Co-prescription of metoprolol and CYP2D6-inhibiting antidepressants before and after implementation of an optimized drug interaction database in Norway.

PURPOSE: To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. METHODS: The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. RESULTS: The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% (P < 0.001) after 5 years and by 40% (P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54-0.69) and OR 0.45 (95% CI 0.40-0.51), respectively, versus OR 0.84 (95% CI 0.74-0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. CONCLUSION: The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.

Statin medication in patients treated with antiepileptic drugs in Norway.

PURPOSE: The lipid-lowering response of statins metabolized by cytochrome P450 3A4 (CYP3A4) has previously been shown to be diminished by concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). The aim of this study was to compare statin prescription in patients receiving EIAEDs versus non-enzyme-inducing antiepileptic drugs (NEIAEDs), before and after introduction of prescribing restrictions for statins in Norway. METHODS: The Norwegian Prescription Database was used to extract data on patients using antiepileptic drugs and statins during 2004 and 2008. Statin type and dose used were compared between patients treated with at least one EIAED (i.e., carbamazepine, phenobarbital, phenytoin, primidone) and those receiving NEIAEDs only (i.e., all other antiepileptic drugs). RESULTS: The number of included patients co-medicated with statins and AEDs was 4855 in 2004 and 9880 in 2008. Among these patients, 2827 and 3160, respectively, were treated with EIAEDs. The CYP3A4 statins (i.e., simvastatin, atorvastatin and lovastatin) accounted for 85% of all statins in 2004, increasing to 93% in 2008. There was no significant difference in the likelihood of being prescribed a CYP3A4 statin versus a non-CYP3A4 statin among patients receiving EIAEDs and NEIAEDs. The average daily dose of individual CYP3A4 statins was not different between the AED groups. CONCLUSIONS: The present study shows that the interaction risk between CYP3A4-metabolized statins and EIAEDs is largely overlooked in Norwegian clinical practice. To avoid therapeutic failure of statin treatment in patients using AEDs, implementation of strategies for systematic management of drug interactions is warranted.

Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro.

Statins exist in both acid and lactone forms in vivo. High plasma levels of the lactone forms have been observed in patients with statin induced myopathy. In the present study, the hypothesis that lactone forms have a higher potency of inducing myotoxicity as compared to acid forms was investigated. Primary human skeletal muscle cells were incubated with increasing concentrations of lactone and acid forms of atorvastatin, fluvastatin, pravastatin and simvastatin. Following incubation, living myotubes were quantified by fluorescence staining. Atorvastatin lactone showed a 14-fold, fluvastatin lactone a 26-fold, pravastatin lactone a 23-fold, and simvastatin lactone a 37-fold higher potency to induce myotoxicity compared to their corresponding acid forms. Thus, for the four different statins the present study shows a significantly higher potency of the lactone forms, than the respective acid forms, to induce myotoxicity in human skeletal muscle cells in vitro. These results clearly indicate the need to differentiate between acid and lactone forms in future investigation of statin myotoxicity.

Characteristics and quality of adverse drug reaction reports by pharmacists in Norway.

PURPOSE: To evaluate the characteristics and quality of adverse drug reaction (ADR) reports submitted by pharmacists, and thereby assess the possible contribution of pharmacists to the spontaneous reporting system for ADRs in Norway. METHODS: An open, prospective study was conducted where dispensing pharmacists from 39 pharmacies were encouraged to report ADRs over a 3-month period. The submitted ADR reports were compared to reports by physicians from the same time period. All reports were evaluated for selected characteristics, that is distribution of Anatomical Therapeutic Chemical (ATC) classification codes of suspected drugs, distribution of ADRs according to system-organ classes and the quality of the reports. RESULTS: A total of 118 reports covering 274 ADRs received from the pharmacists were compared to 109 ADR reports with 304 ADRs submitted by physicians. Pharmacists more often reported ADRs related to cardiovascular drugs, alimentary tract and metabolism drugs and respiratory drugs, whereas physicians more frequently reported ADRs related to musculoskeletal drugs and antineoplastic and immunomodulating agents. ADRs reported by pharmacists more frequently described gastrointestinal reactions while physicians reported more ADRs in relation to the cardiovascular and blood system. Whereas 68% of the physicians' reports were classified as serious, only 5% of the pharmacists' reports were serious. More than 50% of the reports submitted by pharmacists concerned ADRs following a generic substitution, in contrast to only 2% of the physicians' reports. The pharmacists' reports were found to be of a lower documentation grade. However, there was no substantial difference in a subjective assessment of the quality of information in the reports submitted by the two categories of health professionals. CONCLUSIONS: Pharmacists submit valuable ADR reports which provide information complimentary to physicians' reports. This emphasises that pharmacist ADR reporting might constitute an important addition to the spontaneous reporting system.

Quality and impact of problem-oriented drug information: a method to change clinical practice among physicians?

OBJECTIVES: Problem-oriented drug information is characterised by health professionals actively seeking drug information through various sources. In this study our objective was to determine the quality and impact of problem-oriented drug information among physicians. METHODS: Evaluation forms accompanying 163 written answers to physicians from a drug information centre were used to examine the quality and impact of problem-oriented drug information during the period December 1996 to June 1998. Physicians were asked whether the preliminary telephone answer was useful and, furthermore, whether the written answer was fast enough, relevant, adequately comprehensive and had valuable references. Physicians were also asked whether the answer had caused any change in their clinical practice. If yes, they were then asked to describe the actual changes. RESULTS: Of 163 evaluation forms, 117 (72%) were returned by physicians. Eighty-six physicians received a preliminary telephone answer and 83 (97%) stated that this was useful. Among the physicians, 92 (79%) found that the answer was fast enough, relevant, adequately comprehensive and with valuable references, while 19 (16%) found that the answer satisfied three of these four quality criteria. Seventy-one evaluation forms stated that the answer had caused a change in clinical practice. Sixty-eight (96%) of these contained a description of the change. Thirty-five evaluation forms that stated that the answers did not cause any change in clinical practice showed the same quality score as for the total group. Thus, 28 (80%) of these satisfied four and 5 (14%) satisfied three of the quality criteria. Improved routines for and control of ongoing pharmacotherapy was the most common change in clinical practice reported by physicians. CONCLUSION: The results show that, in general, physicians found problem-oriented drug information to be of high quality, and that it had an impact on their clinical practice. Problem-oriented drug information could be a method to change clinical practice among physicians.

Reduced secretion of triacylglycerol in CaCo-2 cells transfected with intestinal fatty acid-binding protein.

The fatty acid-binding proteins are hypothesized to be involved in cellular fatty acid transport and trafficking. We established CaCo-2 cells stably transfected with intestinal fatty acid-binding protein (I-FABP) and examined how the expression of this protein may influence fatty acid metabolism. I-FABP expression was detectable in I-FABP-transfected cells, whereas parent CaCo-2 cells as well as mock-transfected cells failed to express detectable levels of I-FABP mRNA or protein at any stage of differentiation. For studies of lipid metabolism, cells were incubated with [14C]oleic acid in taurocholate micelles containing monoolein, and distribution of labeled fatty acid in cellular and secreted lipids was examined. In one transfected cell clone, expressing the highest level of I-FABP, labeled cellular triacylglycerol increased approximately twofold as compared to control cells. The level of intracellular triacylglycerol in two other I-FABP-transfected clones resembled that of control cells. However, secretion of triacylglycerol was markedly reduced in all the I-FABP-expressing cell lines. Our data suggest that increased expression of I-FABP leads to reduced triacylglycerol secretion in intestinal cells.