The study of pharmacogenetic variants in populations which reside in Oceania has been focused mainly on CYP2C19 and CYP2D6. Statements about the high prevalence of CYP2C19 no function genotype in ...‘Pacific Islanders’ can be found in the literature. This review article summarizes the published information about these pharmacogenes in this geographical region and highlights the differences observed between Melanesian and Polynesian populations. It is not appropriate to combine the prevalence data of pharmacogenetic variants, particularly CYP2C19, across this region. Indeed, apocryphal assumptions about CYP2C19 no function alleles and possible effect on the therapeutic activity of clopidogrel are unhelpful and reiterate the importance of assessing the individual patient rather than relying on inappropriate ethnicity‐based assumptions for drug dosing decisions.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies ...exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response.
Methods
A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria.
Results
Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (
CDKN1A
,
ERCC1
,
ERCC2
,
ERCC4
,
ERCC6
,
EXO1
,
MLH1
,
MNAT1
,
MUTYH
,
PARP4
,
PCNA
,
POLE
,
POLR1G
,
RAD23B
,
RFC1
,
RFC3
,
RPA1
,
RPA3
,
TREX1
,
UNG
,
XPC
,
XRCC1
) and somatic expression (
CDKN1A
,
PARP1
,
PCNA
,
MGMT
,
RECQL
,
RFC5
) were associated with melphalan outcomes in ≥ 1 study.
Conclusion
It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Clozapine-induced myocarditis and cardiomyopathy are difficult to detect clinically and may be fatal if not detected early. The current/routine biomarkers for clozapine-induced myocarditis are ...non-specific indicators of inflammation (C-reactive protein) or cardiomyocyte damage (troponins I and T) that lack sensitivity, and for which changes often arise too late to be clinically useful.
The Clozapine Safety Study was a prospective, longitudinal, observational study to determine what, if any, the plasma concentrations of clozapine, N-desmethylclozapine, and clozapine-N-oxide in patients contribute to cardiotoxicity. Samples were collected and analysed using liquid chromatography mass spectrometry over a 41-month period from patients in the Auckland District Health Board.
Sixty-seven patients were included. Six patients were diagnosed with myocarditis; none were diagnosed with cardiomyopathy in the study period. In patients not undergoing dose titration, clozapine biotransformation may shift to the N-oxide pathway rather than the N-desmethyl pathway with increasing dose. During dose titration, the timeframe in which myocarditis occurs, the rate of increase in the plasma concentration of clozapine-N-oxide, as well as the ratio of N-oxidation relative to N-desmethylation, were significantly higher in patients diagnosed with myocarditis.
The assessment of clozapine-N-oxide formation, and N-oxidation relative to N-desmethylation ratios during treatment, may help identify a biomarker to aid the early detection of patients at risk of developing clozapine-induced cardiotoxicity.
•As clozapine dose increases biotransformation may shift from the N-demethyl to the N-oxide pathway.•The routes of clozapine metabolism may be altered in clozapine-induced myocarditis.•The clozapine N-oxide route appears to be favoured in cases of clozapine-induced myocarditis.•Assessment of metabolite ratios may help identify a biomarker of clozapine-induced myocarditis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inter-individual differences in DNA adduct formation and repair influence the response to melphalan treatment, however, further clinical investigation of this variability requires a logistically ...feasible and reproducible bioassay. Our improved fluorescence-based QPCR-block assay is robust, has good precision, and improved throughput. It also incorporates direct PCR amplification from melphalan exposed PBMC using commercially available blood tubes and extraction kits to maximise the utility of this assay for future clinical studies. Using this assay we have demonstrated reproducible inter-individual differences in melphalan-induced QPCR-block across individual PBMC donors. As proof-of-principle we assessed nine healthy donors and found a 7.8 fold range in sensitivity following exposure of PBMC ex vivo. This likely reflects differences in melphalan transport into cells as well as differences in DNA adduct repair proficiency. This improved bioassay may be useful for assessment of these processes in patients about to receive melphalan treatment.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background
Few Australasian studies have evaluated persistent pain after breast cancer surgery.
Objective
To evaluate the incidence, impact, and risk factors of moderate to severe persistent ...pain after breast cancer surgery in a New Zealand cohort.
Design
Prospective cohort study
Methods
Consented patients were reviewed at 3 timepoints (preoperative, 2 weeks and 6 months postoperative). Pain incidence and interference, psychological distress and upper limb disability were assessed perioperatively. Clinical, demographic, psychological, cancer treatment-related variables, quantitative sensory testing, and patient genotype (COMT, OPRM1, GCH1, ESR1, and KCNJ6) were assessed as risk factors using multiple logistic regression.
Results
Of the 173 patients recruited, 140 completed the 6-month follow-up. Overall, 15.0% (n = 21, 95% CI: 9.5%—22.0%) of patients reported moderate to severe persistent pain after breast cancer surgery with 42.9% (n = 9, 95% CI: 21.9%—66.0%) reporting likely neuropathic pain. Pain interference, upper limb dysfunction and psychological distress were significantly higher in patients with moderate to severe pain (P < .004). Moderate to severe preoperative pain (OR= 3.60, 95% CI: 1.13–11.44, P = .03), COMT rs6269 GA genotype (OR = 5.03, 95% CI: 1.49—17.04, P = .009) and psychological distress at postoperative day 14 (OR= 1.08, 95% CI: 1.02—1.16, P = .02) were identified as risk factors. Total intravenous anesthesia (OR= 0.31, 95% CI: 0.10 – 0.99, P = .048) was identified as protective.
