What is the coverage of retina screening services for people with diabetes? Protocol for a systematic review and meta-analysis.

INTRODUCTION: Diabetic retinopathy is a leading cause of vision impairment globally. Vision loss from diabetic retinopathy can generally be prevented by early detection and timely treatment. The WHO included a measure of service access for diabetic retinopathy as a core indicator in the Eye Care Indicator Menu launched in 2022: retina screening coverage for people with diabetes. The aim of this review is to provide a comprehensive global and regional summary of the available information on retina screening coverage for people with diabetes. METHODS AND ANALYSIS: A search will be conducted in five databases without language restrictions for studies from any country reporting retina screening coverage for adults with any type of diabetes at the national or subnational level using data collected since 1 January 2000 until the search date. We will also seek reports and coverage statistics from government websites of all WHO member states. Two investigators will independently screen studies, extract relevant data and assess risk of bias of included studies. The results of the review will be reported using the Preferred Reporting Items for Systematic Review and Meta-Analysis guideline. We will summarise the range of coverage definitions reported across included studies and present the median retina screening coverage in WHO regions and by World Bank country income level. Depending on the availability of data, we will conduct meta-analysis to assess disparities in retina screening coverage for people with diabetes by factors in the PROGRESS framework (Place of residence, Race/ethnicity/culture/language, Occupation, Gender/sex, Religion, Education, Socioeconomic status and Social capital). ETHICS AND DISSEMINATION: This review will only include published data thus no ethical approval will be sought. The findings of this review will be published in a peer-reviewed journal and presented at relevant conferences. PROTOCOL REGISTRATION NUMBER: OSF registration 17/10/2023: https://osf.io/k5p69.

Use of the CONSIDER statement by eye health researchers when conducting and reporting research involving Indigenous peoples: an online survey.

BACKGROUND: Indigenous peoples experience worse eye health compared to non-Indigenous peoples. Service providers and researchers must avoid perpetuating this inequity. To help achieve this, researchers can use the CONSolIDated critERia for strengthening the reporting of health research involving Indigenous peoples (CONSIDER) statement. This study aimed to identify the degree to which the CONSIDER statement has been used by eye health researchers when conducting and reporting research with an Indigenous component, and how they perceive its relevance in their future research. METHODS: We used purposive sampling to recruit eye health researchers from any country who have undertaken research with an Indigenous component. The online survey collected quantitative and qualitative data and was analysed using descriptive statistics and reflexive thematic analysis. Responses were gathered on a four-point Likert scale (1 to 4), with four being the most positive statement. RESULTS: Thirty-nine eye health researchers from nine countries completed the survey (Aotearoa New Zealand, Argentina, Australia, Brazil, Canada, Colombia, Guatemala, Panama, Peru); almost two-thirds (n = 24) undertake epidemiological research. On average, participants disclosed only 'sometimes' previously reporting CONSIDER items (2.26 ± 1.14), but they thought the items were relevant to eye health research and were motivated to use these guidelines in their future research. Some participants requested clarity about how CONSIDER aligned with existing guidelines, and when and how to apply the statement. Others shared rich experiences of the benefits to their research of Indigenous leadership and collaboration. CONCLUSIONS: The CONSIDER statement is perceived as a valuable tool by these eye health researchers, and there are opportunities to maximise uptake and use, including increasing awareness of the statement, clarity about when it applies, and availability of institutional-level support.

Primary eye health services for older adults as a component of universal health coverage: a scoping review of evidence from high income countries.

In pursuit of Universal Health Coverage (UHC) for eye health, countries must strengthen services for older adults, who experience the highest prevalence of eye conditions. This scoping review narratively summarised (i) primary eye health services for older adults in eleven high-income countries/territories (from government websites), and (ii) the evidence that eye health services reduced vision impairment and/or provided UHC (access, quality, equity, or financial protection) (from a systematic literature search). We identified 76 services, commonly comprehensive eye examinations ± refractive error correction. Of 102 included publications reporting UHC outcomes, there was no evidence to support vision screening in the absence of follow-up care. Included studies tended to report the UHC dimensions of access (n=70), equity (n=47), and/or quality (n=39), and rarely reported financial protection (n=5). Insufficient access for population subgroups was common; several examples of horizontal and vertical integration of eye health services within the health system were described. Funding: This work was funded by Blind Low Vision New Zealand for Eye Health Aotearoa.

Dual-focus contact lenses for myopia control modify central retinal electrophysiology in humans.

INTRODUCTION: Dual-focus contact lenses create two focal planes, one providing a clear retinal image while the other imposes myopic defocus on the retina to slow myopia progression. This study used global-flash multifocal electroretinogram (gmfERG) response amplitudes to compare central versus peripheral retinal responses under dual-focus conditions and to assess the optimal degree of myopic defocus compared with a single-vision control lens. METHODS: Twenty participants each underwent three gmfERG trials, wearing a spectacle correction over dual-focus contact lenses with plano central power and peripheral secondary focal powers of either +2.00D, +4.00D or a plano single-vision lens. We compared amplitudes and latencies of the gmfERG direct and induced components (DC and IC) within participants, between the three different contact lens powers and at different retinal eccentricities (gmfERG ring). RESULTS: We observed significant differences in the gmfERG responses between the single-vision and dual-focus contact lenses. Overall, DC amplitudes peaked between zero and +2.00D secondary power, while IC amplitudes were maximal between +2.00D and +4.00D. Compared with the single-vision control, the greatest increase in DC and IC amplitudes while wearing dual-focus lenses occurred within the central 10° of the retina. There was no interaction effect between gmfERG ring (eccentricity) and secondary power, and no difference in the latency of the gmfERG responses between different powers. CONCLUSION: We found that dual-focus contact lenses with a +2.00D secondary power are close to that expected to induce the greatest increase in gmfERG responses relative to a single-vision lens. Dual-focus lenses produced the highest DC and IC response amplitudes relative to a single-vision lens in the central 10° of the retina. This suggests that dual-focus contact lenses slow myopia progression by modifying central rather than peripheral retinal activity.

Diagnostic accuracy of the Parr vision test, single crowded Lea symbols and Spot vision screener for vision screening of preschool children aged 4-5 years in Aotearoa/New Zealand.

PURPOSE: Preschool children in New Zealand undergo vision screening to detect amblyopia at 4-5 years of age. The current test, the Parr vision test, does not meet international visual acuity chart guidelines and has not been validated against other commonly used paediatric vision tests. New Zealand vision screening protocols are also not targeted for detecting other eye conditions such as uncorrected refractive error, which may affect school performance. We compared the Parr vision test with the single crowded Lea symbols and the Spot vision screener for detecting ocular pathology, refractive error and amblyopic risk factors in preschool children. METHODS: A cross-sectional diagnostic accuracy study recruited children aged 4-5 years via convenience sampling from the University of Auckland Optometry Clinic and through primary schools in Auckland, New Zealand. Participants received vision screening with the three different instruments administered by a lay screener. Comprehensive eye examinations were completed by a paediatric optometrist to determine the presence of vision disorders. RESULTS: Of 197 children who received a comprehensive eye examination, 14 (7.1%) had amblyopic risk factors and 43 (21.8%) had significant refractive error (15.7% with astigmatism, 9.1% with hyperopia). The sensitivity for detecting any ocular condition did not differ significantly between the tests (50.0% for Parr, 43.5% for Lea, 42.5% for Spot). Specificity was significantly lower for the Parr vision test (80.8%) than for the Lea symbols (93.4%) and Spot vision screener (98.0%). Adding the Spot vision screener to measurements of visual acuity significantly improved sensitivity in detecting any ocular condition with the Parr vision test (67.5% for Parr/Spot vs 50% for Parr alone), but not with the Lea symbols (52.5% for Lea/Spot vs 43.5% for Lea alone). CONCLUSION: The sensitivity of the Parr vision test for detecting ocular conditions in preschool children does not vary significantly from that achieved by the Lea symbols or the Spot vision screener. However, current New Zealand vision screening protocols could be improved by expanding the target conditions to include significant refractive error and incorporating the use of the Spot vision screener to increase the accuracy with which children with refractive error are identified. Future research should include longitudinal studies to determine the effect of preschool vision screening on later ocular and academic outcomes.

IVF add-ons in Australia and New Zealand: A systematic assessment of IVF clinic websites.

BACKGROUND: In vitro fertilisation (IVF) 'add-ons' are extra (non-essential) procedures, techniques or medicines, which usually claim to increase the chance of a successful IVF outcome. Use of IVF add-ons is believed to be widespread in many settings; however, information about add-on availability in Australasia is lacking. AIMS: To understand which add-ons are advertised on Australasian IVF clinic websites, and what is the evidence for their benefit. MATERIALS AND METHODS: A systematic assessment of website content was undertaken between December 2019-April 2020, capturing IVF add-ons advertised, including costs, claims of benefit, statements of risk or limitations, and evidence of effectiveness for improving live birth and pregnancy. A literature review assessed the strength and quality of evidence for each add-on. RESULTS: Of the 40 included IVF clinics websites, 31 (78%) listed one or more IVF add-ons. A total of 21 different add-ons or add-on groups were identified, the most common being preimplantation genetic testing for aneuploidies (offered by 63% of clinics), time-lapse systems (33%) and assisted hatching (28%). In most cases (77%), descriptions of the IVF add-ons were accompanied by claims of benefit. Most claims (90%) were not quantified and very few referenced scientific publications to support the claims (9.8%). None of the add-ons were supported by high-quality evidence of benefit for pregnancy or live birth rates. The cost of IVF add-ons varied from $0 to $3700 (AUD/NZD). CONCLUSIONS: There is widespread advertising of add-ons on IVF clinic websites, which report benefits for add-ons that are not supported by high-quality evidence.

Multiple Tools Are Needed for the Detection of Prenatal Alcohol Exposure: Findings From a Community Antenatal Setting.

BACKGROUND: Although the toxic effects of prenatal alcohol exposure (PAE) on children are well established, there is emerging evidence about the dynamics and associated demographics of drinking patterns across pregnancy, with risky drinking more likely to take place in the period before pregnancy awareness. This study investigated the use of complementary measurement tools in the understanding of alcohol use across pregnancy and reports on the rates and patterns of alcohol use in a community antenatal setting. METHODS: Data on alcohol consumption before and after awareness of pregnancy were collected via multiple measurement tools: anonymous lifestyle questionnaire, TWEAK (Tolerance, Worried, Eye-opener, Amnesia, K/Cut down) screener questionnaire, and Substance Use Inventory interviews across multiple pregnancy timepoints. Additionally, phosphatidylethanol (PEth), a direct biomarker of alcohol metabolism, collected from newborns' dried blood spot cards, was analyzed. RESULTS: The TWEAK screener was more likely to identify risky drinking behavior than the lifestyle questionnaire. When pregnancy was unplanned, women were more likely to find out they are pregnant significantly later (p < 0.001) and consume alcohol at moderate-heavy levels (p = 0.03), prolonging the risk to the fetus. There was an association between maternal self-reported alcohol use on the lifestyle questionnaire and Substance Use Inventory interviews, but no association between maternal reports of alcohol use and PEth results (p = 0.72). Women self-reported moderate-heavy alcohol use in early pregnancy only and a positive PEth screen indicated PAE in late pregnancy, suggesting that these methods may identify different groups of women. CONCLUSIONS: Multiple measurement tools and methods are needed to identify PAE at different points across pregnancy. Prospective sensitive interviewing is better suited to detecting PAE in early pregnancy, but not later when social desirability bias is stronger, and the use of an objective biomarker, such a PEth, may be useful for identifying the risk of PAE in late pregnancy.

Reporting assisted reproductive technology success rates on Australian and New Zealand fertility clinic websites.

BACKGROUND: Fertility clinics commonly report their success rates online. These can be difficult to interpret as they are influenced by the way the data are presented. To improve transparency, the Reproductive Technology Accreditation Committee (RTAC) has published guidelines to support fertility clinics with their online reporting of success rates. However, it is unclear whether compliance with these guidelines will allow patients to make fair comparisons between clinics. AIMS: To illustrate the variability in patient and treatment populations that contribute to fertility clinic published rates. MATERIALS AND METHODS: Fertility clinics offering in vitro fertilisation treatment in Australia or New Zealand were assessed for compliance with six guidelines adapted from RTAC's code of practice, for reporting success rates in the public domain. All graphs and/or tables reporting clinic success rates were assessed to illustrate the combination of outcome or treatment variables contributing to each dataset. RESULTS: Twenty of the 30 fertility clinic websites reported success rates. Of these only 17 reported live births. The median compliance score with RTAC guidelines was 8/8 (interquartile range: 6-8). Of 41 figures published across all websites, five reported clinical pregnancy rates as their only outcome measure. Thirty-seven figures reported success rates 'per embryo transfer', two figures used 'per egg collection', and no figures described success rates 'per cycle started'. Thirty-two different combinations of reporting variables were observed. CONCLUSIONS: Websites were broadly compliant with RTAC's guidelines. However, considering the variability in patient and treatment groups contributing to success rate data, patients cannot be expected to make an informed decision based on clinics' self-reported outcomes. RTAC guidelines could be improved by providing a clear definition of success, including the appropriate use of denominators.

Global-flash mfERG responses to local differences in spherical and astigmatic defocus across the human retina.

PURPOSE: Emmetropisation is essentially a visually guided, within-eye process. We investigated differences in global-flash multifocal electroretinogram (gmfERG) responses to naturally occurring differences in spherical and astigmatic defocus across the retina, which might provide a basis for guiding eye growth. METHODS: Experiment 1: The gmfERG responses (direct, DC, and induced, IC, amplitudes and latencies) recorded simultaneously from six retinal areas (15° eccentricity, spaced at 60°, areas 3.2°2 ) were correlated with the uncorrected retinal defocus measured at the six corresponding retinal locations in 20 adults with foveal refractive errors (-4.75 to +1.25D). No correcting lenses were used to avoid introduction of lens-induced aberrations and magnification. Experiment 2 investigated the effect of superimposing astigmatic defocus (+2.00/-4.00D Jackson Cross Cylinder presented at four orientations) on gmfERG responses. RESULTS: Experiment 1: DC and IC response amplitudes were greater in retinal regions naturally exposed to more hyperopic spherical defocus (DC: rho = 0.26, p = 0.005; IC: rho = 0.29, p = 0.001), but response latencies were unaffected by sign or magnitude of spherical defocus (DC: p = 0.34; IC: p = 0.40). Response amplitudes and latencies were unaffected by astigmatic defocus. Experiment 2: Rotating the JCC axis to four different orientations had no effect on the gmfERG responses (DC amplitude, p = 0.39; DC latency, p = 0.10; IC amplitude, p = 0.51; IC latency, p = 0.64). CONCLUSION: The gmfERG responses from discrete retinal areas varied with the sign and magnitude of local spherical defocus, but we found no evidence that retinal responses were affected by astigmatic defocus. Therefore, local astigmatism is unlikely to provide cues for controlling eye growth, whereas differences in response to spherical defocus between different retinal regions could potentially provide cues for controlling eye growth in emmetropisation.

Classical Short-Delay Eyeblink Conditioning in One-Year-Old Children.

Classical eyeblink conditioning (EBC) refers to the learned association between a conditioned stimulus (an auditory tone) and an unconditioned stimulus (a puff of air to the cornea). Eyeblink conditioning is often used experimentally to detect abnormalities in cerebellar-dependent learning and memory that underlies this type of associative learning. While experiments in adults and older children are relatively simple to administer using commercial equipment, eyeblink conditioning in infants is more challenging due to their poor compliance, which makes correct positioning of the equipment difficult. To achieve conditioning in one-year-old infants, a custom-made or an adapted commercial system can be used to deliver the air puff to the infant's cornea. The main challenge lies in successfully detecting and classifying the behavioral responses. We report that automated blink detection methods are unreliable in this population, and that conditioning experiments should be analyzed using frame-by-frame analysis of supplementary video camera recordings. This method can be applied to study developmental changes in eyeblink conditioning and to examine whether this paradigm can detect children with neurological disorders.

The futility of fertility research? Barriers to embryo research in New Zealand.

AIMS: Successive New Zealand Health Ministers have failed to approve guidelines for research using viable human embryos, which effectively places a blanket ban on all research that "uses" viable human embryos in this country. This includes research that aims to improve currently available reproductive technologies, illustrated by a failed application to ministerial ethics committees for a clinical research project investigating the efficacy of in vitro fertilisation procedures. However, no data currently exists describing the degree to which these restrictions are inhibiting reproductive research in this country. METHODS: We have conducted a qualitative survey of New Zealand researchers from 20 major academic, clinical and governmental institutes to qualify the impact these restrictions are having on New Zealand's research outputs. RESULTS: The results suggest dissatisfaction with the current guidelines, and the lack of guidance from the Ministry of Health and associated ethics committees regarding what constitutes embryo research and therefore what research can be performed. CONCLUSIONS: The lack of current guidelines regarding the use of embryos for research is restricting improvements to established reproductive technologies, and any future research. We suggest that the Minister of Health instructs ministerial advisory and ethics committees to review the current guidelines and to define the term "use of embryos".

Vision screening at two years does not reduce the prevalence of reduced vision at four and a half years of age.

BACKGROUND: There is currently insufficient evidence to recommend vision screening for children < 36 months of age. This study assessed the effect of comprehensive vision screening, as well as the sensitivity of age-appropriate vision tests, at two years of age on habitual visual acuity at 4.5 years of age. METHODS: Children born at risk of neonatal hypoglycaemia (n = 477) underwent vision assessment at 54 ± 2 months of age including measurement of monocular and binocular habitual visual acuity, assessment of binocularity and stereopsis. Of these children, 355 (74.4 per cent) had also received vision screening at two years of age (mean age = 24± 1 months), while 122 were not screened. RESULTS: Eighty (16.8 per cent) children were classified as having reduced vision at 4.5 years of age, but the prevalence of reduced vision did not differ between children who had previously been screened at two years of age and those who had not (15.5 per cent versus 20.5 per cent, p = 0.153). However, children with reduced vision at 4.5 years of age were more likely to have had visual abnormalities requiring referral detected at two years of age (p = 0.02). Visual acuity and mean spherical equivalent autorefraction measurements were also worse (higher values) in two-year-old children who were later classified with reduced habitual visual acuity (p = 0.031 and p = 0.001, respectively). Nevertheless, unaided binocular visual acuity, non-cycloplegic refractive error, and stereopsis at two years all showed poor sensitivity and specificity for predicting visual outcomes at 4.5 years of age. CONCLUSION: Our findings do not support the adoption of early vision screening in children as current vision tests suitable for use with two-year-old children have poor sensitivity for predicting mild-moderate habitual vision impairment at 4.5 years of age.

N-terminal SAP97 isoforms differentially regulate synaptic structure and postsynaptic surface pools of AMPA receptors.

The location and density of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is controlled by scaffolding proteins within the postsynaptic density (PSD). SAP97 is a PSD protein with two N-terminal isoforms, α and ß, that have opposing effects on synaptic strength thought to result from differential targeting of AMPA receptors into distinct synaptic versus extrasynaptic locations, respectively. In this study, we have applied dSTORM super resolution imaging in order to localize the synaptic and extrasynaptic pools of AMPA receptors in neurons expressing α or ßSAP97. Unexpectedly, we observed that both α and ßSAP97 enhanced the localization of AMPA receptors at synapses. However, this occurred via different mechanisms: αSAP97 increased PSD size and consequently the number of receptor binding sites, whilst ßSAP97 increased synaptic receptor cluster size and surface AMPA receptor density at the PSD edge and surrounding perisynaptic sites without changing PSD size. αSAP97 also strongly enlarged presynaptic active zone protein clusters, consistent with both presynaptic and postsynaptic enhancement underlying the previously observed αSAP97-induced increase in AMPA receptor-mediated currents. In contrast, ßSAP97-expressing neurons increased the proportion of immature filopodia that express higher levels of AMPA receptors, decreased the number of functional presynaptic terminals, and also reduced the size of the dendritic tree and delayed the maturation of mushroom spines. Our data reveal that SAP97 isoforms can specifically regulate surface AMPA receptor nanodomain clusters, with ßSAP97 increasing extrasynaptic receptor domains at peri-synaptic and filopodial sites. Moreover, ßSAP97 negatively regulates synaptic maturation both structurally and functionally. These data support diverging presynaptic and postsynaptic roles of SAP97 N-terminal isoforms in synapse maturation and plasticity. As numerous splice isoforms exist in other major PSD proteins (e.g., Shank, PSD95, and SAP102), this alternative splicing may result in individual PSD proteins having divergent functional and structural roles in both physiological and pathophysiological synaptic states.

Fluoxetine Does Not Enhance Visual Perceptual Learning and Triazolam Specifically Impairs Learning Transfer.

The selective serotonin reuptake inhibitor fluoxetine significantly enhances adult visual cortex plasticity within the rat. This effect is related to decreased gamma-aminobutyric acid (GABA) mediated inhibition and identifies fluoxetine as a potential agent for enhancing plasticity in the adult human brain. We tested the hypothesis that fluoxetine would enhance visual perceptual learning of a motion direction discrimination (MDD) task in humans. We also investigated (1) the effect of fluoxetine on visual and motor cortex excitability and (2) the impact of increased GABA mediated inhibition following a single dose of triazolam on post-training MDD task performance. Within a double blind, placebo controlled design, 20 healthy adult participants completed a 19-day course of fluoxetine (n = 10, 20 mg per day) or placebo (n = 10). Participants were trained on the MDD task over the final 5 days of fluoxetine administration. Accuracy for the trained MDD stimulus and an untrained MDD stimulus configuration was assessed before and after training, after triazolam and 1 week after triazolam. Motor and visual cortex excitability were measured using transcranial magnetic stimulation. Fluoxetine did not enhance the magnitude or rate of perceptual learning and full transfer of learning to the untrained stimulus was observed for both groups. After training was complete, trazolam had no effect on trained task performance but significantly impaired untrained task performance. No consistent effects of fluoxetine on cortical excitability were observed. The results do not support the hypothesis that fluoxetine can enhance learning in humans. However, the specific effect of triazolam on MDD task performance for the untrained stimulus suggests that learning and learning transfer rely on dissociable neural mechanisms.

AMPA Receptors as Therapeutic Targets for Neurological Disorders.

Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction. The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. Benzamide compounds that act as positive allosteric AMPA receptor modulators, known as AMPAkines, can act on specific brain regions and were initially proposed to revolutionize the treatment of cognitive deficits associated with neurological disorders. Their therapeutic potential has since declined due to inconsistent results in clinical trials. However, recent advances in basic biomedical research are significantly increasing our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins. In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits have been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity. These proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders.

Excitatory binocular interactions in two cases of alternating strabismus.

PURPOSE: Individuals with alternating fixation due to strabismus have often been considered prime examples of monocular visual function. A growing body of evidence suggests, however, that, at least in the case of a fixed-angle strabismus, excitatory binocular function is possible in the strabismic visual cortex if interocular suppression is taken into account. We investigated whether excitatory binocular function might also be possible for patients with alternating strabismus. METHODS: Suprathreshold binocular interaction was tested in two individuals with alternating fixation and no amblyopia using a dichoptic motion coherence paradigm that can measure and account for interocular suppression. RESULTS: Both participants exhibited strong interocular suppression when stimuli of the same contrast were presented to each eye, whereas no such suppressive interactions were present for controls; however, in significantly reducing the contrast of the stimuli presented to the fixing eye, excitatory binocular interactions were demonstrated in both participants similar to those measured in controls without the contrast imbalance. CONCLUSIONS: The cortical mechanisms necessary for combining information from the two eyes seem to have been present but suppressed in our 2 participants with alternating fixation, just as they have been shown to be present in patients with fixed-angle strabismus.

Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II.

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes - in particular, CYP3A4 and CYP3A5 - and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacodynamics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed and all relevant primary research articles were critiqued and summarized. There is no evidence that the CYP3A4 -392A>G SNP has an effect on the pharmacodynamics of either ciclosporin or tacrolimus; however, studies have been limited. For patients prescribed ciclosporin, the CYP3A5 6986A>G SNP may influence long-term survival, possibly because of a different metabolite pattern over time. This SNP has no clear association with acute rejection during ciclosporin therapy. Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression. This is likely to be explained by the practice of performing tacrolimus dose adjustments in the early phase after transplantation. The effect of the CYP3A5 6986A>G SNP on ciclosporin- and tacrolimus-related nephrotoxicity and development of hypertension is unclear. Similarly, the ABCB1 SNPs exert no clear influence on either ciclosporin or tacrolimus pharmacodynamics, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity. In kidney transplant patients, consideration of the donor kidney genotype rather than the recipient genotype may be more important when assessing development of nephrotoxicity. Studies with low patient numbers may account for many inconsistent results to date. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful, particularly ones that consider both donor and recipient genotype. The effects of polymorphisms associated with the pregnane X receptor, organic anion transporting polypeptides, calcineurin inhibitor target sites and immune response pathways need to be further investigated. A large standardized clinical trial is now required to evaluate the relationship between the pharmacokinetics and pharmacodynamics of CYP3A5-mediated tacrolimus metabolism, particularly in regard to the outcomes of acute rejection and nephrotoxicity. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.

Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I.

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes--in particular, CYP3A4 and CYP3A5--and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 -392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.