Ischemic Stroke and Transient Ischemic Attack Risk Following Vitamin K Antagonist Cessation in Newly Diagnosed Atrial Fibrillation: A Cohort Study.

Background In nonvalvular atrial fibrillation (AF), oral anticoagulants prevent ischemic strokes and transient ischemic attacks (TIAs), but nonpersistence with vitamin K antagonist (VKA) oral anticoagulant therapy (20-50% at 1 year) is problematic. The precise risk of stroke/TIA after VKA cessation and its time course during extended follow-up is unknown. Methods and Results The study cohort of incident AF in patients receiving initial VKA between 2001 and 2013 was identified from the UK Clinical Practice Research Datalink (linked hospitalizations and causes of death). Using a nested case-control analysis, patients with incident stroke/TIA were matched to patients without stroke/TIA (controls). Relative risk with time since VKA cessation compared with current VKA use was approximated from conditional logistic regression. We studied 16 696 patients with incident AF and initial VKA treatment. There were 489 stroke/TIA cases matched to 2137 controls (mean CHA2DS2-VASc score 4.3). Compared with current VKA use, the excess incidence rate of stroke/TIA following VKA cessation in the first year after AF diagnosis was 2.29 (95% CI, 0.98-3.90) per 100 person-years of VKA cessation or 1 additional stroke/TIA per 43 patients per year discontinuing VKA, compared with 1.43 (95% CI, 0.97-1.88) per 100 person-years corresponding to 1 additional stroke/TIA per 70 patients per year, when VKA was discontinued more than 1 year after AF diagnosis. Conclusions VKA cessation is associated with a continuous excess thromboembolic stroke/TIA risk. Increasing oral anticoagulant persistence, especially in the year after AF diagnosis, should be a therapeutic target to reduce stroke/TIA in AF.

How effective are dose-adjusted warfarin and aspirin for the prevention of stroke in patients with chronic atrial fibrillation? An analysis of the UK General Practice Research Database.

The objective of this study was to evaluate the rate of stroke associated with aspirin and warfarin in routine clinical practice. The study included patients aged 40+ with chronic atrial fibrillation (cAF) registered in the UK General Practice Research Database. The outcome was the rate of stroke during current, past and no use of aspirin and warfarin. The study included 51,807 cAF patients. There was no difference in the rate of stroke between current and past use of aspirin (relative rate [RR] = 1.04 [95% confidence interval (CI) 0.94 - 1.15]), while the rate of stroke was reduced during current warfarin use compared to past use (RR = 0.62 [95% CI 0.54 - 0.71]). For warfarin, a pattern of lower rates of stroke during current exposure and higher rates with past exposure was seen only in patients treated for at least 6-12 months. For aspirin, no changes in the rates of stroke were observed with discontinuation of aspirin. The effectiveness of warfarin was dependent on the level of anticoagulation, with optimal risk reduction occurring within the recommended international normalised ratio (INR) range of 2.0 to 3.0. The proportion of patients achieving a stable INR within the target therapeutic range was at its lowest during the first three months of warfarin treatment. In conclusion, the results of this study support the effectiveness of warfarin treatment to reduce the rate of stroke in cAF patients in the general clinical practice setting, however the risk reduction is lower than that reported in clinical trials.

Incidence of Lyme disease in the UK: a population-based cohort study.

OBJECTIVES: The purpose of this study was to estimate the annual incidence of Lyme disease (LD) in the UK. DESIGN: This was a retrospective descriptive cohort study. SETTING: Study data were extracted from the Clinical Practice Research Datalink (CPRD), a primary care database covering about 8% of the population in the UK in 658 primary care practices. PARTICIPANTS: Cohort of 8.4 million individuals registered with general practitioners with 52.4 million person-years of observation between 1 January 2001 and 31 December 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: LD was identified from recorded medical codes, notes indicating LD, laboratory tests and use of specific antibiotics. Annual incidence rates and the estimated total number of LD cases were calculated separately for each UK region. RESULTS: The number of cases of LD increased rapidly over the years 2001 to 2012, leading to an estimated incidence rate of 12.1 (95% CI 11.1 to 13.2) per 100 000 individuals per year and a UK total of 7738 LD cases in 2012. LD was detected in every UK region with highest incidence rates and largest number of cases in Scotland followed by South West and South England. If the number of cases has continued to rise since the end of the study period, then the number in the UK in 2019 could be over 8000. : Conclusions : The incidence of LD is about threefold higher than previously estimated, and people are at risk throughout the UK. These results should lead to increased awareness of the need for preventive measures. TRIAL REGISTRATION NUMBER: This study was approved by the Independent Scientific Advisory Committee for CPRD research (Protocol number 13_210R).

Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme.

BACKGROUND: The aim of the study is to estimate the incidence and prevalence of chronic AF (cAF) in the United Kingdom and test the accuracy of the CHADS2 score for stroke prediction. METHODS: The General Practice Research Database was used to identify patients aged 40+ years diagnosed with cAF and control patients. Harrell's C-statistic was used to test possible improvements in CHADS2. RESULTS: The study population included 51,807 cAF patients. The incidence of cAF increased by age and was higher in men than women. The prevalence of cAF has increased over time. The excess 5-year risk for stroke in cAF patients correlated well with CHADS2 as follows: score 0, 1.9% (95% CI 1.6-2.1); 1, 3.0% (95% CI 2.7-3.3); 2, 4.7% (95% CI 4.3-5.1); 3, 7.2% (95% CI 6.6-7.9); 4, 10.5% (95% CI 9.4-11.5); 5, 13.9% (95% CI 12.2-15.5); and 6, 15.8% (95% CI 13.5-18.1). Adding sex, the extension of age categories and reweighing of established risk factors improved CHADS2 accuracy (C-statistic 0.68-0.72). Applying the reclassification resulted in a substantial number of patients changing stroke risk category. CONCLUSION: Atrial fibrillation is a prevalent and growing problem, which significantly increases the risk of ischemic stroke. The CHADS2 score is a good predictor of the stroke risk but could be improved.

Thirteen-year trend in the persistence with vitamin K antagonists for venous thromboembolism in the UK: a cohort study.

BACKGROUND: Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE) and is associated with significant recurrence and mortality risk. Standard VTE treatment includes at least 3 months anticoagulation. The objective was to describe time trends in the duration of oral anticoagulation in patients initially treated with vitamin K antagonists (VKAs). METHODS: A retrospective cohort study was conducted on patients with first VTE and VKA treatment initiation within 30 days, identified from the UK Clinical Practice Research Datalink from 2001 to 2014. VKA users were followed for the duration of oral anticoagulation which included switching to non-VKA oral anticoagulants. The probability of remaining on anticoagulation treatment (persistence) was estimated using Kaplan-Meier survival functions. RESULTS: A total of 16,018 patients with VTE initiated VKA; 48.2% males, mean age 62.1 years, median VKA treatment duration 6.5 months. The 90-day persistence increased from 75.6% in 2001 to 91.2% in 2013 (p < .0001) and the 180-day persistence from 39.3% in 2001 to 61.1% in 2013 (p < .0001). This time trend was also shown for patients with DVT, PE, provoked VTE, unprovoked VTE, provoked DVT, unprovoked DVT, provoked PE and unprovoked PE. There were no major differences in persistence between patients with provoked and unprovoked VTE, but persistence was lower following DVT than PE (p < .0001). CONCLUSIONS: The increase in persistence was independent of the presentation of the first VTE (provoked or unprovoked), but higher for first PE. Whether the increasing persistence resulted in decreasing risk of recurrent VTE needs to be confirmed.

Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin's lymphoma and its effect on myelotoxicity.

