Relationship Between Time Consumption and Quality of Responses to Drug-Related Queries : A Study From Seven Drug Information Centers in Scandinavia

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Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

Metabolic drug interactions in man : methodological aspects on in vivo studies

The aim of this thesis was to investigate methodological aspects on in vivo metabolic drug interaction studies in man. Five pharmacokinetic studies in healthy persons or patients are presented. Together, they represent a set of model studies to evaluate the occurrence of, and extent of metabolic drug interactions in vivo. They are all based on previous in vitro findings, and were designed to take advantage of the current knowledge concerning specificity and selectivity of drug metabolising enzymes and interindividual differences in drug metabolising capacity. A special focus was the study of omeprazole as a probe for, and ketoconazole as an inhibitor of the CYP3A4 enzyme. Ketoconazole (repeated doses) markedly inhibited the CYP3A4 mediated sulphoxidation of omeprazole (single doses) in a dose-dependant manner, in both extensive and poor hydroxylators (CYP2C19) of omeprazole. This study confirms that omeprazole sulphoxidation is the main metabolic pathway in individuals devoid of CYP2C19 activity, and shows that these subjects develop very high omeprazole concentrations during ketoconazole co-administration. Tolterodine, which is mainly metabolised by CYP2D6, was given in repeated doses to both poor and extensive metabolisers (CYP2D6), but did not influence the metabolism (as indicated by metabolite ratios) of single doses of the probe drugs debrisoquine (CYP2D6), omeprazole (CYP2C19 and CYP3A4) or caffeine (CYP1A2), given on three consecutive days. Tolterodine is thus unlikely to inhibit the metabolism of drugs eliminated via these enzymes. Data from the above studies, together wit data from two other omeprazole studies, support the use of omeprazole as a probe for the evaluation of CYP3A4 activity, as well as its previously suggested use as a probe for CYP2C19. Fluvoxamine (a CYP1A2 inhibitor), but not ketoconazole, had a significant effect on the clearance of intravenously administered ropivacaine. This study confirms in vitro and in vivo pharmacokinetic findings indicating CYP1A2 as the most important enzyme in ropivacaine metabolism, and shows that CYP1A2 inhibitors may cause clinically relevant interactions with ropivacaine. Concomitant administration of single doses of sirolimus and diltiazem lead to increased sirolimus exposure in 16 out of 18 subjects, presumably by inhibition of intestinal CYP3A4 and/or P-glycoprotein. This interaction needs further evaluation during steady-state conditions, but does point to the possibility of other CYP3A4 inhibitors interacting with sirolimus. Lamotrigine drug interactions were studied in a therapeutic drug monitoring material including 104 patients. A widespread intra- and interindividual variation in the concentration/dose ratio for lamotrigine could largely be explained by pharmacokinetic interactions with phenytoin, carbamazepine, phenobarbital (all three inducing lamotrigine metabolism) and valproic acid (an inhibitor of lamotrigine glucuronidation). The systematic knowledge concerning drug metabolising pathways and mechanisms of metabolic drug interactions is growing. Effective and informative in vitro studies are already in use, and are also being continuously developed. So far, there is no universally reliable method to extrapolate in vitro findings to in vivo clinical conditions. However, with the current knowledge of drug metabolism and a base of in vitro study methods, it is possible to use a confined number of well designed interaction studies in vivo, with specific and selective inhibitors and probe drugs in appropriate doses, given to panels of extensive and poor metabolisers. Such studies, in combination with routine evaluation of data from therapeutic drug monitoring, as exemplified in this work, can provide clinically useful information concerning pharmacokinetic drug interactions, leading to safer, better individualised and more cost-effective drug treatment

Adjuvant use of melatonin for pain management in dysmenorrhea - a randomized double-blinded, placebo-controlled trial

Purpose Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment. Methods Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis. Results Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant. Conclusion This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed.Funding Agencies|Karolinska InstituteKarolinska Institutet; Stockholm County CouncilStockholm County Council [20180306]; AFA insurance [170157]</p

Adjuvant use of melatonin for pain management in endometriosis-associated pelvic pain-A randomized double-blinded, placebo-controlled trial.

Considering the pharmacological treatment options for endometriosis-associated pain are confined to hormonal therapy and analgesics, we studied the analgesic effect of 20 mg melatonin as an adjuvant therapy in women with endometriosis-associated pain. This randomized double-blinded, placebo-controlled trial was conducted at the Research Center for Womens' Health at Södersjukhuset, a university hospital in Stockholm, Sweden. Forty women from 18 to 50 years of age with endometriosis and severe dysmenorrhea with or without chronic pelvic pain were given 20 mg Melatonin or placebo orally daily for two consecutive menstrual cycles or months. The level of pain was recorded daily on the 11-point numeric rating scale, a difference of 1.3 units was considered clinically significant. Clincaltrials.gov nr NCT03782740. Sixteen participants completed the study in the placebo group and 18 in the melatonin group. The difference in endometriosis-associated pain between the groups showed to be non-significant statistically as well as clinically, 2.9 (SD 1.9) in the melatonin group and 3.3 (SD 2.0) in the placebo group, p = 0.45. This randomized, double-blinded, placebo-controlled trial could not show that 20 mg of melatonin given orally at bedtime had better analgesic effect on endometriosis-associated pain compared with placebo. No adverse effects were observed

Clinical relevance of alerts from a decision support system, PHARAO, for drug safety assessment in the older adults

BackgroundPHARAO is a decision support system developed to evaluate the risk for a set of either common or serious side-effects resulting from a combination of pharmacodynamic effects from a patients medications. The objective of this study was to investigate the validity of the risk scores for the common side-effects generated by PHARAO in older patients.MethodsSide-effects included were sedation, constipation, orthostatic symptoms, anticholinergic and serotonergic effects. The alerts generated by PHARAO were tested in 745 persons 65years old. Dispensed prescriptions retrieved from the Swedish prescribed drug register were used to generate the pharmacological risk scores of patients medications. Symptoms possibly related to side-effects were extracted from medical records data.ResultsThe PHARAO system generated 776 alerts, most often for the risk of anticholinergic symptoms. The total specificity estimates of the PHARAO system were 0.95, 0.89 and 0.78 for high, intermediate and low risk alerts, respectively. The corresponding sensitivity estimates were between 0.12 and 0.37. The negative predictive value was 0.90 and the positive predictive value ranged between 0.20-0.25.ConclusionsThe PHARAO system had a high specificity and negative predictive value to detect symptoms possibly associated with the of patients medications, while the sensitivity and positive predictive value were low. The PHARAO system has the potential to minimise the risk of over-alerts in combination with a drug-drug interaction alert system, but should be used in connection with a medical evaluation of the patient.Funding Agencies|National Corporation of Swedish Pharmacies (Apoteket AB); Linkoping university; Region Ostergotland; Region Vastra Gotaland</p

Factors associated with time consumption when answering drug-related queries to Scandinavian drug information centres: a multi-centre study

Purpose There is little research-based documentation on the services provided by drug information centres (DICs). The aim of this multi-centre study was to explore for the first time the factors associated with time consumption when answering drug-related queries at eight different but comparable DICs. Methods During an 8-week period, staff members at eight Scandinavian DICs recorded the number of minutes during which they responded to queries. Mixed model linear regression analyses were used to explore the factors associated with time consumption when answering queries. Results The mean time consumption per query was 178 min (range 4–2540 min). The mean time consumed per query increased by 28 (95 % confidence interval (CI) 23 to 33, p < 0.001) min higher for queries for which there was a lack of documentation and 139 (95 % CI 74 to 203, p < 0.001) min higher when conflicting information was present in the literature. Staff members with less than 1 year of experience consumed a mean of 91 more minutes (95 % CI 32 to 150, p = 0.003) per query than staff members with more than 2 years of experience. Conclusions This study demonstrates the large variation in time consumed answering queries posed to Scandinavian DICs. The results highlight the need for highly competent staff members and easy access to drug information sources. Further studies are required to explore the association between time consumption and response quality

Evaluation of usage patterns and user perception of the drug-drug interaction database SFINX

Purpose: The aim of the present study was to investigate how prescribers and pharmacists use and perceive the drug-drug interaction database SFINX in their clinical work. Methods: A questionnaire was developed with questions aimed at the usage of SFINX, and the perceptions of the database. The questionnaire was sent out to all registered users of the web application of SFINX. The anonymous answers from the target users, prescribers and pharmacists were summarized using descriptive statistics. Statistical analysis was performed on age and gender differences for some questions regarding different usage patterns. Results: The questionnaire was sent to 11,763 registered SFINX users. The response rate was 23%, including 1871 answers from prescribers or pharmacists. SFINX was reported to be used at least weekly or more often by 45% of the prescribers and 51% of the pharmacists. Many prescribers reported using the database during the patient consultation (60%) or directly before or after (56%). Among the prescribers, 74% reported that the information received made them change their action at least sometimes. About 20% of the prescribers and 25% of the pharmacists considered the information as irrelevant sometimes or more often. Conclusion: Most prescribers and pharmacists reported using SFINX in direct association with a patient consultation. Information received by using SFINX makes prescribers and pharmacists change their handling of patients. DDI databases with relevant information about patient handling might improve drug treatment outcome. (C) 2015 Elsevier Ireland Ltd. All rights reserved