No effects of Hypericum -containing complex on dolutegravir plasma trough concentrations: a case report

Disproportionality analysis for identification of drug safety signals in a database shared by the Norwegian network of drug information centres (RELIS)

Efficacy of triptans for the treatment of acute migraines: a quantitative comparison based on the dose-effect and time-course characteristics Abstract Objectives This study aimed to establish a pharmacodynamic model to quantitatively compare the efficacy characteristics of seven kinds of triptans and their different dosage forms in the treatment of acute migraines. Methods Clinical studies of triptans in the treatment of acute migraines were comprehensively searched in the public databases. Pharmacodynamic models were established to describe the dose-effect and time-course of each kind of triptan for the proportion of patients who became pain free or had pain relief. Results A total of 92 articles involving 47,376 subjects were included in the analysis. After eliminating the placebo effect, oral eletriptan (40 mg) had the highest efficacy among all oral drugs at the maximum approved dose, and the proportion of patients who became pain free and had pain relief were 30.9% and 37.9% at 2 h, respectively. However, oral naratriptan (2.5 mg) had the lowest efficacy, and the proportion of patients who became pain free and had pain relief was 10.3% and 21.6% at 2 h, respectively. The efficacy of subcutaneous administration was significantly higher than that of oral administration, and the efficacy of nasal spray administration was comparable to that of oral administration. Regarding the dose-effect, the efficacy of the sumatriptan nasal spray significantly increased within the FDA (Food and Drug Administration)-approved dose range. When the dose was increased from 5 to 20 mg of sumatriptan nasal spray, the proportion of patients who became pain free and had pain relief increased by 16.8% and 18.3% at 2 h, respectively. Regarding the time-course, the time of onset of subcutaneous sumatriptan (6 mg) was the fastest, and the fraction of patients who were pain free at 2 h accounted for 90.6% of that at 4 h. Conclusions This study evaluated the efficacy characteristics of seven kinds of triptans and their different dosage forms. The present findings provide necessary quantitative information for migraine medication guidelines.

The effect of simvastatin on warfarin anticoagulation: a Swedish register-based nationwide cohort study Abstract Purpose Some data indicate that simvastatin may increase the anticoagulative effect in patients treated with warfarin, but the evidence is scarce. The aim of the present study was to investigate how the anticoagulative effect of warfarin is affected by the initiation of simvastatin in a very large patient sample. Methods In a retrospective cohort study, we included 5637 individuals on warfarin treatment initiating simvastatin. INR values and warfarin doses were calculated week-by-week during co-treatment. Data were obtained from two large Swedish warfarin registers and from the Swedish Prescribed Drug Register. Results INR increased from 2.43 at baseline to 2.58, 4 weeks after simvastatin initiation, and did not stabilize until the last quarter of the year studied. Consequently, the proportion of patients with an INR above 3 increased from around 8 to 15%. Conclusions In conclusion, initiation of simvastatin resulted in moderately increased INR values and subsequent dose decreases in patients already on warfarin. In order to avoid the increased risk of bleeding, the initiation of simvastatin may be accompanied by closer INR monitoring.

2015 Beers Criteria and STOPP v2 for detecting potentially inappropriate medication in community-dwelling older people: prevalence, profile, and risk factors Abstract Purpose To comparatively assess the prevalence rates of potentially inappropriate medications (PIMs) obtained by the former and latest versions of American Geriatrics Society Beers Criteria (AGS BC) and screening tool of older person’s potentially inappropriate prescriptions (STOPP), and analyze the factors of influence on PIM. Methods Cross-sectional study including 582 community-dwelling older adults over the age of 65. Sociodemographic, clinical, functional, and comprehensive drug therapy data were collected. The primary endpoint was the percentage of patients receiving at least one PIM. Results A total of 3626 prescriptions were analyzed. PIMs were detected in 35.4% and 47.9% of patients according to the STOPP v1 and the 2012 AGS BC, respectively. This percentage rose to 54% when 2015 AGS BC were used and reached 66.8% with STOPP v2. The kappa coefficient between STOPP v2 and its former version was lower than the one between the updated Beers Criteria and their former version (0.41 vs 0.85). The agreement was good (0.65) between both latest criteria. The number of medications, psychological disorders, and insomnia were predictors of PIM. A novel finding was that bone and joint disorders increased the odds for PIM by 78%. Conclusions The 2015 AGS BC showed high sensitivity and good applicability to the European older patients. Both updated tools identified some pharmacological groups (benzodiazepines, PPIs, and opioids, among others) and certain health problems (insomnia, psychological disorders, and osteoarticular diseases) as factors of influence on PIM. Based on these findings, interventions aimed at promoting appropriate use of medications should be developed.

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation Abstract Purpose There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population.

