The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype.

AIMS: 1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype. METHODS: A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTS: Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUC(PT) (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUC(PT) (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUC(PT((R)-warfarin)) : AUC(PT((S)-warfarin))) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS: (R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.

Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Management of pain in opioid dependent individuals is problematic due to numerous issues including cross-tolerance to opioids. Hence there is a need to find alternative analgesics to classical opioids and tramadol is potentially one such alternative. Methadone inhibits CYP2D6 in vivo and in vitro. We aimed to investigate the effect of methadone on the pathways of tramadol metabolism: O-demethylation (CYP2D6) to the opioid-active metabolite M1 and N-demethylation (CYP3A4) to M2 in subjects maintained on methadone or buprenorphine as a control. WHAT THIS STUDY ADDS: Compared with subjects on buprenorphine, methadone reduced the clearance of tramadol to active O-desmethyl-tramadol (M1) but had no effect on N-desmethyltramadol (M2) formation. Similar to other analgesics whose active metabolites are formed by CYP2D6 such as codeine, reduced formation of O-desmethyltramadol (M1) is likely to result in reduced analgesia for subjects maintained on methadone. Hence alternative analgesics whose metabolism is independent of CYP2D6 should be utilized in this patient population. AIMS: To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects. METHODS Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites. RESULTS: The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012-0.103)] compared with those taking buprenorphine [0.192 (0.108-0.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower in subjects taking methadone compared with buprenorphine (0.069 (0.044-0.093) and 0.126 (0.069-0.187), respectively, P= 0.04, probability score 0.19), M2 was significantly higher in subjects taking methadone compared with buprenorphine (0.048 (0.033-0.085) and 0.033 (0.014-0.049), respectively, P= 0.04, probability score 0.81). Tramadol was similar (0.901 (0.635-1.30) and 0.685 (0.347-1.04), respectively, P= 0.35, probability score 0.65). CONCLUSIONS: Methadone inhibited the CYP2D6-mediated metabolism of tramadol to M1. Hence, as the degree of opioid analgesia is largely dependent on M1 formation, methadone maintenance patients may not receive adequate analgesia from oral tramadol.

Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects.

AIMS: To compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone- and buprenorphine-maintained CYP2D6 extensive metabolizer subjects. METHODS: Ten methadone- and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3- and -6-glucuronides and codeine-6-glucuronide. RESULTS: The urinary metabolic ratio for O-demethylation was significantly higher (P= 0.0044) in the subjects taking methadone (mean ± SD, 2.8 ± 3.1) compared with those taking buprenorphine (0.60 ± 0.43), likewise for 6-glucuronide formation (0.31 ± 0.24 vs. 0.053 ± 0.027; P < 0.0002), but there was no significant difference (P= 0.36) in N-demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone-maintained subjects had increased codeine and norcodeine concentrations (P < 0.004), similar morphine (P= 0.72) and lower morphine-3- and -6- and codeine-6-glucuronide concentrations (P < 0.008). CONCLUSION: Methadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6.

The impact of teleneurologists on acute stroke care at an advanced primary stroke centre.

INTRODUCTION: We evaluated the impact of teleneurologists on the time to initiating acute stroke care versus traditional bedside neurologists at an advanced stroke center. METHODS: This observational study evaluated time to treatment for acute stroke patients at a single hospital, certified as an advanced primary stroke centre, with thrombectomy capabilities. Consecutive stroke alert patients between 1 March, 2016 and 31 March, 2018 were divided into two groups based on their neurology consultation service (bedside neurology: 1 March, 2016-28 February, 2017; teleneurology: 1 April, 2017-31 March, 2018). Door-to-tPA time and door-to-IR time for mechanical thrombectomy were compared between the two groups. RESULTS: Nine hundred and fifty-nine stroke patients met the inclusion criteria (436 bedside neurology, 523 teleneurology patients). There were no significant differences in sex, age, or stroke final diagnosis between groups (p > 0.05). 85 bedside neurology patients received tPA and 35 had mechanical thrombectomy, 84 and 44 for the teleneurology group respectively. Door-to-tPA time (median (IQR)) was significantly higher among teleneurology (64 min (51.5-83.5)) than bedside neurology patients (45 min (34-69); p < 0.0001). There was no difference in door-to-IR times (mean ± SD) between bedside neurology (87.2 ± 33.3 min) and teleneurology (90.4 ± 33.4 min; p = 0.67). DISCUSSION: At this facility, our teleneurology services vendor was associated with a statistically significant delay in tPA administration compared with bedside neurologists. There was no difference in door-to-IR times. Delays in tPA administration make it harder to meet acute stroke care guidelines and could worsen patient outcomes.