BACKGROUND AND OBJECTIVE: The BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy regimen for the treatment of advanced Hodgkin's lymphoma has a superior outcome, but its toxicity (mainly haematotoxicity) is pronounced and highly variable. The present study was conducted to address the role of pharmacokinetics in individual toxicity. STUDY DESIGN: Three plasma samples and a 24-hour urine collection for day 1 of the first three cycles of chemotherapy were analysed in 30 patients, and the pharmacokinetic parameters of the respective drugs were estimated by population pharmacokinetic methods (nonlinear mixed-effects model [NONMEM] software). Demographic data, doses and durations of infusion were also recorded. The effect of these parameters on platelet counts was estimated by analysis of covariance using a general linear model. RESULTS: The pharmacokinetic parameters and respective covariates were similar to the published data. The body surface area, peak concentrations of etoposide, urinary recovery of dechloroethylcyclophosphamide (formed by cytochrome P450 [CYP] 3A4) relative to the cyclophosphamide dose and number of cycles had a significant effect on toxicity. These factors explained 37% of the interindividual variability in the change in platelet counts from day 1 to day 8 of each cycle. CONCLUSION: The results show that the individual pharmacokinetics of BEACOPP drugs are an important link between dosage and toxicity. Accordingly, individualisation of treatment based on pharmacokinetics may result in more uniform toxicity. Individualisation may also allow escalation of the mean dose, which is probably related to better efficacy. As a consequence of the present study, infusion rates should be standardised, and the potential of a dose reduction in the first cycle and of CYP3A4 phenotyping should be addressed in clinical studies.

Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study.

Population studies on the incidence of venous thromboembolism (VTE) in patients with active cancer are limited. An observational cohort study was undertaken to estimate the incidence of first and recurrent VTE. The source population consisted of all patients in the UK Clinical Practice Research Datalink, with additional information on hospitalisation and cause of death, between 2001 and 2011. A cancer-related clinical diagnosis or therapy within the 90 days before or after a VTE constituted an active-cancer-associated VTE. Incidence rates of first VTE among patients with active cancer and incidence rates of recurrent VTE during the 10-year observational period after a first VTE event were estimated. Incidence rates of all-cause mortality and age- and gender-specific mortality were also calculated. There were 6,592 active-cancer-associated VTEs with a total of 112,738 cancer-associated person-years of observation. The incidence rate of first VTE in patients with active cancer was 5.8 (95 % confidence interval 5.7-6.0) per 100 person-years. A first VTE recurrence was observed in 591 patients. The overall incidence rate for recurrence was 9.6 (95 % confidence interval 8.8-10.4) per 100 person-years, with a peak at 22.1 in the first six months. Recurrence rates were similar after initial pulmonary embolism and after initial deep-vein thrombosis. The mortality risk after VTE was considerable, with 64.5 % mortality after one year and 88.1 % after 10 years. VTE in patients with active cancer is common and associated with high recurrence and mortality rates. Efforts are needed to prevent VTE and reduce recurrence, especially in the first year after VTE diagnosis.

Testosterone treatment and risk of venous thromboembolism: population based case-control study.

OBJECTIVE:  To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk. DESIGN:  Population based case-control study SETTING:  370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality. PARTICIPANTS:  19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013. EXPOSURE OF INTEREST:  Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was subdivided into duration of more or less than six months. MAIN OUTCOME MEASURE:  Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for comorbidities and all matching factors. RESULTS:  The adjusted rate ratio of venous thromboembolism was 1.25 (95% confidence interval 0.94 to 1.66) for current versus no testosterone treatment. In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10 000 person years. The rate ratio after more than six months' treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07). Increased rate ratios within the first six months of treatment were observed in all strata: the rate ratio was 1.52 (0.94 to 2.46) for patients with pathological hypogonadism and 1.88 (1.02 to 3.45) for those without it, and 1.41 (0.82 to 2.41) for those with a known risk factor for venous thromboembolism and 1.91 (1.13 to 3.23) for those without one. CONCLUSIONS:  Starting testosterone treatment was associated with an increased risk of venous thromboembolism, which peaked within six months and declined thereafter.

Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac.

