Interaction potential between clarithromycin and individual statins—A systematic review

The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug‐drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5‐fold increase in area under the plasma concentration‐time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2‐ to 4‐fold AUC increase) and slightly increase pravastatin exposure (≈2‐fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin‐clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4‐metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4‐metabolized statins to be associated with a doubled risk of hospitalization with rhabdomyolysis or other statin‐related adverse events as compared with azithromycin‐statin co‐administration. If clarithromycin is necessary, we recommend (a) avoiding co‐administration with simvastatin, lovastatin or atorvastatin; (b) withholding or dose‐reducing pitavastatin; (c) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily; and (d) continuing fluvastatin or rosuvastatin with caution.     

Fatal liver failure after therapeutic doses of paracetamol in a patient with Duchenne muscular dystrophy and atypical pharmacogenetic profile of drug‐metabolizing enzymes

Paracetamol has a good safety profile, but pharmacogenetic differences in drug‐metabolizing enzymes may have an impact on its risk of hepatotoxicity. We present a case of fatal acute liver failure (ALF) after therapeutic doses of paracetamol in a patient with Duchenne muscular dystrophy, where pharmacogenetic screening was conducted. This 30‐year‐old man was electively admitted for a tracheostomy. A total of 14.5 g paracetamol was given over four days. He developed a severe ALF and died 11 days after admission. Pharmacogenetic screening showed absent CYP2D6 metabolism and increased CYP1A2 activity, which may have increased the formation of toxic intermediate metabolite, N‐acetyl‐p‐benzo‐quinone imine (NAPQI). He also had decreased function of UGT2B15, which increases the amount of paracetamol available for metabolism to NAPQI. Having a reduced muscle mass and thus a reduced glutathione levels to detoxify produced NAPQI may add to the risk of toxicity. This case may indicate that pharmacogenetic variability is of potential relevance for the risk of paracetamol‐induced hepatotoxicity in patients with neuromuscular diseases. Further studies should investigate if pharmacogenetic screening could be a tool to detect potentially increased risk of hepatotoxicity in these patients at therapeutic doses of paracetamol and hence provide information for selection of analgesic treatment.     

Bleeding complications in primary percutaneous coronary intervention of ST-elevation myocardial infarction in a radial center

Objectives : We evaluated the incidence, types, and prognostic impact of bleeding complications in a non‐selected patient population with ongoing STEMI treated with aggressive antithrombotic treatment and routine radial primary PCI. Background : Bleeding complications remain frequent and deleterious in primary PCI through femoral approach. Methods : STEMI patients (n = 671) were evaluated for bleeding complications using a web‐based registry (e‐PARIS). In‐hospital bleeding was adjudicated using the TIMI definition. Results : In this non‐selected, high risk population, 6.1% had cardiogenic shock on admission, 3.9% out‐of‐hospital cardiac arrest. Radial access (88%) was the default strategy as was abciximab (78%). Clopidogrel loading dose ranged from 300 to 900 mg. Pre‐hospital fibrinolysis was rare (7.1%). Hemodynamic support devices (IABP, ECMO, Tandem Heart) were needed in 7.0%. In‐hospital TIMI Major and TIMI Major/minor bleedings occurred in 2.5 and 5.7% of the population, respectively. In‐hospital and 1‐year mortality rates were 5.5 and 8.2%, respectively. Patients with in‐hospital TIMI Major/minor bleeding had a higher 1‐year mortality rate (31.6% vs. 3.8%, P < 0.001). The most frequent bleeding site was gastro‐intestinal. Radial access was a strong predictor of survival (OR 0.33; 95%CI 0.17–0.56; P = 0.002). Conclusions : In the setting of radial primary PCI, the rates and types of bleeding complications are somewhat different from those observed with femoral primary PCI. The gastro‐intestinal tract has become the most frequent site of bleeding after radial primary PCI. The use of radial access appears independently associated with survival. © 2011 Wiley Periodicals, Inc     

Effect on anxiety and depression of a multifactorial risk factor intervention program after stroke and TIA: a randomized controlled trial

Objectives: Depression and anxiety related to stroke are caused by vascular lesions and psychological reactions. Treatment of vascular and modifiable behavioral risk factors reduces the risk of stroke and may also reduce the risk of emotional changes after stroke. We aimed to investigate whether a multifactorial risk factor intervention program in patients with first-ever stroke or transient ischemic attack (TIA) can influence post-stroke anxiety and depressive symptoms in patients one year post-stroke.

Method: The study population consisted of first-ever stroke and TIA patients allocated in a randomized, evaluator-blinded, controlled trial to care as usual or a structured and multidisciplinary follow-up including intensive treatment of vascular risk. The primary endpoint (cognition) has previously been reported. The secondary endpoint, reported here, was changes in the Hospital Anxiety and Depression Scale (HADS) from baseline to 12-month follow-up.