Protective efficacy of a polyvalent influenza A DNA vaccine against both homologous (H1N1pdm09) and heterologous (H5N1) challenge in the ferret model.

This study describes the protective efficacy of a novel influenza plasmid DNA vaccine in the ferret challenge model. The rationally designed polyvalent influenza DNA vaccine encodes haemagglutinin and neuraminidase proteins derived from less glycosylated pandemic H1N1 (2009) and H3N2 (1968) virus strains as well as the nucleoprotein (NP) and matrix proteins (M1 and M2) from a different pandemic H1N1 (1918) strain. Needle-free intradermal immunisation with the influenza DNA vaccine protected ferrets against homologous challenge with an H1N1pdm09 virus strain, demonstrated by restriction of viral replication to the upper respiratory tract and reduced duration of viral shedding post-challenge. Breadth of protection was demonstrated in two heterologous efficacy experiments in which animals immunised with the influenza DNA vaccine were protected against challenge with a highly pathogenic avian influenza H5N1 virus strain with reproducible survival and clinical outcomes.

Improving partner services by embedding disease intervention specialists in HIV-clinics.

BACKGROUND/OBJECTIVES: Notifying partners of HIV-infected persons and referring them for testing and treatment is an effective method of disease control and identification of undiagnosed STD and/or HIV. To improve partner elicitation interviews, disease intervention specialists (DIS) were placed in 3 HIV clinics during 2008 and 2009. METHODS: We reviewed the Arizona state STD surveillance database for 2007 to identify the providers (outside of the public STD clinics) reporting the highest number of syphilis cases. DIS were placed in the clinics for half a day per week (2 clinics) or on an on-call basis (1 clinic) to deliver penicillin and interview patients. We calculated changes in the number of patients interviewed, days elapsed from specimen collection to treatment (time to treatment), days elapsed from specimen collection to initial DIS contact (time to interview), and number of reported and locatable partners from these 3 clinics before and after the clinic placement of DIS. RESULTS: Before the placement of clinic-based DIS, 219 syphilis cases were diagnosed at the 3 clinics (January 2006 through January 2008). After DIS placement, 115 syphilis cases were diagnosed (February 2008 through September 2009) for a total of 334 cases in this analysis. A greater percent of patients completed a partner elicitation interview during the period of DIS placement (94% after vs. 81% before, P = 0.001). There were increases in the average number of locatable partners (1.1 after vs. 0.6 before, P = 0.004) and an increase in the average number of partners exposed and brought to treatment (CDC Disposition A) or infected and brought to treatment (CDC Disposition C) (0.6 after vs. 0.3 before, P = 0.02), and the time to interview decreased (18 days before vs. 9 days after, P = 0.02). CONCLUSIONS/IMPLICATIONS: Placing DIS within community HIV clinics improved partner services. STD and/or HIV programs should consider this method to improve partner notification.

Population modelling and genetics of a critically endangered Madagascan palm Tahina spectabilis.

