A structure–activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying. We built a structure-activity relationship (SAR) model for evaluating hepatotoxicity . (chlorpheniramine, disopyramide, doxapam, methadone, and tolterodine). It matches four compounds, three of them are retinoids (etretinate, vitamin A, .. de Abajo, F. J., Montero, D., Madurga, M., and García-Rodríguez, L. A. (). fentanyl, hydrocodone, hydromorphone, meperidine, methadone, , role in mental diseases, – structure activity relationships, therapy of, – Ovulation, renal-vitamin D endocrine system and.
This data set, compiled using the data mining procedure, suffers some limitations. Firstly it does not make any distinction between idiosyncratic and dose-dependent toxicity. Idiosyncratic toxicity refers to an abnormal reaction to a drug that is not connected to its pharmacological activity but is due to individual hypersensitivity Cheng and Dixon, ; Russmann et al.
This toxicity does not follow any specific mode of action, but the adverse reactions to drugs are of unknown etiology and involved only a small proportion of the population Walgren et al.
This means that where information is lacking it has been assumed that the compound was negative. Even if it is true that for well-known and investigated drugs, the lack of information can be taken as negative Hewitt et al. When the hepatocyte membrane is damaged these enzymes, which are normally located in the cytosol, are released into the bloodstream Pari and Murugan, Although the serum transaminases are commonly used as indicators of liver injury and reflect damage to hepatocytes Ozer et al.
For example, ALT and AST are present in other tissues heart, brain and skeletal muscle besides the liver and so they are released into the circulation when there is damage to these tissues. AST mostly increases in case of myocyte damage due to extreme physical effort Ozer et al. LDH is another enzyme occasionally used as a biomarker of hepatocellular injury.
However, it is not routinely employed since its specificity is questionable Ramaiah, More recently genomics, proteomics and metabolomics have been proposed as valuable techniques for discovering biomarkers Amacher et al. However, the most of the datasets is not suitable to be used alone for classification modeling. In conclusion, the data we used for modeling have a certain level of uncertainty due to these points which may have influenced the reliability and performance of the model.
An alternative that could limit the uncertainty linked to hepatotoxicity data is to use in vitro data obtained if possible on the same cell lines and using the same laboratory assay and conditions.
However, not much public data is available in the open literature for this purpose and this approach too suffers some limitations such as the influence of genetic and environmental factors in the variations of biochemistry Przybylak and Cronin, Mechanistic Explanation of SAs We propose, when possible, a mechanistic rationale using the information in the literature and in public databases PubChem https: N-Containing Heterocyclic Aromatic Compounds: Pyridine, Pyrazine, Pyrimidine This SA, identified by the ID number 1 Table 1is a generic chemical structure that may be seen in several different chemical families.
In the training set it matches 57 compounds covering different chemical and therapeutic classes41 of them classified as hepatotoxic. Considering the lack of specificity of this SA, it is impossible to highlight any single mechanism of action that may explain the toxicity.
Low Vitamin D Status of Patients in Methadone Maintenance Treatment
In the training set this chemical fragment correctly identified hepatotoxic compounds in However, we identified two sub-families in this large group of drugs. The first comprises a group of three drugs used for the treatment of malaria amodiaquin, primaquine, mefloquine. The hepatotoxicity of these molecules are mainly linked to hypersensitivity reactions LiverTox database, http: The second includes seven chemical compounds used in the therapy of several cancer types methotrexate, amsacrine, bortezomib, imatinib mesilate, intoplicine, OSI, rubitecan.
Methotrexate is a methyl analog of folic acid, used in the treatment of various neoplastic diseases. A reasonable part of the population treated with this drug reported liver injury. Thin fibrous septa extending from the portal tracts into the lobules, often in a stellate configuration is the typical pattern of liver fibrosis induced by methotrexate. Persistent fibrosis eventually may lead to cirrhosis Hytiroglou et al.
The mechanisms of liver injury of bortezomib are still unclear.
Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain.
It is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate LiverTox database. Therapy with imatinib may lead to three forms of acute liver injury: Metabolism of OSI occurs in liver and preclinical repeated dose toxicity studies reported liver injury at higher doses. In a recent study O'Bryant et al. Impact of opioid use on dentistry. Serum hydroxyvitamin D and bone mineral density in a racially and ethnically diverse group of men.
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J Am Geriatr Soc. Important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers.
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