Results: One hundred and ninety-five patients were randomized. The estimated difference between treatment groups, in changes in HADS, from baseline to 12 months was ?1.32 (95% confidence interval: ?2.61, ?0.04; P = 0.044) in favor of the intervention group. One year post-stroke, 4/85 (4.7%) patients in the intervention group and 12/89 (13.5%) in the control group suffered from depression (P = 0.045), while 7/85 (8.2%) patients in the intervention group and 13/89 (14.6%) patients in the control group suffered from anxiety (P = 0.19).

Conclusion: A structured, multidisciplinary, multifactorial risk factor program including vascular risk factor management may be associated with reduced HADS scores and a lower prevalence of depressive symptoms one year after stroke.     

Progression‐free survival in oncology: Caveat emptor!

Overall survival (OS) is the undisputed gold standard efficacy end‐point in cancer drug trials. It is with growing concern that we observe how progression‐free survival (PFS) gains ground as surrogate end‐point in its place. PFS has appeal because it is resource‐efficient, but it has severe shortcomings. Our concern is that uncritical use of PFS will harm the evidence‐based evaluation of cancer drugs when considering them for standard use in publicly financed health care systems. PFS is only valid as a surrogate end‐point for OS if it correlates strongly with OS and if the cancer drug being investigated has the same effect on PFS and OS such that effects on one predict effects on the other. The latter might be less obvious than the former but is no less critical. Research indicates that in a majority of cases, correlation between surrogate end‐points and OS is of medium strength or lower. PFS is therefore unreliable as a surrogate for OS. We do not find it justified to use PFS as surrogate for OS without first having assessed its validity. Stakeholders who take part in evaluating cancer drugs considered for standard use in a health care system must be particularly vigilant about this issue to minimize the risk of introducing cancer drugs that have an unacceptable cost‐risk‐benefit profile.     

The ETFDH c.158A>G Variation Disrupts the Balanced Interplay of ESE‐ and ESS‐Binding Proteins thereby Causing Missplicing and Multiple Acyl‐CoA Dehydrogenation Deficiency

Multiple acyl‐CoA dehydrogenation deficiency is a disorder of fatty acid and amino acid oxidation caused by defects of electron transfer flavoprotein (ETF) or its dehydrogenase (ETFDH). A clear relationship between genotype and phenotype makes genotyping of patients important not only diagnostically but also for prognosis and for assessment of treatment. In the present study, we show that a predicted benign ETFDH missense variation (c.158A>G/p.Lys53Arg) in exon 2 causes exon skipping and degradation of ETFDH protein in patient samples. Using splicing reporter minigenes and RNA pull‐down of nuclear proteins, we show that the c.158A>G variation increases the strength of a preexisting exonic splicing silencer (ESS) motif UAGGGA. This ESS motif binds splice inhibitory hnRNP A1, hnRNP A2/B1, and hnRNP H proteins. Binding of these inhibitory proteins prevents binding of the positive splicing regulatory SRSF1 and SRSF5 proteins to nearby and overlapping exonic splicing enhancer elements and this causes exon skipping. We further suggest that binding of hnRNP proteins to UAGGGA is increased by triggering synergistic hnRNP H binding to GGG triplets located upstream and downsteam of the UAGGGA motif. A number of disease‐causing exonic elements that induce exon skipping in other genes have a similar architecture as the one in ETFDH exon 2.     

Decision-making and cognitive control in adolescent suicidal behaviors: a qualitative systematic review of the literature

Suicide and suicidal behaviors represent a leading cause of morbidity and mortality during adolescence. While several lines of evidence suggest that suicidal behaviors are associated with risky decisions and deficient cognitive control in laboratory tasks in adults, comparatively less is known about adolescents. Here, we systematically reviewed the literature on the association between these neurocognitive variables and adolescent suicidal behaviors. The online search strategy identified 17 neurocognitive studies examining either cognitive control or decision-making processes in adolescents with past suicidal behaviors. Several studies have reported that adolescents with a history of suicidal behaviors present neuropsychological differences in the cognitive control (using Go/NoGo, suicide Stroop Test, continuous performance test, suicide/death Implicit Association Test), and decision-making (Iowa Gambling Task, Cambridge Gambling Task, cost computation, delay discounting, loss aversion tasks) domains. Due to a lack of replication or conflicting findings, our systematic review suggests that no firm conclusion can be drawn as to whether altered decision-making or poor cognitive control contribute to adolescent suicidal behaviors. However, these results collectively suggest that further research is warranted. Limitations included scarcity of longitudinal studies and a lack of homogeneity in study designs, which precluded quantitative analysis. We propose remediating ways to continue neuropsychological investigations of suicide risk in adolescence, which could lead to the identification of novel therapeutic targets and predictive markers, enabling early intervention in suicidal youth.