Madagascar is home to 208 indigenous palm species, almost all of them endemic and >80% of which are endangered. We undertook complete population census and sampling for genetic analysis of a relatively recently discovered giant fan palm, the Critically Endangered Tahina spectablis in 2008 and 2016. Our 2016 study included newly discovered populations and added to our genetic study. We incorporated these new populations into species distribution niche model (SDM) and projected these onto maps of the region. We developed population matrix models based on observed demographic data to model population change and predict the species vulnerability to extinction by undertaking population viability analysis (PVA). We investigated the potential conservation value of reintroduced planted populations within the species potential suitable habitat. We found that the population studied in 2008 had grown in size due to seedling regeneration but had declined in the number of reproductively mature plants, and we were able to estimate that the species reproduces and dies after approximately 70 years. Our models suggest that if the habitat where it resides continues to be protected the species is unlikely to go extinct due to inherent population decline and that it will likely experience significant population growth after approximately 80 years due to the reproductive and life cycle attributes of the species. The newly discovered populations contain more genetic diversity than the first discovered southern population which is genetically depauperate. The species appears to demonstrate a pattern of dispersal leading to isolated founder plants which may eventually lead to population development depending on local establishment opportunities. The conservation efforts currently put in place including the reintroduction of plants within the species potential suitable habitat if maintained are thought likely to enable the species to sustain itself but it remains vulnerable to anthropogenic impacts.

A descriptive study of peripheral intravenous catheters in patients admitted to a pediatric unit in one Australian hospital.

Over a 5-month period, 496 peripheral intravenous catheters (PIVs) inserted into neonates, infants, and children were prospectively studied. Data were collected on demographic patient characteristics, PIV indications for use, dwell time, and reasons for removal, together with nursing actions. The results showed that most PIVs were removed within 72 hours. In 6.6% of cases, some degree of phlebitis was present at PIV removal. The risk of phlebitis increased when the PIV remained in place longer, the child was younger, or medication was administered. The greatest risk was age, with neonates being 5(1/2) times more likely to have some degree of phlebitis than non-neonates.

ICU nurses' perceptions of discharge planning: a preliminary study.

The role that intensive care unit (ICU) nurses could play in hospital discharge planning remains relatively unexplored. Using a case study, all ICU nurses in one hospital were surveyed about their perceptions of their role in the discharge process. Over 70% of the 58 nurses who responded thought that discharge planning was both appropriate in the ICU and not premature. However, several obstacles including patient acuity, time constraints and limited experience with this process were evident. While ICU nurses are aptly placed to manage discharge planning, they cannot be expected to undertake this important role without a systematic approach to its implementation.

The impact of a liaison nurse on ICU nurses' perceptions of discharge planning.

The objective of the study was to examine the impact of a discharge liaison nurse on intensive care unit (ICU) nurses' perceptions of discharge planning. The discharge liaison nurse coordinated the discharge of patients from ICU to the ward, assisted with hospital discharge, provided clinical teaching and support to both ICU and ward nurses and supported patients and families during hospitalisation. A block intervention design was used. All ICU nurses within one Australian teaching hospital were surveyed prior to and following the implementation of the discharge liaison nurse. Measures included the perceptions of discharge planning scale and the general perceived self-efficacy scale. Following implementation of the liaison nurse, less nurses perceived that discharge planning in the ICU was premature (chi2(2, n=117)=7.759, p=0.021) and that ICU nurses lack an understanding of the discharge planning process (chi2(2, n=118)=15.557, p<0.001). Discharge planning was more frequently seen as the responsibility of the bedside nurse (chi2(2, n=115) =15.270, p<0.005) but there was greater recognition of discharge planning as a time consuming process (chi2(2, n=117)=8.560, p=0.015). Self efficacy in relation to discharge planning did not change over time. Some support was found for the role of the discharge liaison nurse in promoting attitudinal change towards discharge planning in the ICU. Future research is needed to investigate the processes by which the liaison nurse fosters attitudinal change and to document the actual discharge planning practices undertaken in ICU.

Targeting community-dwelling urinary incontinence sufferers: a multi-disciplinary community based model for conservative continence services.