Conclusion
The incidence of moderate to severe persistent pain after breast cancer surgery is high with associated pain interference, physical disability, and psychological distress. Important modifiable risk factors were identified to reduce this important condition.
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly ...1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15542. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A ...thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity.
Methods
Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC–MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases.
Results
There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), U
norm
p
= 0.0004; U/DHU
norm
p
= 0.0083. These two parameters had a sensitivity of 29%, compared with 57% for the THY challenge test in the same patients. Genotyping for clinically relevant
DPYD
variants was inferior to either of these pyrimidine phenotyping tests (sensitivity of 14%).
Conclusions
The endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than
DPYD
genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Few Australasian studies have assessed persistent pain after breast cancer surgery. This study aims to evaluate the prevalence, impact, and risk factors of moderate to severe persistent pain after ...breast cancer surgery in a New Zealand population.
Retrospective cross-sectional study of patients who underwent breast cancer surgery between six and 48 months previously. Validated questionnaires were used to assess pain prevalence and impact, psychological distress, and upper limb function. Patients' clinical records were assessed for potential risk factors.
Of the 375 patients who were sent questionnaires, 201 were included in the study. More than half of the patients (N = 111, 55%) reported breast surgery related-persistent pain, with 46 (23%) rating the pain as moderate to severe. Neuropathic pain was reported by 21 (46%) patients with moderate to severe pain. Pain interference, upper limb dysfunction, and psychological distress were significantly higher in patients with moderate to severe pain (P < 0.001). Non-European ethnicity (odds ratio OR = 5.02, 95% confidence interval CI = 2.05-12.25, P < 0.001), reconstruction surgery (OR = 4.10, 95% CI = 1.30-13.00, P = 0.02), and axillary node dissection (OR = 4.33, 95% CI = 1.19-15.73, P < 0.03) were identified as risk factors for moderate to severe pain by multivariate logistic regression analysis.
Moderate to severe persistent pain after breast cancer surgery affects many New Zealand patients, and is associated with impaired daily life activities, physical disability, and psychological distress. Large numbers of patients undergo breast cancer surgery annually. This study emphasizes the importance of identification and management of these patients perioperatively.
Purpose
Fluorouracil (5-FU), a chemotherapeutic agent widely used in the treatment of numerous common malignancies, causes oral mucositis in a proportion of patients. The contribution of drug ...transport processes to the development of this toxicity is currently unknown. This work aimed to establish and optimise a simple phenotyping assay for 5-FU uptake into primary buccal mucosal cells (BMC).
Methods
The uptake kinetics of radiolabelled 5-FU were determined in pooled BMC freshly collected from healthy volunteers. The inter- and intra-individual variability in 5-FU uptake was then assessed across a cohort that included both healthy volunteers and cancer patients.
Results
5-FU uptake into pooled primary BMC was both time and concentration dependent. An Eadie–Hofstee analysis suggested two components; a high-affinity (
K
M
= 3.3 µM) low-capacity (
V
MAX
= 57.8 pmol min
−1
10
5
viable cells
−1
) transporter, and a high-capacity (
V
MAX
= 1230 pmol min
−1
10
5
viable cells
−1
) low-affinity (
K
M
= 3932 µM) transporter. There was 180-fold variation in the rate of 5-FU uptake into BMC (0.10–17.86 pmol min
−1
10
5
viable cells
−1
) across the 34 subjects (healthy participants
N
= 24, cancer patients
N
= 10). Notably, retesting of a subset of these participants (
N
= 16) multiple times over a period of up to 140 days demonstrated poor stability of the uptake phenotype within individuals.
Conclusion
The uptake of 5-FU into healthy oral mucosal cells is a highly variable process facilitated by membrane transporters at pharmacologically relevant concentrations. This bioassay is simple, minimally invasive, and suitable for phenotypic analysis of drug transport in healthy primary cells.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims
A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The ...preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case–control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5‐fluorouracil or capecitabine.
Methods
Patients (n = 37) received a 250 mg (per os) dose of THY and a cumulative urine sample was collected for 0–4 h. The urinary amounts of THY and metabolite dihydrothymine (DHT) were determined by liquid chromatography/mass spectrometry. Genomic DNA was analysed for DPYD gene variants. Renal function was estimated from blood creatinine levels. Cases (n = 9) and noncases (n = 23) of severe (grade ≥ 3) gastrointestinal toxicity were defined based on Common Terminology Criteria for Adverse Events.
Results
The median THY/DHT ratios were 6.2 (interquartile range 2.9–6.4) in cases, including the 2 patients who were DPYD heterozygous carriers. However, this was not significantly different (P = .07) from the THY/DHT in noncases (median 2.6, interquartile range 2.8–4.2). Although creatinine clearance was lower (P = .001) in cases, renal function could not discriminate cases from noncases. However, logistic regression analysis using both of these explanatory variables could discriminate most cases (receiver operating characteristic area 0.8792, 95% confidence interval 0.72–1.00).
Conclusions
The THY challenge test combined with a patient's renal function may be useful as a phenotypic diagnostic test to detect risk of life‐threatening fluoropyrimidine gastrointestinal toxicity.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
