Pharmacogenomic associations of adverse drug reactions in
            asthma: systematic review and research prioritisation

King, Charlotte; McKenna, Amanda; Farzan, Niloufar; Vijverberg, Susanne J. H.; Schee, Marc P. van der; Zee, Anke‐Hilse Maitland‐van der; Arianto, Lambang; Bisgaard, Hans; Bønnelykke, Klaus; Berce, Vojko; Potočnik, Uroš; Repnik, Katja; Carleton, Bruce; Daley, Denise; Chew, Fook Tim; Chiang, Wen Chin; Sio, Yang Yie; Cloutier, Michelle M.; Dekker, Herman T. den; Jongste, Johan C. de; Dijk, F. Nicole; Koppelman, Gerard H.; Flores, Carlos; Hernandez‐Pacheco, Natalia; Pino-Yanes, María; Mukhopadhyay, Somnath; Basu, K; Bignell, Lauren; Tantisira, Kelan G.; Turner, Steve; Verhamme, Katia; Francis, Ben; Pirmohamed, Munir; Sinha, Ian; Hawcutt, Daniel B

doi:10.1038/s41397-019-0140-y

Cited by 12 publications

(12 citation statements)

References 28 publications

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“…While pharmacogenomic testing is currently used in some rare paediatric diseases, current national and international guidelines for asthma do not recommend it 3 4 14. Despite the number of studies carried out, there have been contradictory results, the endpoints have not been well aligned to the established core outcome set for childhood asthma and there has been disproportionate focus on efficacy (rather than adverse effects) 22. Despite all this, international consortia have coalesced29 and through rigorous meta-analysis of studies, there is now evidence supporting pilot pharmacogenomic testing of four or more drug–gene pairs 23.…”

Section: Discussionmentioning

confidence: 99%

“…Despite over 50 pharmacogenomic studies undertaken in CYP with asthma worldwide, there are no published data on the views of CYP themselves, their parents/legal guardians or HCPs, on the acceptability of using genetic information to guide treatment, and the factors influencing these decisions 21–23. Lessons learnt from the UK National Health Service (NHS) England care.data programme, launched in 2013, show that in attempting to centralise and share patient health and social care data, it is important to ensure clear two-way communications with the public, to ensure patient satisfaction and also safety of an individual’s data 24 25…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenomics and asthma treatment: acceptability to children, families and healthcare professionals

et al. 2022

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BackgroundEvidence supporting personalised treatment for asthma based on an individual’s genetics is mounting. The views of children and young people (CYP), parents and healthcare professionals (HCPs) about this evolution of clinical care are not known.MethodsA pilot prospective questionnaire-based study was undertaken of CYP with asthma, their parents and HCPs at a secondary/tertiary children’s hospital in the UK.ResultsFifty-nine questionnaires were distributed and 50 returned (response rate 84.7%), comprising 26 CYP (10 were 5–11 years, 11 were 12–15 years and 5 were 16–18 years old), 13 parents and 11 HCPs. For all types of data, personal information was ranked as the ‘most important’ (n=19, 47.5%) and ‘most private’ (n=16, 40%), but with considerable variation across groups. Within health data, allergies were rated as ‘most important’ (n=12, 30.8%), and mental health records the ‘most private’ (n=21, 53.8%), again with variation across groups. A ‘personalised genetic asthma plan’ was acceptable to the majority overall (n=40, 80.0%). With regard to sharing CYP’s genetic data, 23 (46%) of participants were happy for unconditional sharing between HCPs, and 23 (46%) agreed to sharing solely in relation to the CYP’s asthma management. Forty-two (84.0%) of participants felt CYP should be informed about genetic data being shared, and the majority felt this should commence by 12 years of age.ConclusionThe use of genetic information to guide management of asthma in CYP is largely acceptable to CYP, parents/guardians and HCPs. However, there are key differences between the opinions of CYP, parents and HCPs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacogenomics and asthma treatment: acceptability to children, families and healthcare professionals

et al. 2022

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“…The long-term intake of asthma medication often leads to bone-related complications, 48 such as low BMD level. 49 Terbutaline, as a commonly used asthma treatment drug, mainly acts as a ligand to adrenergic receptors on airway smooth muscles and thereby facilitates bronchiectasis.…”

Section: Discussionmentioning

confidence: 99%

Mechanical loading alleviated the inhibition of β2‐adrenergic receptor agonist terbutaline on bone regeneration

et al. 2021

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The long-term use of adrenergic medication in treating various conditions, such as asthma, increases the chances of bone fracture. Dynamic mechanical loading at a specific time is a method for improving bone quality and promoting healing.Therefore, we hypothesized that precisely controlling the mechanical environment can contribute to the alleviation of the negative effects of chronic treatment with the common asthma drug terbutaline, which is a β2adrenergic receptor agonist that facilitates bone homeostasis and defect repair through its anabolic effect on osteogenic cells. Our in vitro results showed that terbutaline can directly inhibit osteogenesis by impairing osteogenic differentiation and mineralization. Chronic treatment in vivo was simulated by administering terbutaline to C57BL/6J mice for 4 weeks before bone defect surgery and mechanical loading.We utilized a stabilized tibial defect model, which allowed the application of anabolic mechanical loading. During homeostasis, chronic terbutaline treatment reduced the bone formation rate, the fracture toughness of long bones, and the concentrations of bone formation markers in the sera. During defect repair, terbutaline decreased the bone volume, type H vessel, and total blood vessel volume. Terbutaline treatment reduced the number of osteogenic cells. Periostin, which was secreted mainly by Prrx1+ osteoprogenitors and F4/80+ macrophages, was inhibited by treating the bone defect with terbutaline. Interestingly, controlled mechanical loading facilitated the recovery of bone volume and periostin expression and the number of osteogenic cells within the defect. In conclusion, mechanical loading can rescue negative effects on new bone accrual and repair induced by chronic terbutaline treatment.

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“…Notwithstanding all the benefits of small molecule drugs, it remains the case that they are also widely associated with various morbidities and mortalities, often referred to as “adverse drug reactions” (ADRs) (e.g., [ 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 , 335 , 336 , 337 , 338 , 339 , 340 , 341 , 342 , 343 , 344 , 345 , 346 ]). Despite the lengthy and complex regulatory hurdles that drugs must overcome before being marketed (and toxicity remains a major cause of so-called “attrition” where drug candidates are pulled before they even get to market [ 347 , 348 , 349 , 350 , 351 , 352 , 353 ]), ADRs are extremely common (and hard to anticipate, given the huge genetic and phenotypic variation in human populations [ 354 ]).…”

Section: Introductionmentioning

confidence: 99%

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

Kell

2021

Molecules

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Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport “phospholipid bilayer transport is negligible”.

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Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation

Cited by 12 publications

References 28 publications

Pharmacogenomics and asthma treatment: acceptability to children, families and healthcare professionals

Pharmacogenomics and asthma treatment: acceptability to children, families and healthcare professionals

Mechanical loading alleviated the inhibition of β2‐adrenergic receptor agonist terbutaline on bone regeneration

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

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