This paper presents an argument that there is a need to provide services that target community-dwelling incontinence sufferers, and presents a demonstration case study of a multi-disciplinary, community-based conservative model of service delivery: The Waterworx Model. Rationale for approaches taken, implementation of the model, evaluation and lessons learned are discussed. In this paper community-dwelling sufferers of urinary incontinence are identified as an underserved group, and useful information is provided for those wishing to establish services for them. The Waterworx Model of continence service delivery incorporates three interrelated approaches. Firstly, client access is achieved by using community-based services via clinic and home visits, creating referral pathways and active promotion of services. Secondly, multi-disciplinary client care is provided by targeting a specific client group, multi-disciplinary assessment, promoting client self-management and developing client knowledge and health literacy. Finally, interdisciplinary collaboration and linkages is facilitated by developing multidisciplinary assessment tools, using interdisciplinary referrals, staff development, multi-disciplinary management and providing professional education. Implementation of the model achieved greater client access, improvement in urinary incontinence and client satisfaction. Our experiences suggest that those suffering urinary incontinence and living in the community are an underserved group and that continence services should be community focussed, multi-disciplinary, generalist in nature.

Perceptions of medical students and their supervisors of the preparation of students for clinical placement in obstetrics and gynecology.

BACKGROUND: Research is limited regarding the adequacy of preparation of medical students for their placement in obstetrics and gynecology. The aim of this study was to determine the perceptions of a cohort of undergraduate medical students from an Australian university and their clinical supervisors of the on-campus preparation of students for their clinical rotation in obstetrics and gynecology. METHODS: We used a descriptive exploratory qualitative research approach and purposive sampling to address the aim of the study. Ten undergraduate medical students and 4 of their supervisors participated in the study. Data were collected from focus group discussions, follow-up interviews, and individual semistructured interviews. Interview transcripts were analyzed using an inductive coding approach. RESULTS: Students and their clinical supervisors who participated in the study agreed that students should be as well prepared as possible by the university prior to their placement in obstetrics and gynecology because adequate preparation would provide a solid clinical framework upon which the discipline's knowledge and skills could be built. Overall, participants considered that the on-campus preparation was adequate in many aspects; however, they identified some specific areas in which preparation could be enhanced. These preparation enhancements included specific skills related to examining pregnant women, interpreting cardiotocography, conversing with patients and their families, and improving students' understanding of the hospital culture. CONCLUSION: These findings provide an increased understanding of the factors a cohort of medical students and their clinical supervisors consider essential for student preparation for the clinical rotation in obstetrics and gynecology.

Detection of African swine fever virus by loop-mediated isothermal amplification.

A loop-mediated isothermal amplification (LAMP) assay was developed for the detection of African swine fever virus (ASFV). This assay targets the topoisomerase II gene of ASFV and its specificity was confirmed by restriction enzyme digestion of the reaction products. The analytical sensitivity of this ASFV LAMP assay was at least 330 genome copies, and the test was able to detect representative isolates of ASFV (n=38) without cross-reacting with classical swine fever virus. The performance of the LAMP assay was compared with other laboratory tests used for ASF diagnosis. Using blood and tissue samples collected from pigs experimentally infected with ASFV (Malawi isolate), there was good concordance between the LAMP assay and real-time PCR. In addition to detecting the reaction products using either agarose gels or real-time PCR machines, it was possible to visualise dual-labelled biotin and fluorescein ASFV LAMP amplicons using novel lateral flow devices. This assay and detection format represents the first step towards developing a practical, simple-to-use and inexpensive molecular assay format for ASF diagnosis in the field which is especially relevant to Africa where the disease is endemic in many countries.

Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis.

OBJECTIVE: To study genetic polymorphisms in the folate pathway, a site of action of methotrexate (MTX) and sulfasalazine (SSZ), as predictors of efficacy of combination disease modifying antirheumatic drug (DMARD) regimens containing MTX and SSZ in early rheumatoid arthritis (RA). METHODS: Ninety-eight Caucasian patients with early RA received MTX with SSZ, hydroxychloroquine, and folate according to a standardized protocol. Efficacy was evaluated using the Disease Activity Score (DAS28) and European League Against Rheumatism response criteria at 12 months. Nine polymorphisms in 7 genes of the folate pathway were studied. RESULTS: Response to therapy was associated with SLC19A1, MTR, and TYMS polymorphisms. Two favorable allele combinations associated with responder status at 12 months were identified: the MTR 2756A allele in combination with either the SLC19A1 80A allele or the TYMS 3R-del6 haplotype (multivariate analysis, p = 0.0002, p = 0.009 respectively). Seventy of the 72 patients with these allele combinations responded compared to 12/24 patients without [odds ratio (OR) 35.0, 95% confidence interval (CI) 6.9-176, p < 0.0001]. An association with remission (DAS28 < 2.6) was also observed (OR 3.4, 95% CI 1.1-10.0, p = 0.04). When analyzed over 3 years, both the change in DAS score from baseline and the final DAS scores were significantly higher and lower, respectively, with the favorable genotype group (p < 0.0001, p < 0.0001). CONCLUSION: Polymorphic variations in the MTR, SLC19A1, and TYMS genes were associated with better clinical response to combination DMARD regimens containing MTX and SSZ. Allele combinations of these genes may predict response to combination DMARD and assist in treatment decisions in patients with early RA.

Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia.

AIMS: This study investigated the effects of increasing doses of rac-perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (-)-perhexiline. METHODS: In a prospective study, steady-state plasma concentrations of (+) and (-)-perhexiline were quantified in 10 CYP2D6 genotyped patients following dosing with 100 mg/day rac-perhexiline maleate, and following a subsequent dosage increase to 150 or 200 mg/day. In a retrospective study, steady-state plasma concentrations of (+) and (-)-perhexiline were obtained from 111 CYP2D6 phenotyped patients receiving rac-perhexiline maleate. RESULTS: In the prospective study, comprising one poor and nine extensive/intermediate metabolizers, the apparent oral clearance (CL/F) of both enantiomers increased with the number of functional CYP2D6 genes. In the nine extensive/intermediate metabolizers receiving the 100 mg/day dose, the median CL/F of (+)-perhexiline was lower than that of (-)-perhexiline (352.5 versus 440.6 l/day, P<0.01). Following the dosage increase, the median CL/F of both enantiomers decreased by 45.4 and 41.4%, respectively. In the retrospective study, the median (+)-/(-)-perhexiline plasma concentration ratio was lower (P<0.0001) in phenotypic extensive/intermediate (1.41) versus poor metabolizers (2.29). Median CL/F of (+) and (-)-perhexiline was 10.6 and 24.2 l/day (P<0.05), respectively, in poor metabolizers, and 184.1 and 272.0 l/day (P<0.001), respectively, in extensive/intermediate metabolizers. CONCLUSIONS: Perhexiline's pharmacokinetics exhibit significant enantioselectivity in CYP2D6 extensive/intermediate and poor metabolizers, with both enantiomers displaying polymorphic and saturable metabolism via CYP2D6. Clinical use of rac-perhexiline may be improved by developing specific enantiomer target plasma concentration ranges.

The influence of CYP2D6 genotype on trough plasma perhexiline and cis-OH-perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia.

AIMS: CYP2D6 protein expression is determined by the number of functional CYP2D6 alleles. It is also higher in individuals with at least one CYP2D6*2 allele. This study has investigated the effect of the number of functional CYP2D6 alleles and the influence of CYP2D6*2 alleles on plasma perhexiline concentrations in patients administered a standard loading regimen over 3 days. METHODS: Eighteen patients with myocardial ischaemia who were not taking any drugs known to inhibit CYP2D6 metabolism in vivo commenced treatment with 200 mg of perhexiline twice per day. On the fourth day, blood was drawn for genotyping and the measurement of trough plasma concentrations of perhexiline and its major metabolite, cis-OH-perhexiline. RESULTS: The only genotypic CYP2D6 poor metabolizer had a trough plasma perhexiline concentration of 2.70 mg l-1 and no detectable cis-OH-perhexiline. The mean+/-SD trough plasma perhexiline concentration in patients with one functional allele was significantly higher (0.63+/-0.31 mg l-1, n=8, P=0.05) than in patients with two functional alleles (0.37+/-0.17 mg l-1, n=9). Conversely, the mean metabolic ratio was significantly lower in patients with one functional allele (2.90+/-1.76, P<0.01) compared with patients with two functional alleles (6.52+/-3.26). Patients with at least one CYP2D6*2 allele had a lower plasma perhexiline concentration (0.20+/-0.09 mg l-1, n=5, P<0.001) and a higher metabolic ratio (7.86+/-2.51, P<0.01) than the non-poor metabolizer patients with no CYP2D6*2 alleles (0.62+/-0.23 mg l-1 and 3.55+/-2.54, respectively, n=12). CONCLUSION: Patients with only one functional allele and not CYP2D6*2 have diminished CYP2D6 metabolic capacity for perhexiline.

"Oh, that's a bit of a nuisance": community-dwelling clients ' perspectives of urinary continence health service provision.

OBJECTIVE: This study explored clients' perspectives of urinary continence service provision for community-dwelling people from a primary health care perspective. DESIGN: For this interpretive study, data were collected from 11 clients via in-depth interviews and a questionnaire eliciting demographic details and written comment. A focus group was also held with 7 people belonging to an existing continence self-help group. RESULTS: Clients indicated that appropriate and acceptable continence care was accessible, affordable, and based on accurate knowledge. They valued practitioners who were empathetic, interested, had good networks, and could assist in practical ways. They looked for explanation, information, and discussion, often finding this when they accessed continence specialists. However, they often found it difficult to access this type of care, with many clients finding that urinary incontinence was treated as a secondary issue or a nuisance by generalist health practitioners. Clients believed that many health practitioners lacked knowledge and/or interest in urinary incontinence. In particular, there was very poor transitional care between hospital and community. The cost of consulting a health practitioner was seen as secondary to the cost of continence equipment and aids. CONCLUSIONS: This study found that the principles of primary health care were not being realized in generalist continence care. Client- centered services that address individual needs, relationships, psychological factors, emotional needs, financial circumstances, social contexts, and lifestyle factors, particularly in transition between sectors, are needed.

Clinical inhibition of CYP2D6-catalysed metabolism by the antianginal agent perhexiline.

AIMS: Perhexiline is an antianginal agent that displays both saturable and polymorphic metabolism via CYP2D6. The aim of this study was to determine whether perhexiline produces clinically significant inhibition of CYP2D6-catalysed metabolism in angina patients. METHODS: The effects of perhexiline on CYP2D6-catalysed metabolism were investigated by comparing urinary total dextrorphan/dextromethorphan metabolic ratios following a single dose of dextromethorphan (16.4 mg) in eight matched control patients not taking perhexiline and 24 patients taking perhexiline. All of the patients taking perhexiline had blood drawn for CYP2D6 genotyping as well as to measure plasma perhexiline and cis-OH-perhexiline concentrations. RESULTS: Median (range) dextrorphan/dextromethorphan metabolic ratios were significantly higher (P < 0.0001) in control patients, 271.1 (40.3-686.1), compared with perhexiline-treated patients, 5.0 (0.3-107.9). In the perhexiline-treated group 10/24 patients had metabolic ratios consistent with poor metabolizer phenotypes; however, none was a genotypic poor metabolizer. Interestingly, 89% of patients who had phenocopied to poor metabolizers had only one functional CYP2D6 gene. There was a significant negative linear correlation between the log of the dextrorphan/dextromethorphan metabolic ratio and plasma perhexiline concentrations (r(2) = 0.69, P < 0.0001). Compared with patients with at least two functional CYP2D6 genes, those with one functional gene were on similar perhexiline dosage regimens but had significantly higher plasma perhexiline concentrations, 0.73 (0.21-1.00) vs. 0.36 (0.04-0.69) mg l(-1) (P = 0.04), lower cis-OH-perhexiline/perhexiline ratios, 2.85 (0.35-6.10) vs. 6.51 (1.84-11.67) (P = 0.03), and lower dextrorphan/dextromethorphan metabolic ratios, 2.51 (0.33-39.56) vs. 11.80 (2.90-36.93) (P = 0.005). CONCLUSIONS: Perhexiline significantly inhibits CYP2D6-catalysed metabolism in angina patients. The plasma cis-OH-perhexiline/perhexiline ratio may help to both phenotype patients and predict those in whom perhexiline may be most likely to cause clinically significant metabolic inhibition.