Repurposing Statins for Renal Protection: Is It a Class Effect?

There has been a great deal of excitement regarding the potential benefits of statins beyond their lipid-lowering effect, and repurposing them for other indications. In this commentary, we evaluate the role of statins in protecting the kidneys, with a focus on three areas: cardiac surgery, contrast-induced nephropathy, and aminoglycoside-induced nephrotoxicity

Identifying new antiepileptic drugs through genomics-based drug repurposing

Currently available antiepileptic drugs (AEDs) fail to control seizures in 30% of patients. Genomics-based drug repurposing (GBR) offers the potential of savings in the time and cost of developing new AEDs. In the current study, we used published data and software to identify the transcriptomic signature of chornic temporal lobe epilepsy and the drugs that reverse it. After filtering out compounds based on exclusion criteria, such as toxicity, 36 drugs were retained. 11 of the 36 drugs identified (>30%) have published evidence of the antiepileptic efficacy (for example, curcumin) or antiepileptogenic affect (for example, atorvastatin) in recognised rodent models or patients. By objectively annotating all ∼20,000 compounds in the LINCS database as either having published evidence of antiepileptic efficacy or lacking such evidence, we demonstrated that our set of repurposable drugs is ∼6-fold more enriched with drugs having published evidence of antiepileptic efficacy in animal models than expected by chance (P-value <0.006). Further, we showed that another of our GBR-identified drugs, the commonly-used well-tolerated antihyperglycemic sitagliptin, produces a dose-dependent reduction in seizures in a mouse model of pharmacoresistant epilepsy. In conclusion, GBR successfully identifies compounds with antiepileptic efficacy in animal models and, hence, it is an appealing methodology for the discovery of potential AEDs

Patients’ use of information about medicine side effects in relation to experiences of suspected adverse drug reactions

Background Adverse drug reactions (ADRs) are common, and information about medicines is increasingly widely available to the public. However, relatively little work has explored how people use medicines information to help them assess symptoms that may be suspected ADRs. Objective Our objective was to determine how patients use patient information leaflets (PILs) or other medicines information sources and whether information use differs depending on experiences of suspected ADRs. Method This was a cross-sectional survey conducted in six National Health Service (NHS) hospitals in North West England involving medical in-patients taking at least two regular medicines prior to admission. The survey was administered via a questionnaire and covered use of the PIL and other medicines information sources, perceived knowledge about medicines risks/ADRs, experiences of suspected ADRs, plus demographic information. Results Of the 1,218 respondents to the survey, 18.8 % never read the PIL, whilst 6.5 % only do so if something unexpected happens. Educational level was related to perceived knowledge about medicines risks, but not to reading the PIL or seeking further information about medicines risks. Over half the respondents (56.0 %) never sought more information about possible side effects of medicines. A total of 57.2 % claimed they had experienced a suspected ADR. Of these 85.9 % were either very sure or fairly sure this was a reaction to a medicine. Over half of those experiencing a suspected ADR (53.8 %) had read the PIL, of whom 36.2 % did so before the suspected ADR occurred, the remainder afterwards. Reading the PIL helped 84.8 % of these respondents to decide they had experienced an ADR. Educational level, general knowledge of medicines risks and number of regular medicines used all increased the likelihood of experiencing an ADR. Conclusion More patients should be encouraged to read the PIL supplied with medicines. The results support the view that most patients feel knowledgeable about medicines risks and suspected ADRs and value information about side effects, but that reading about side effects in PILs or other medicines information sources does not lead to experiences of suspected ADRs

Enhancing Communication about Paediatric Medicines: Lessons from a Qualitative Study of Parents' Experiences of Their Child's Suspected Adverse Drug Reaction

Background: There is little research on parents’ experiences of suspected adverse drug reactions in their children and hence little evidence to guide clinicians when communicating with families about problems associated with medicines. Objective: To identify any unmet information and communication needs described by parents whose child had a suspected adverse drug reaction. Methods: Semi-structured qualitative interviews with parents of 44 children who had a suspected adverse drug reaction identified on hospital admission, during in-patient treatment or reported by parents using the Yellow Card Scheme (the UK system for collecting spontaneous reports of adverse drug reactions). Interviews were conducted face-to-face or by telephone; most interviews were audiorecorded and transcribed. Analysis was informed by the principles of the constant comparative method. Results: Many parents described being dissatisfied with how clinicians communicated about adverse drug reactions and unclear about the implications for their child’s future use of medicines. A few parents felt that clinicians had abandoned their child and reported refusing the use of further medicines because they feared a repeated adverse drug reaction. The accounts of parents of children with cancer were different. They emphasised their confidence in clinicians’ management of adverse drug reactions and described how clinicians prospectively explained the risks associated with medicines. Parents linked symptoms to medicines in ways that resembled the established reasoning that clinicians use to evaluate the possibility that a medicine has caused an adverse drug reaction. Conclusion: Clinicians’ communication about adverse drug reactions was poor from the perspective of parents, indicating that improvements are needed. The accounts of parents of children with cancer indicate that prospective explanation about adverse drug reactions at the time of prescription can be effective. Convergence between parents and clinicians in their reasoning for linking children’s symptoms to medicines could be a starting point for improved communication

Phenotype standardization for statin-induced myotoxicity

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.</p

Quantification of Urinary Mevalonic Acid as a Biomarker of HMG-CoA Reductase Activity by a Novel Translational LC-MS/MS Method

Background: Mevalonic acid (MVA), as a product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, represents a potential multipurpose biomarker in health and disease. A translational urinary MVA quantification method was developed, validated and used to demonstrate the diurnal variation of urinary MVA excretion in rats and healthy children. Methods: Urinary MVA was converted to mevalonolactone at pH 2, extracted with ethyl acetate and quantified by reversed-phase liquid chromatography-tandem mass spectrometry. Results: The assay had a dynamic range of 0.0156-10 µg/ml with precision <15% CV, accuracy 85-115% and was transferred between laboratories. Urinary MVA excretion in rats and healthy children displayed a diurnal variation consistent with the known diurnal variation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Conclusion: Urinary MVA can be quantified accurately over a wide dynamic range by a validated translational and transferable method with biomarker capability

Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?

Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups