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Frailty is a common clinical syndrome that predisposes older adults to an increased risk of adverse health outcomes. With population aging, this will become an increasing challenge for the healthcare services; therefore, different models of healthcare training and provision are required to address these increasing demands. In Ireland, the National Clinical Programme for Older People (NCPOP) has partnered with The Irish Longitudinal Study on Ageing (TILDA) to deliver the National Frailty Education Programme. This demonstrates an innovative way in which evidence-based longitudinal research can be translated into clinical education and practice to improve patient care, following a Knowledge to Action (KTA) process. To the authors' knowledge, it is the first time that a longitudinal research study such as TILDA has employed such methods of translation and therefore, this collaboration could serve as an international model of translation and implementation for frailty and other areas of clinical priority.

Background : Frailty is associated with a prodromal stage called pre-frailty, a potentially reversible and highly prevalent intermediate state before frailty becomes established. Despite being widely-used in the literature and increasingly in clinical practice, it is poorly understood. Objective : To establish consensus on the construct and approaches to diagnose and manage pre-frailty. Methods : We conducted a modified (electronic, two-round) Delphi consensus study. The questionnaire included statements concerning the concept, aspects and causes, types, mechanism, assessment, consequences, prevention and management of pre-frailty. Qualitative and quantitative analysis methods were employed. An agreement level of 70% was applied. Results : Twenty-three experts with different backgrounds from 12 countries participated. In total 70 statements were circulated in Round 1. Of these, 52.8% were accepted. Following comments, 51 statements were re-circulated in Round 2 and 92.1% were accepted. It was agreed that physical and non-physical factors including psychological and social capacity are involved in the development of pre-frailty, potentially adversely affecting health and health-related quality of life. Experts considered pre-frailty to be an age-associated multi-factorial, multi-dimensional, and non-linear process that does not inevitably lead to frailty. It can be reversed or attenuated by targeted interventions. Brief, feasible, and validated tools and multidimensional assessment are recommended to identify pre-frailty. Conclusions : Consensus suggests that pre-frailty lies along the frailty continuum. It is a multidimensional risk-state associated with one or more of physical impairment, cognitive decline, nutritional deficiencies and socioeconomic disadvantages, predisposing to the development of frailty. More research is needed to agree an operational definition and optimal management strategies.

Background Although not an inevitable part of ageing, frailty is an increasingly common condition in older people. Frail older patients are particularly vulnerable to the adverse effects of hospitalisation, including deconditioning, immobility and loss of independence (Chong et al, J Am Med Dir Assoc 18:638.e7–638.e11, 2017). The ‘Systematic Approach to improving care for Frail older patients’ (SAFE) study co-designed, with public and patient representatives, quality improvement initiatives aimed at enhancing the delivery of care to frail older patients within an acute hospital setting. This paper describes quality improvement initiatives which resulted from a co-design process aiming to improve service delivery in the acute setting for frail older people. These improvement initiatives were aligned to five priority areas identified by patients and public representatives. Methods The co-design work was supported by four pillars of effective and meaningful public and patient representative (PPR) involvement in health research (Bombard et al, Implement Sci 13:98, 2018; Black et al, J Health Serv Res Policy 23:158–67, 2018). These pillars were: research environment and receptive contexts; expectations and role clarity; support for participation and inclusive representation and; commitment to the value of co-learning involving institutional leadership. Results Five priority areas were identified by the co-design team for targeted quality improvement initiatives: Collaboration along the integrated care continuum; continence care; improved mobility; access to food and hydration and improved patient information. These priority areas and the responding quality improvement initiatives are discussed in relation to patient-centred outcomes for enhanced care delivery for frail older people in an acute hospital setting. Conclusions The co-design approach to quality improvement places patient-centred outcomes such as dignity, identity, respectful communication as well as independence as key drivers for implementation. Enhanced inter-personal communication was consistently emphasised by the co-design team and much of the quality improvement initiatives target more effective, respectful and clear communication between healthcare personnel and patients. Measurement and evaluation of these patient-centred outcomes, while challenging, should be prioritised in the implementation of quality improvement initiatives. Adequate resourcing and administrative commitment pose the greatest challenges to the sustainability of the interventions developed along the SAFE pathways. The inclusion of organisational leadership in the co-design and implementation teams is a critical factor in the success of interventions targeting service delivery and quality improvement.

