbutazone; Rheumatic Fever; Toxicology
PubMed: 14201254
DOI: No ID Found -
Gut Jul 1972
Review
Topics: Animals; Benzene; Biotransformation; Codeine; Cytochromes; Endoplasmic Reticulum; Humans; Kidney; Liver; Mitochondria, Liver; NADP; Pharmaceutical Preparations; Phenacetin; Phenobarbital; Phenols; Serotonin; Thalidomide; Thiopental
PubMed: 4403576
DOI: 10.1136/gut.13.7.579 -
British Medical Journal Jul 1969
Review
Topics: Arthritis, Rheumatoid; Edema; Female; Forearm; Gastrointestinal Diseases; Gold; Hand; Humans; Kidney Diseases; Lung Diseases; Lymphadenitis; Male; Nervous System Diseases; Phenacetin; Rheumatic Heart Disease; Skin Diseases; Uveitis; Vascular Diseases
PubMed: 4893425
DOI: 10.1136/bmj.3.5663.131 -
Medical Principles and Practice :... 2022Although acetaminophen is one of the most widely used over-the-counter drugs, the mechanisms by which this classical drug exerts analgesic, hepatotoxic, and nephrotoxic...
OBJECTIVE
Although acetaminophen is one of the most widely used over-the-counter drugs, the mechanisms by which this classical drug exerts analgesic, hepatotoxic, and nephrotoxic effects remain unclear. We hypothesized that acetaminophen might act on cellular membranes of nerves, liver, and kidneys. In order to verify this hypothesis, we studied the interactivity of acetaminophen with biomimetic lipid bilayer membranes by comparing with structurally related phenacetin.
METHODS
Liposomal membranes (unilamellar vesicles suspended in the buffer of pH 7.4) were prepared with phospholipids and cholesterol to mimic the membrane lipid composition of neuronal cells, hepatocytes, and nephrocytes. They were subjected to reactions with acetaminophen and phenacetin at clinically relevant concentrations, followed by measuring fluorescence polarization to determine their membrane interactivity to modify membrane fluidity.
RESULTS
Acetaminophen and phenacetin interacted with neuro-mimetic and hepato-mimetic membranes to increase membrane fluidity at 10-100 μM. Both drugs were more effective in fluidizing hepato-mimetic membranes than neuro-mimetic membranes. Although the relative membrane-interacting potency was phenacetin >> acetaminophen in neuro-mimetic and hepato-mimetic membranes, such membrane effects conflicted with their relative analgesic and hepatotoxic effects. Acetaminophen and phenacetin strongly interacted with nephro-mimetic membranes to increase membrane fluidity at 2-100 μM and 0.1-100 μM, respectively. Phenacetin interacted significantly with nephro-mimetic membranes at lower concentrations (<2 μM) than acetaminophen, which was consistent with their relative nephrotoxic effects.
CONCLUSION
In comparison with phenacetin, lipid composition-dependent membrane interactivity of acetaminophen could be related to nephrotoxicity but not to analgesic activity and hepatotoxicity.
Topics: Acetaminophen; Analgesics; Chemical and Drug Induced Liver Injury; Humans; Phenacetin; Phospholipids
PubMed: 35316804
DOI: 10.1159/000524210