The Concise Guide to PHARMACOLOGY 2023/24: Enzymes

Alexander, Stephen P. H.; Fabbro, Doriano; Kelly, Eamonn; Mathie, Alistair A.; Peters, John A.; Veale, Emma L.; Armstrong, Jane F.; Faccenda, Elena; Harding, Simon D.; Davies, Jamie A.; Annett, Stephanie; Boison, Detlev; Burns, Kathryn Elisa; Dessauer, Carmen; Gertsch, Jurg; Helsby, Nuala Ann; Izzo, Angelo A.; Ostrom, Rennolds; Papapetropoulos, Andreas; Pyne, Nigel J.; Pyne, Susan; Robson, Tracy; Seifert, Roland; Stasch, Johannes‐Peter; Szabo, Csaba; van der Stelt, Mario; van der Vliet, Albert; Watts, Val; Wong, Szu Shen

doi:10.1111/bph.16181

Cited by 171 publications

(24 citation statements)

References 85 publications

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org , the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, 19 and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20. 20 …”

Section: Methodsmentioning

confidence: 99%

Adherence to newer second‐line oral antidiabetic drugs among people with type 2 diabetes—A systematic review

Holdt‐Caspersen,

Dethlefsen,

Vestergaard

et al. 2024

Pharmacology Res & Perspec

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The adherence to oral antidiabetic drugs (OADs) among people with type 2 diabetes (T2D) is suboptimal. However, new OADs have been marketed within the last 10 years. As these new drugs differ in mechanism of action, treatment complexity, and side effects, they may influence adherence. Thus, the aim of this study was to assess the adherence to newer second‐line OADs, defined as drugs marketed in 2012–2022, among people with T2D. A systematic review was performed in CINAHL, Cochrane Trials, Embase, PubMed, PsycINFO, and Scopus. Articles were included if they were original research of adherence to newer second‐line OADs and reported objective adherence quantification. The quality of the articles was assessed using JBI's critical appraisal tools. The overall findings were reported according to the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) guidelines and summarized in a narrative synthesis. All seven included articles were European retrospective cohort studies investigating alogliptin, canagliflozin, dapagliflozin, empagliflozin, and unspecified types of SGLT2i. Treatment discontinuation and medication possession ratio (MPR) were the most frequently reported adherence quantification measures. Within the first 12 months of treatment, 29%–44% of subjects on SGLT2i discontinued the treatment. In terms of MPR, 61.7%–94.9% of subjects on either alogliptin, canagliflozin, dapagliflozin, empagliflozin or an unspecified SGLT2i were adherent. The two investigated adherence quantification measures, treatment discontinuation and MPR, suggest that adherence to the newer second‐line OADs may be better than that of older OADs. However, a study directly comparing older and newer OADs should be done to verify this.

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Section: Methodsmentioning

confidence: 99%

Adherence to newer second‐line oral antidiabetic drugs among people with type 2 diabetes—A systematic review

Holdt‐Caspersen,

Dethlefsen,

Vestergaard

et al. 2024

Pharmacology Res & Perspec

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 (Alexander, Christopoulos, et al, 2023;Alexander, Fabbro, et al, 2023).…”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Why classical receptor theory, which ignores allostery, can effectively measure the strength of an allosteric effect as agonist's efficacy

Onaran,

Costa

2024

British J Pharmacology

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Background and PurposeThe classical theory of receptor action has been used for decades as a powerful tool to estimate molecular determinants of ligand‐induced receptor activation (i.e., affinity and efficacy) from experimentally observable biological responses. However, it is also a well‐recognized fact that the receptor‐binding and activation mechanisms, and the parameters thereof, described in the classical theory contradict with the modern view of receptor activation based on allosteric principles.Experimental ApproachWe used mathematical analysis, along with some numerical simulations, to answer the key question as to what extent the classical theory is compatible—if at all—with the modern understanding of receptor activation.Key ResultsHere, we showed conclusively that (1) receptor activation equations based on allosteric principles contain the logic of the classical theory in disguise, and therefore, (2) estimates of “intrinsic efficacy” (ε) obtained by means of classical techniques (i.e., null methods or fitting the operational model to concentration‐response data) are equivalent to the allosteric coupling factors that represent the molecular efficacy of ligands.Conclusion and ImplicationsThus, we conclude that despite the justified criticisms it has received so far, the classical theory may continue to be useful in estimating ligand efficacy from experimental data, if used properly. Here, we also provide rigorous criteria for the proper use of the theory. These findings not only have implications for ligand classification but also resolve some long lasting discussions in the field of bias agonism in GPCR, which requires reasonable estimates of relative ligand efficacies at different signalling pathways.

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org , the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 21 and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24. 22 …”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Coadministration of fluconazole to boost subtherapeutic sirolimus concentrations: A case report

Scherkl,

Meid,

Cuntz

et al. 2024

Pharmacology Res & Perspec

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Individual sirolimus whole blood concentrations are highly variable, critically influenced by the concomitant use of cytochrome P450 (CYP) 3A inducers or inhibitors, and also modulated by food. Therapeutic drug monitoring is therefore recommended, especially at treatment start or in circumstances that can influence sirolimus exposure. In this case report, we highlight the challenge of achieving therapeutic sirolimus concentrations and present pragmatic solutions with regimen adaptions, pharmacokinetic enhancement (use of a drug–drug interaction), concentration monitoring, and subsequent modeling of population pharmacokinetics to support treatment decisions. In a 69‐year‐old female patient with allogeneic hematopoietic stem cell transplantation, tacrolimus concentrations were stable until she developed cerebral toxoplasmosis with tonic–clonic seizures. During treatment of this acute infection, tacrolimus concentrations dropped to subtherapeutic levels and remained largely unaffected by dose increases. Only the simultaneous administration of the CYP3A4 inhibitor fluconazole and a shortening of the sirolimus dosing intervals to a (non‐approved) twice‐daily administration led to successful control of the concentrations, which ultimately even made a dose reduction possible. This intervention resulted in an increase of sirolimus mean trough concentration to 5.85 ng/mL, i.e., into the desired target range. Additionally, a higher ratio of sirolimus trough levels/daily dose from 26.9 to 109 ng/mL/mg/kg/day was achieved with the initiation of fluconazole. Thus, this case report describes the use of clinical pharmacological concepts and pharmacokinetic modeling to optimize treatment strategies in an individual patient. This strategy could be generalized to other CYP inhibitors and other treatment regimens.

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The Concise Guide to PHARMACOLOGY 2023/24: Enzymes

Cited by 171 publications

References 85 publications

Adherence to newer second‐line oral antidiabetic drugs among people with type 2 diabetes—A systematic review

Adherence to newer second‐line oral antidiabetic drugs among people with type 2 diabetes—A systematic review

Why classical receptor theory, which ignores allostery, can effectively measure the strength of an allosteric effect as agonist's efficacy

Coadministration of fluconazole to boost subtherapeutic sirolimus concentrations: A case report

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