Introduction: The best interventions to address frailty among older adults have not yet been fully defined, and the diversity of interventions and outcome measures makes this process challenging. Consequently, there is a lack of guidance for clinicians and researchers regarding which interventions are most likely to help older persons remain robust and independent. This paper uses meta-analysis to assess effectiveness of primary care interventions for physical frailty among community-dwelling adults aged 60+ and provides an up-to-date synthesis of literature in this area. Methods: PubMed, CINAHL, Cochrane Register of Controlled Trials, and PEDro databases were searched, and RCTs, controlled pilot studies, or trials with similar study designs addressing frailty in the primary care setting among persons aged 60+ were chosen. Study data was abstracted following PRISMA guidelines, then meta-analysis was performed using the random effects model. Results: 31 studies with a total of 4794 participants were analysed. Interventions using predominantly resistance-based exercise and nutrition supplementation seemed to improve frailty status versus control (RR = 0.62 (CI 0.48-0.79), I2 = 0%). Exercise plus nutrition education also reduced frailty (RR = 0.69 (CI 0.58-0.82), I2 = 0%). Exercise alone seemed effective in reducing frailty (RR = 0.63 (CI 0.47-0.84), I2 = 0%) and improving physical performance (RR = 0.43 (CI 0.18-0.67), I2 = 0%). Exercise alone also appeared superior to control in improving gait speed (SMD = 0.36 (CI 0.10-0.61, I2 = 74%), leg strength (SMD = 0.61 (CI 0.09-1.13), I2 = 87%), and grip strength (Mean Difference = 1.08 (CI 0.02-2.15), I2 = 71%) though a high degree of heterogeneity was observed. Comprehensive geriatric assessment (RR = 0.77 (CI 0.64-0.93), I2 = 0%) also seemed superior to control in reducing frailty. Conclusion: Exercise alone or with nutrition supplementation or education, and comprehensive geriatric assessment, may reduce physical frailty. Individual-level factors and health systems resource availability will likely determine configuration of future interventions.

We addressed the research question “what factors enable the successful development and implementation of a frail older person’s pathway within the acute setting”. A rapid realist review (RRR) was conducted by adopting the RAMESES standards. We began with a sample of 232 articles via database searches supplemented with 94 additional records including inputs from a twitter chat and a hospital site visit. Our final sample consisted of 18 documents. Following review and consensus by an expert panel we identified a conceptual model of context-mechanism-(resources)-outcomes. There was overall agreement frailty should be identified at the front door of the acute hospital. Significant challenges identified related to organisational boundaries both within the acute setting and externally, the need to shift outcomes to patient orientated ones, to support staff to sustain the pathway by providing ongoing education and by providing role clarity. RRRs can support research such as the systematic approach to improving care for frail older adults (SAFE) study by producing accounts of what works based on a wide range of sources and innovative engagement with stakeholders. It is evident from our provisional model that numerous factors need to combine and interact to enable and sustain a successful frail older person’s pathway. Health Research Board

Objective The objective of this review is to critically examine, evaluate, and synthesize the literature on resilience in family caregiving for people with dementia. Methods A systematic literature review was conducted according to PRISMA guidelines to identify articles which examined resilience and related concepts in family caregiving for people with dementia. The review was based on a systematic search of scholarly databases, to yield peer-reviewed articles and grey literature, published between 2006 and 2016. Two independent reviewers prescreened the search results and conducted formal assessments and quality appraisals of the retrieved articles. Results A total of 13 863 articles were identified by the systematic search, and 52 articles were included in the review. Based on a critical narrative synthesis of the literature, the study proposes a model of resilience for family carers of people with dementia, which incorporates the context of caring, social and cultural characteristics, and psychological dimensions of caring. Conclusions The results indicate that there is no single approach to enhancing resilience among family carers of people with dementia. Resilience is a multifaceted response to the caregiving role, and is influenced by a multitude of interrelated factors. However, the factors and resources outlined have been addressed, with limited success in some cases, by psychosocial interventions in the field. While the work conducted to date to develop resilience-enhancing interventions has been marked with some success, the next wave of carer research could usefully examine ecological perspectives on carer outcomes, including carer resilience.

Purpose: Over 5100 colorectal cancers (CRCs) are diagnosed in the United Kingdom in 85 years and older age group per year but little is known of cancer progression in this group. We assessed clinical, pathological and molecular features of CRC with early and late mortality in such patients. Methods: Data were analysed in relation to early mortality and long-term survival in 90 consecutive patients with CRC aged 85 years or older in a single hospital. Results: Patients not undergoing operation, those with an ASA score of III or greater and those with advanced tumour stage were more likely to die within 30 days. Regression analysis showed that 30 day mortality was independently related to failure to undergo resection (odds ratio (O.R.), 10.0; 95% confidence interval [C.I.], 1.7–58.2; p = 0.01) and an ASA score of III or greater (O.R. 13.0; 95% C.I., 1.4–12.6; p = 0.03). All cause three and five year survival were 47% and 23% respectively for patients who are alive 30 days after diagnosis. Three and five year relative survivals were 64% and 54%, respectively. Long-term outcome was independently related to tumour stage (relative risk [R.R.], 2; 95% C.I., 1.3–3.1; p = 0.001), presence of co-morbid diseases (R.R., 2.8; 95% C.I., 1.3–6.0; p = 0.007) and lipid peroxidation status (R.R., 2.9; 95% C.I., 1.1–7.5; p = 0.025). Conclusions: An active multidisciplinary approach to the care of patients with CRC at the upper extreme of life is reasonable. It also seems sensible to individualise care based upon the extent of disease at diagnosis and the presence of co-morbid conditions. Further studies to examine the role of lipid peroxidation are warranted.

Establishing a neurocardiovascular investigation unit for the investigation of falls and syncope in the elderly is feasible. With the increasing growth in the elderly population, these units will be required to play an equally increasing role in both the clinical management of patients and the ongoing clinical research into the conditions that cause falls and blackouts in the elderly.

Objective To determine in humans the relative roles of intestinal and hepatic metabolism in the oral first-pass elimination of a CYP3A substrate using midazolam as a model compound. Methods Midazolam was administered intravenously (1 mg) or orally (2 mg) to 20 healthy young subjects (10 men and 10 women) in a random fashion, and the disposition of the drug and its 1′-hydroxy metabolite were determined. In separate in vitro studies, the CYP3A-mediated formation of 1′-hydroxymidazolam by human hepatic and intestinal microsomes was investigated. Results No gender-related differences were noted in either the systemic (370 ± 114 ml/min [mean ± SD]) or oral (1413 ± 807 ml/min) clearance values of midazolam. Despite complete oral absorption, measured oral bioavailability was on average about 50% less than that predicted on the assumption that only the liver contributed to first-pass metabolism. Pharmacokinetic estimation of the intestinal component indicated an extraction ratio (0.43 ± 0.24) that was similar to that of the liver (0.44 ± 0.14). 1′-Hydroxymidazolam was extensively but variably formed in vitro by both hepatic and intestinal microsomes and, although the intrinsic clearance (Vmax/Km) was higher in the liver (540 ± 747 versus 135 ± 92 μl/min/mg protein), this difference was not statistically significant. Conclusions These results show that the small intestine can be a major site for presystemic, CYP3A-mediated metabolism after oral administration. Moreover, it appears that this represents a true first-pass effect. In addition, intestinal and hepatic metabolism may be important factors in interindividual variability in disposition after oral administration of midazolam and similar CYP3A substrates. Finally, intestinal localization of CYP3A may be significant in metabolism-based drug-drug interactions. Clinical Pharmacology & Therapeutics (1996) 59, 491–502; doi

Summary Introduction: Many advantages to community-oriented medical education have already been described. Responding to reforms in undergraduate medical education policy, our medical school reconfigured its clinical curriculum to include a module with a broad community focus, based in primary and secondary care. We describe our initial experience developing, implementing and evaluating this module. Methods: The aim of the module was to provide students with an understanding of medicine as practised, and health care as delivered, in the community. The 6-week module is delivered four times annually in the final stage of the medical degree programme, with 40–50 students attending each time. Learning experiences encompass clinical attachments, lectures, workshops, seminars and group presentations, with multifaceted assessment and formal student feedback at the end of the module (Ramsden’s Module/Course Experience Questionnaire, and student self-assessment of specified learning objectives, using a five-point Likert scale). Results of student feedback: A total of 104 out of 181 (57.5%) students completed the evaluation. Of these, 69.3 per cent were satisfied with the course (with a mean Likert score of 3.7). More than 75 per cent of the students agreed or strongly agreed that they had attained 12 of 13 specified learning objectives, and 64.6 per cent (95% CI 55.0–74.2%) agreed that they could use common diagnostic/therapeutic equipment. The mean Likert scores for Ramsden questionnaire subscales were: good teaching, 3.5; clarity of goals, 3.1; appropriate assessment, 3.6; appropriate workload, 3.7; and generic skills development, 3.4. The most positive scores were attained for teachers’ ability to explain (3.95; 77.5% agreed or strongly agreed) and effort at making subjects interesting (3.83; 73.5% agreed or strongly agreed). Conclusion: Our experience shows a community-based module with a strong combined primary care and elderly care focus is feasible, and enables the achievement of valuable learning objectives.

To identify predictors of negative in-patient outcomes (prolonged hospital stay and death) in nursing home (NH) residents admitted to the hospital as medical emergencies.This was a retrospective patient series set at St James's Hospital (Dublin, Ireland). The participants were all NH patients requiring acute medical admission under the on-call medical team between 1 January 2002 and 31 December 2010. Patient characteristics on admission, such as demographics, comorbidity level, major diagnostic categories, vital signs and laboratory profile, were measured. The outcomes of the study were prolonged hospital stay (≥ 30 days) and in-hospital mortality. The characteristics of NH patients were compared with those of non-NH patients aged ≥ 65 years. Multivariate analyses were based on generalized estimating equations and classification trees.There were 55,763 acute medical admissions over the period, of which 1938 (3.5%) were from NH. As compared with non-NH patients aged ≥ 65 years, NH patients had greater acute illness severity. NH patients had a median length of stay of 7 days, and 17% had a prolonged admission. Their overall mortality rate was 23%. However, the classification analysis showed substantial patient heterogeneity; the subgroup with the highest mortality (54%, n = 100) had positive serum troponin and a respiratory major diagnosis. The lowest mortality rate (4%) was seen in those without positive troponin, urea of 12 mmol/L or less, and albumin of more than 37 mg/L (n = 226).Simple serum markers, such as troponin, urea and albumin, might predict mortality in medically admitted NH patients. This might help health-care practitioners to anticipate their clinical course at an early stage.

The adoption of a frailty paradigm in primary care would be helpful to identify adults who need priority access to specialised resources. The frailty phenotype by Fried et al is a popular operationalisation of frailty, but it is not easily applicable in routine primary care practice. We recently created and validated a frailty instrument based on the Survey of Health, Ageing and Retirement in Europe (SHARE-FI), in order to provide primary care practitioners with an easy, reliable and freely accessible tool for the assessment and monitoring of frailty in community dwelling adults over the age of 50 years (www.biomedcentral.com/1471-2318/10/57).To provide further prospective validation of SHARE-FI, with a focus on disability.longitudinal study (wave 1: 2004-2006; mean follow-up: 2.4 years).European population-based survey (12 countries).17 567 community dwelling participants (mean age 63.3 years), of whom 13 378 (76.2%) were non-frail, 3438 (19.6%) pre-frail and 751 (4.3%) frail.number of difficulties with basic (ADL) and instrumental (IADL) activities of daily living.repeated measures ANOVA with adjustment for baseline age.By wave 2, 3.6% of the non-frail, 12.2% of the pre-frail and 30.4% of the frail had increased their number of ADL difficulties by at least one. Likewise, 6.6% of the non-frail, 20.4% of the prefrail and 36.6% of the frail had, by wave 2, increased their number of IADL difficulties by at least one. Table 1 shows the repeated measures ANOVA suggested.SHARE-FI may contribute to quality in primary care by offering a quick and reliable way to assess and monitor frailty in community dwelling individuals over the age of 50 and prioritize their access to resources, and it serves as a novel tool for audit and research.

Background: the primary prevention of ischaemic stroke in chronic non-valvular atrial fibrillation (AF) typically involves consideration of aspirin or warfarin. CHA2DS2-VASc estimates annual stroke rates for untreated AF patients, which are reduced by 60% with warfarin and by 20% with aspirin. HAS-BLED estimates annual rates of major bleeding on warfarin. The latter risk with aspirin is 0.5–1.2% per year. Hypothesis: given a ‘warfarin, aspirin or no therapy’ choice, AF patients will prefer the option that maximises the annual probability of not having a stroke and not having a major bleed. Methods: decision tree applied to the 60 possible combinations of CHA2DS2-VASc and HAS-BLED scores. Results: according to the pre-specified hypothesis, when CHA2DS2-VASc is

Background: orthostatic hypotension (OH) is a physical sign that reflects a final common pathway of various forms of disordered physiology, which is the hallmark of geriatric frailty. Fried et al. recognise three increasing frailty phenotypes in older people, based on measurements of weight loss, exhaustion, grip strength, walking speed and physical activity. Orthostatic haemodynamics have not been considered as markers of frailty in older people. Objective: to classify a community sample of older people into three increasing frailty phenotypes and compare their orthostatic haemodynamics. Design: cross-sectional study. Setting: geriatric research clinic. Subjects: a total of 442 subjects (mean age 72, 72% females) without dementia or risk factors for autonomic neuropathy. Methods: the sample was classified according to modified Fried criteria. Orthostatic systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) responses were monitored during an active stand with Finometer®. Results: one hundred and ninety-eight subjects (44.8%) were classified as non-frail, 213 (48.2%) as pre-frail, and 31 (7.0%) as frail. Across groups, there was a significant increasing gradient in baseline HR (P= 0.008) and decreasing gradients in Delta HR (i.e. maximum HR within 30 s—baseline HR) (P< 0.001) and maximum HR by 30 s (P< 0.001). On average, by 30 s after stand, non-frail subjects had recovered 98% of their baseline SBP, while pre-frail and frail subjects had recovered 95 and 92%, respectively (P for trend = 0.064). Conclusions: the orthostatic HR response and, to a lesser extent, SBP recoverability, appear impaired in frailty. Orthostatic haemodynamics may be useful markers of frailty.

This study evaluated outcomes for the first 100 bariatric surgical procedures in a single, publicly funded Irish centre.This was a retrospective, chart-based study. Demographics and comorbidities of patients, peri- and post-operative outcomes and health benefits obtained by surgery were assessed.In total, 87 patients underwent Roux-en-Y gastric bypass procedures, 11 underwent sleeve gastrectomies and 2 underwent duodenal switch. The first 13 operations were done as open procedures. Of the remaining 87 cases, 85 were started laparoscopically. Postoperatively, 2 laparotomies were performed for bleeding and 2 patients developed incarcerated incisional hernias that required repair. The 30-day readmission rate was 6% of which 2 patients required emergency surgery. There was one postoperative mortality from cardio-respiratory failure.This series audits the introduction of a publicly funded bariatric service in Ireland and reports a high percentage of procedures completed laparoscopically with an acceptable morbidity and mortality.

Head-up tilt testing is the investigation of choice in the diagnosis of vasovagal syncope. The test is time consuming and labour intensive, with conventional tilt testing taking up to 45 min. We compared a shortened 'front-loaded' 20-min glyceryl trinitrate-provoked head-up tilt (FLGTN-HUT) with the standard 40-min passive tilt (HUT) as first line investigations in patients with unexplained syncope and asymptomatic controls. In the study, 149 consecutive patients with unexplained syncope and 83 asymptomatic controls were enrolled. Subjects were randomly assigned to FLGTN-HUT (800 mcg, metred spray) or HUT, then the opposite tilt-test 1 week later. Seventeen (11.4%) patients had diagnostic haemodynamic changes and symptom reproduction during HUT and 54 (36.2%) during FLGTN-HUT. A total of 24.8% more patients had a positive test with FLGTN-HUT than with passive HUT (95% CI: 16.3%, 33.4%). Nine (10.8%) controls had significant haemodynamic changes during HUT and 23 (27.7%) during GTN provocation. Seven controls had haemodynamic changes on both HUT and FLGTN-HUT testing. The controls group had 16.8% more significant haemodynamic changes with FLGTN-HUT than with HUT (95% CI: 0.06, 27.4). The front-loaded GTN protocol provided a higher diagnostic rate than passive tilt testing, and provides a rapid alternative to conventional methods, though false positivity rates are higher.

As the risk of early stroke following transient ischaemic attack (TIA) is increasingly recognised, the management of patients presenting with symptoms suggestive of TIA presents a clinical challenge.Analysis of prospectively collected data on patients referred to a TIA clinic in St. Vincent's University Hospital, between January 2003 and July 2004.One-hundred-and-seventeen (117) patients (mean age 75.5 years) were assessed. The majority (79%) were referred from Accident and Emergency and 61% were seen within one week of referral. Seventy-two patients (62%) had a final diagnosis of cerebrovascular disease (56 TIA, 16 completed strokes), of whom five (7%) and four (5.5%) had severe (70%) and moderate (50%) symptomatic carotid artery stenosis, respectively, whilst seven patients (10%) had newly diagnosed atrial fibrillation, five of whom were anticoagulated. Non-cerebrovascular diagnoses were made in twenty-seven patients (24%).A TIA clinic, in co-ordination with Accident and Emergency Services, provides a safe and efficient alternative to hospital admission for patients with TIA symptoms and a low early stroke risk.

Dizziness, syncope, and falls are common occurrences in elderly people. Neurocardiovascular investigation units aim to detect those patients who fall due to disturbances of blood pressure control or cardiac conduction. Specialist units have a high diagnostic yield in the investigation of these problems. Does this translate to less specialized centers? We report on the diagnostic findings of a district general hospital neurocardiovascular investigation unit.A total of 120 consecutive patients over the age of 65 presenting to a single geriatrician were assessed. After a full history and physical examination, patients underwent neurocardiovascular investigation: blood pressure and heart rate response to active stand, carotid sinus massage, and 30-minute head-up tilt.The 120 patients assessed had a mean age of 78 years (range 66-94 years); in this group, 85 were women. Of these patients, 23% presented with falls, 14% with blackouts, and 30% with dizziness. The remaining 33% had overlap of symptoms. Neurocardiovascular investigations produced a diagnosis in 57% of the patients: 22% had cardioinhibitory carotid sinus syndrome (CSS): 15% had vasodepressor CSS; 29% had orthostatic hypotension; and 3% had vasovagal syncope. Thirteen percent had more than one neurocardiovascular abnormality, and 18% had benign positional vertigo. Five patients had postural instability causing falls. Hyperventilation syndrome, aortic stenosis, dysrhythmia, cervical spondylosis, and epilepsy each accounted for one case. Seventeen percent of the subjects remained undiagnosed after integrated neurocardiovascular assessment.Management of falls requires access to neurocardiovascular assessment. It is feasible to provide such a service in the district general hospital setting, with a comparable diagnostic yield to tertiary referral centers.

Background Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability, and an in vivo probe to measure such differences would serve several purposes. The erythromycin breath test (ERBT) is an established approach that has proven useful in this regard, but it has several limitations. More recently, the hydroxylation of midazolam has been suggested as an alternative in vivo probe approach, because it is possible to estimate CYP3A activity in the intestinal epithelium as well as in the liver. The purpose of this study was to investigate the relationship, if any, between the ERBT and midazolam's CYP3A-mediated metabolism. Methods Twenty healthy, medication-free young (24 to 46 years) European Americans (10 women) each received on separate days, in random order, either 3 μCi [14C-N-methyl]-erythromycin intravenously, 1 mg midazolam intravenously, or 2 mg midazolam orally. An ERBT value was determined 60 minutes after administration, and clearances were estimated after midazolam administration. In addition, an endogenous 0- to 4-hour urinary 6β-hydroxycortisol/cortisol ratio was measured. Results All three measured drug trait values varied approximately threefold to fivefold, whereas the endogenous phenotype measure exhibited far greater variability (>100-fold). No statistically significant (P < .05) correlations existed between any of the trait values, including the ERBT value, obtained after intravenous administration of the radiolabeled probe and the systemic clearance of midazolam, expressed in terms of either total or unbound drug, or on an absolute or a body weight-corrected basis (r = 0.03 to r = 0.24; P = .08 to P = .90). Substratification according to sex generally did not improve such relationships. Conclusion Although both erythromycin N-demethylation and the metabolism of midazolam by hydroxylation are mediated by CYP3A, the phenotypic trait measures associated with these two in vivo probe drugs do not provide the same information about the catalytic activity of the enzyme. An indirect measure such as the ERBT may reflect CYP3A activity and be useful for some purposes, but the estimation of the oral and intravenous clearance of midazolam has additional advantages, and they may be more applicable and have broader usefuleness as quantitative estimates of CYP3A activity. Clinical Pharmacology & Therapeutics (1999) 66, 224–231; doi

Chlorzoxazone 6-hydroxylation is mediated by CYP2E1, and its measurement provides an in vivo probe of the enzyme's activity. To determine the population distribution of such activity, the disposition of chlorzoxazone and its 6-hydroxy metabolite was determined after oral administration to 70 white subjects (40 men and 30 women) residing in middle Tennessee. Both oral (330 ± 111 ml · min−1, mean ± SD) and fractional (213 ± 86 ml · min−1) clearances varied fourfold to fivefold within the population and were unimodally distributed in a visually normal fashion. Clearance values were one-third greater in men than in women, but such differences were less striking after normalization according to body weight. Attempts to develop a single-time-point measure of 6-hydroxylating ability on the basis of plasma levels or urinary excretion of chlorzoxazone or its metabolite were unsuccessful. Genetic polymorphisms (Pst I and Rsa I restriction fragment length polymorphisms) in the 5′-flanking region of CYP2E1 deoxyribonucleic acid obtained from peripheral leukocytes were not associated with differences in the disposition of chlorzoxazone. Similarly, no major effects on 6-hydroxylation were associated with mutations in intron 6 associated with a Dra I restriction fragment length polymorphism. The interindividual variability in CYP2E1 activity as measured in vivo in healthy subjects appears to be considerably less than that expected based on in vitro studies. Whether such variability is associated with individual susceptibility to CYP2E1-mediated toxicity remains to be determined. Clinical Pharmacology & Therapeutics (1995) 57, 645–655; doi

In vitro studies with human liver microsomes have shown that erythromycin N-demethylation, dapsone N-hydroxylation, and the 6 beta-hydroxylation of cortisol are all primarily mediated by P4503A4. Trait measurements to assess the in vivo level of activity of these separate oxidations have also been developed previously. This study investigated the relationships among the three phenotypic trait measurements in 30 young healthy white men. The frequency distributions of the trait values were all unimodal, with a twofold range for the erythromycin breath test and the urinary dapsone recovery ratio; the urinary 6 beta-hydroxycortisol/cortisol ratio was more variable, with a 17-fold range of values. No statistically significant correlations were observed among any of the trait measurements (dapsone recovery ratio versus erythromycin breath test: r = -0.07, p = 0.7; urinary 6 beta-hydroxycortisol/cortisol ratio versus erythromycin breath test: r = -0.12, p = 0.6; urinary 6 beta-hydroxycortisol/cortisol ratio versus dapsone recovery ratio: r = 0.13, p = 0.5. This lack of any relationship was unexpected and the reason(s) is unknown; however, it is possible that factors such as route of administration and extrahepatic metabolism in the intestinal epithelium and kidney are involved. Further studies are required to identify and validate the use of an appropriate in vivo probe of P4503A4 in humans.