THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Transporters

Alexander, Stephen P.H.; Kelly, Eamonn; Mathie, Alistair; Peters, John A.; Veale, Emma L.; Armstrong, Jane F.; Faccenda, Elena; Harding, Simon D; Pawson, Adam J.; Southan, Christopher; Davies, Jamie A.; Amarosi, Laura; Anderson, Catriona M.H.; Beart, Philip M; Bröer, Stefan; Dawson, Paul A.; Hagenbuch, Bruno; Hammond, James R.; Inui, Ken Ichi; Kanai, Yoshikatsu; Kemp, Stephan; Stewart, Gavin; Thwaites, David T.; Verri, Tiziano

doi:10.1111/bph.15543

Cited by 146 publications

(154 citation statements)

References 177 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, 46 and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22. 47 , 48 …”

Section: Discussionmentioning

confidence: 99%

Nucleoside analog GS‐441524: pharmacokinetics in different species, safety, and potential effectiveness against Covid‐19

Rasmussen

Thomsen

Hansen

2022

Pharmacology Res & Perspec

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GS‐441524, the parent nucleoside of remdesivir, has been proposed to be effective against Covid‐19 based on in vitro studies and studies in animals. However, randomized clinical trials of the agent to treat Covid‐19 have not been conducted. Here, we evaluated GS‐441524 for Covid‐19 treatment based on studies reporting pharmacokinetic parameters of the agent in mice, rats, cats, dogs, monkeys, and the single individual in the first‐in‐human trial supplemented with information about its activity against severe acute respiratory syndrome coronavirus 2 and safety. A dosing interval of 8 h was considered clinically relevant and used to calculate steady‐state plasma concentrations of GS‐441524. These ranged from 0.27 to 234.41 μM, reflecting differences in species, doses, and administration routes. Fifty percent maximal inhibitory concentrations of GS‐441524 against severe acute respiratory syndrome coronavirus 2 ranged from 0.08 μM to above 10 μM with a median of 0.87 μM whereas concentrations required to produce 90% of the maximal inhibition of the virus varied from 0.18 µM to more than 20 µM with a median of 1.42 µM in the collected data. Most of these concentrations were substantially lower than the calculated steady‐state plasma concentrations of the agent. Plasma exposures to orally administered GS‐441524, calculated after normalization of doses, were larger for dogs, mice, and rats than cynomolgus monkeys and humans, probably reflecting interspecies differences in oral uptake with reported oral bioavailabilities below 8.0% in cynomolgus monkeys and values as high as 92% in dogs. Reported oral bioavailabilities in rodents ranged from 12% to 57%. Using different presumptions, we estimated human oral bioavailability of GS‐441524 at 13% and 20%. Importantly, doses of GS‐441524 lower than the 13 mg/kg dose used in the first‐in‐human trial may be effective against Covid‐19. Also, GS‐441524 appears to be well‐tolerated. In conclusion, GS‐441524 has potential for oral treatment of Covid‐19.

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Section: Discussionmentioning

confidence: 99%

Nucleoside analog GS‐441524: pharmacokinetics in different species, safety, and potential effectiveness against Covid‐19

Rasmussen

Thomsen

Hansen

2022

Pharmacology Res & Perspec

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

Section: Discussionmentioning

confidence: 99%

Central histaminergic signalling, neural excitability and epilepsy

Yang

Wang

Chen

2021

British J Pharmacology

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Epilepsy is a common neurological disorder characterized by repeated and spontaneous epileptic seizures and is not well controlled by current medication. Traditional theory suggests that epilepsy results from an imbalance of excitatory glutamate neurons and inhibitory GABAergic neurons. However, new evidence from clinical and preclinical research suggests that histamine in the CNS plays an important role in the modulation of neural excitability and in the pathogenesis of epilepsy. Many histamine receptor ligands have achieved curative effects in animal epilepsy models, among which the histamine H 3 receptor antagonist pitolisant has shown anti-epileptic effects in clinical trials. Recent studies, therefore, have focused on the potential action of histamine receptors to control and treat epilepsy. In this review, we summarize the findings from animal and clinical epilepsy research on the role of brain histamine and its receptors. We also identify current gaps in the research and suggest where further studies are most needed.

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“…Two recent studies 41,42 have shown that tramadol is associated with an increased risk of mortality in the adult population compared to NSAIDs or non‐use. However, both study results were limited by confounding by indication as patients with multiple comorbidities such as cardiovascular, renal or bleeding disorders, who were at higher risk of mortality, may have been prescribed tramadol due to potential contraindication to NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

Tramadol versus codeine and the short‐term risk of cardiovascular events in patients with non‐cancer pain: A population‐based cohort study

Azoulay

Reynier

et al. 2021

Brit J Clinical Pharma

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Aims:The effect of tramadol on the cardiovascular system is largely unknown. There is concern that, with its multimodal mechanism of action to increase serotonin and norepinephrine levels in the body, it could increase the risk of arterial ischaemia and cardiovascular events. We aimed to compare the short-term risk of cardiovascular events with the use of tramadol to that of codeine among patients with non-cancer pain.Methods: We conducted a retrospective population-based cohort study using data from the Clinical Practice Research Datalink (CPRD) with new users of tramadol or codeine from April 1998 to March 2017. Exposure was defined using an approach analogous to an intention-to-treat, with a maximum follow-up of 30 days. The primary endpoint was myocardial infarction, and secondary endpoints were unstable angina, ischaemic stroke, coronary revascularization, cardiovascular death and allcause mortality. Hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusted for high-dimensional propensity score. Results:The final cohort included 123 394 tramadol users and 914 333 codeine users. When tramadol was compared to codeine, the adjusted hazard ratio (HR) of myocardial infarction was 1.00 (95% CI 0.81-1.24). There was also no evidence of elevated risks of unstable angina (0.92; 95% CI 0.67-1.27), ischaemic stroke (0.98; 95% CI 0.82-1.17), coronary revascularization (0.97; 95% CI 0.69-1.38), cardiovascular death (1.07; 95% CI 0.93-1.23) or all-cause mortality (1.03; 95% CI 0.94-1.14) when tramadol was compared to codeine.Conclusions: Short-term use of tramadol, compared with codeine, was not associated with an increased risk of cardiac events among patients with non-cancer pain.

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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Transporters

Cited by 146 publications

References 177 publications

Nucleoside analog GS‐441524: pharmacokinetics in different species, safety, and potential effectiveness against Covid‐19

Nucleoside analog GS‐441524: pharmacokinetics in different species, safety, and potential effectiveness against Covid‐19

Central histaminergic signalling, neural excitability and epilepsy

Tramadol versus codeine and the short‐term risk of cardiovascular events in patients with non‐cancer pain: A population‐based cohort study

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