Premedication with intravenous steroids does not influence the incidence of infusion reactions following infliximab infusions in pediatric inflammatory bowel disease patients—a case-control study Abstract Purpose Infusion reactions (IR) are commonly described side effects of infliximab (IFX) infusions, often leading to discontinuation of IFX. This study aimed to investigate the influence of steroid premedication (PM) on incidence of IR in pediatric inflammatory bowel disease (PIBD) patients receiving IFX. Methods A case-control study in two tertiary centers in Amsterdam, The Netherlands, including PIBD patients receiving IFX. PM with steroids was part of standard care in one center (PM+) but not in the other center (PM−). Acute IR were divided into mild/severe reactions and in grade 1/2/3/4 for detailed exploration. Differences between subgroups were assessed with the T or chi-square test. Multivariate logistic regression was used to assess associations between PM and IR incidence, correcting for co-medication usage. Results We included 226 patients (91 PM+, 50% male, mean age at onset of IBD 12.7 years), receiving 3433 infusions. There was no difference between the PM+ and PM− subgroups in incidence of IR (14.3% vs. 17.0% of patients, p = 0.58) and in percentage of infusions followed by IR (1.4% in both subgroups). The OR of developing IR when using PM was 1.06 (95% CI 0.49–2.27, p = 0.89), and the OR of developing a grade 3 or 4 IR when using PM was 0.90 (95% CI 0.24–3.39, p = 0.88) when correcting for co-medication usage. Conclusion The incidence of IR was low, and premedication with steroids did not decrease the incidence of IR in this cohort of PIBD patients receiving IFX. Our results indicate that PM with steroids is not indicated in PIBD to prevent IR.

Non-commercial trials on medicines submitted to the Ethics Committee of the University Hospital of Bologna (Italy) along 8 years of activity: time to update rules and recommendations Abstract Purpose In Italy, the non-commercial trials on medicines are regulated by the Ministry Decree 17 December, 2004. Its intent is of encouraging the independent research for the improvement of clinical practice. We aimed to analyze the main features of the proposals of non-commercial clinical trials on medicines submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010–2017. Methods Data were extracted from IEC registry and were organized with an ad hoc database. The relationships between the variables were examined using contingency tables. When appropriate, we applied the chi-square statistical test for the comparison of the categorical variables. Results Over the 8-year period, the IEC evaluated 2931 studies, of which 1156 (39.4%) related to clinical trials on medicines; 245 (21.2%) out of the latter were non-commercial ones. A percentage of 49.8 of the trials were of phase II; 137 trials (55.9%) were promoted by hospitals, medical schools or institutes for research, hospitalization and health care. Non-profit organizations and scientific societies were promoters of 88 trials (35.9%). Most phase I and phase II trials received additional support from pharmaceutical companies. Conclusions Our results show a not negligible industrial influence on non-commercial trials through additional support, mostly to those of phase II. An update of the present legislation on this matter is desirable, adopting clearer rules on the relations sponsor-industry.

Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis Abstract Purpose Tendinopathy is a known adverse reaction associated to fluoroquinolones, but a meta-analysis was not yet published. The aim of this study was to conduct a systematic review and a meta-analysis of the scientific evidence evaluating the risk of tendon injury associated with fluoroquinolones. Methods A literature search was conducted to identify observational studies which reported results on the risk of Achilles tendon rupture (ATR), risk of Achilles tendinitis (AT), or risk of any tendon disorders (ATD). A meta-analysis was performed by pooling odds ratios (ORs) with their 95% confidence intervals (CIs). Results Fifteen studies were included in the meta-analysis. Treatment with fluoroquinolones was associated with an increased risk of ATR (OR 2.52 (95% CI 1.81–3.52), p < 0.001, I2 = 76.7%), an increased risk of AT (OR 3.95 (95% CI 3.11–5.01), p < 0.001, I2 = 0%), and increased risk of ATD (OR 1.98 (95% CI 1.62–2.43), p < 0.001, I2 = 84.5%). The initial risk estimates remained statistically significant among patients aged ≥ 60 years old. Risk estimates did not significantly change after depending on the concomitant use of corticosteroids or studies methodological quality assessment. The analysis according to the type of fluoroquinolones was only possible for ATR, which were ofloxacin and norfloxacin were found to increase the risk of this outcome, but not ciprofloxacin and levofloxacin. Conclusions The results of this meta-analysis confirm the risk of tendon injuries associated with fluoroquinolones. Older age and concomitant use of corticosteroids seem to be additional risk factors for tendinopathy.

UK medical students’ perspectives on practical prescribing teaching and learning provisions: a cross-sectional survey Abstract Purpose To determine medical students’ perspectives on the provision for the teaching and learning of processes that lead to and include the writing of a clear, safe and legal prescription (practical prescribing) in UK medical schools. Methods We designed a cross-sectional survey of UK medical students in years three, four and five. Students were asked about their experiences and views of practical prescribing teaching and learning they had encountered on their medical course. Results A total of 1023 medical students responded (7% response rate), from 25 UK medical schools: 22%, 37% and 41% in the third, fourth and final years, respectively. Teaching of practical prescribing was widespread, with 94.3% of final year (n = 396, 95% confidence interval [CI] = 92–97%), 86.8% of fourth year (n = 328, CI = 83–90%) and 73.8% of third year (n = 166, CI = 67–80%) students reporting they had received it. Availability of this teaching appeared to vary by medical school. Self-directed learning was the most frequently reported mode of delivery (90.9%, n = 809). Validated pre-prescribing and simulation were perceived by students in each year group as the most effective methods. Clinical pharmacologists, clinical pharmacists and junior doctors were perceived by the students as being the most effective professional groups at teaching practical prescribing. Conclusions UK medical students reported a variety of methods utilised in the teaching and learning of practical prescribing. However, methods they perceived to be very effective (simulation and pre-prescribing) do not appear to be widely available or are only reserved for the final year of study. Combining such methods with involvement of professional groups perceived to be most effective should be explored.