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1.
Pharmacoepidemiol Drug Saf ; 28(9): 1175-1179, 2019 09.
Article in English | MEDLINE | ID: mdl-31209934

ABSTRACT

PURPOSE: Little is known about adverse drug events (ADEs) experienced over time during chronic drug use. The purpose of this study was to assess ADE patterns experienced by patients with diabetes. METHODS: Patients who received an oral glucose-lowering drug completed a daily diary for 13 weeks. The diary asked for experienced symptoms and whether patients related these symptoms to any drug they used. Summaries of Product Characteristics were used to check whether the ADEs were known adverse drug reactions (ADRs) of the drugs used. Patterns of weekly occurring ADEs were assessed with descriptive statistics. RESULTS: We included 78 patients. Almost half of them reported at least one ADE (N = 36; 46%). In total, 80 ADEs were reported. Of these ADEs, 71 (90%) were known ADRs. ADEs lasted less than 1 week in 27 cases (34%) and between 2 and 12 weeks in 15 cases (19%). The remaining ADEs fluctuated (16 cases; 20%) or persisted (22 cases; 28%) during the entire study period. CONCLUSIONS: ADEs experienced by patients with diabetes can fluctuate or persist over long periods of drug use.


Subject(s)
Diabetes Mellitus/drug therapy , Drug-Related Side Effects and Adverse Reactions/epidemiology , Hypoglycemic Agents/adverse effects , Medical Records/statistics & numerical data , Primary Health Care/statistics & numerical data , Administration, Oral , Adult , Aged , Aged, 80 and over , Diaries as Topic , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Hypoglycemic Agents/administration & dosage , Male , Middle Aged , Netherlands/epidemiology , Prospective Studies , Time Factors
2.
Arch Toxicol ; 91(10): 3403-3413, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28391356

ABSTRACT

Drug-induced cholestasis (DIC) is one of the leading manifestations of drug-induced liver injury (DILI). As the underlying mechanisms for DIC are not fully known and specific and predictive biomarkers and pre-clinical models are lacking, the occurrence of DIC is often only reported when the drug has been approved for registration. Therefore, appropriate models that predict the cholestatic potential of drug candidates and/or provide insight into the mechanism of DIC are highly needed. We investigated the application of rat precision-cut liver slices (PCLS) to predict DIC, using several biomarkers of cholestasis: hepatocyte viability, intracellular accumulation of total as well as individual bile acids and changes in the expression of genes known to play a role in cholestasis. Rat PCLS exposed to the cholestatic drugs chlorpromazine, cyclosporine A and glibenclamide for 48 h in the presence of a 60 µM physiological bile acid (BA) mix reflected various changes associated with cholestasis, such as decrease in hepatocyte viability, accumulation and changes in the composition of BA and changes in the gene expression of Fxr, Bsep and Ntcp. The toxicity of the drugs was correlated with the accumulation of BA, and especially DCA and CDCA and their conjugates, but to a different extent for different drugs, indicating that BA toxicity is not the only cause for the toxicity of cholestatic drugs. Moreover, our study supports the use of several biomarkers to test drugs for DIC. In conclusion, our results indicate that PCLS may represent a physiological and valuable model to identify cholestatic drugs and provide insight into the mechanisms underlying DIC.


Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Liver/drug effects , Organ Culture Techniques/methods , Toxicity Tests/methods , ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics , Animals , Bile Acids and Salts/metabolism , Cholestasis/chemically induced , Gene Expression Regulation/drug effects , Liver/metabolism , Liver/pathology , Male , Organic Anion Transporters, Sodium-Dependent/genetics , Rats, Wistar , Symporters/genetics
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