OBJECTIVE: The mechanism of action of aceclofenac is currently unclear. This study investigated whether biotransformation to metabolites (4'-hydroxy-aceclofenac, diclofenac, 4'-hydroxy-diclofenac) contributes to inhibitory effects on the cyclooxygenase (COX) isozymes in vitro and ex vivo. METHODS: In vitro investigations were performed with human whole blood and human blood monocytes. A randomized crossover study was performed in volunteers receiving 100 mg aceclofenac or a sustained-release resinate formulation of 75 mg diclofenac to assess the pharmacokinetics and the ex vivo inhibition of COX-1. RESULTS: In short-term in vitro assays, neither aceclofenac nor 4'-hydroxy-aceclofenac affected COX-1 or COX-2, whereas diclofenac and 4'-hydroxy-diclofenac inhibited both isoforms. In long-term in vitro assays, aceclofenac and 4'-hydroxy-aceclofenac suppressed both COX isoforms. However, this inhibition was paralleled by a conversion to diclofenac and 4'-hydroxy-diclofenac, respectively. Maximal plasma concentrations of diclofenac after oral administration of aceclofenac (0.39 micromol/L) or diclofenac (1.28 micromol/L) were sufficient for a greater than 97% inhibition of COX-2 (50% inhibitory concentration, 0.024 micromol/L) and a 46% (aceclofenac treatment) or 82% inhibition (diclofenac treatment) of COX-1 (50% inhibitory concentration, 0.43 micromol/L). Moreover, ex vivo COX-1-dependent thromboxane B(2) synthesis was inhibited significantly less by aceclofenac than by diclofenac. CONCLUSIONS: Inhibition of COX isozymes by aceclofenac requires conversion into diclofenac. Although 100 mg aceclofenac yielded diclofenac concentrations substantially lower than 75 mg diclofenac, these were sufficient for a sustained block of COX-2 but caused a minor and shorter inhibition of COX-1 than 75 mg diclofenac. In conclusion, both COX-1-sparing and COX-2-inhibitory actions of aceclofenac may rest in its limited but sustained biotransformation to diclofenac.

Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene.

OBJECTIVE: We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine. METHODS: Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype-phenotype and haplotype-phenotype relationships. RESULTS: The area under the plasma concentration-time curve from time zero to 4 hours [AUC(0-4)] (P =.042) and C(max) (P =.043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0-4) (P =.034) and C(max) (P =.039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values (P =.009) than were found in noncarriers (mean +/- SD, 5.7 +/- 0.9 microg. h/L [n = 7] versus 4.8 +/- 0.9 microg. h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P =.013) compared with those of noncarriers (mean +/- SD, 4.7 +/- 0.9 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies. CONCLUSION: Haplotype 12 codes for high values of AUC(0-4) and C(max) of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.

Trends in the prevalence of antipsychotic drug use among patients with Alzheimer's disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study.

OBJECTIVE: To investigate the pattern and trends of use of antipsychotics, antidepressants, hypnotics and anxiolytics in Alzheimer's disease and other dementias and in patients treated with antidementia medications. DESIGN: Cohort study with dementia patients formed in the UK Clinical Practice Research Datalink. Participants Patients with incident dementia, between 1995 and 2011 and a reference non-dementia cohort matched on age, gender and date of dementia diagnosis. Two subcohorts included new users of acetylcholinesterase inhibitors (AChEIs) and memantine. The study endpoint was use of antipsychotics, antidepressants, hypnotics and anxiolytics up to 10 years before and 4 years after dementia diagnosis, and for up to 5 years before and 1 year after first use of AChEI or memantine. RESULTS: 50 349 patients with incident dementia diagnosis and 50 349 matched controls, 10 794 first-time users of AChEI and 669 of memantine. The mean prevalence of antipsychotic use from 1995 to 2011 on diagnosis of dementia was 12.5%, decreasing from 19.9% in 1995 to 7.4% in 2011. There was an increase in antidepressant use (10.7-26.3%) and a small increase in anxiolytic use. The matched cohort showed a lower use of antipsychotics and anxiolytics but a rise in antidepressants (5.9-13.4%). Both groups showed a decrease in hypnotic use. 10.6% of AChEI and 26.3% of memantine users were prescribed antipsychotics, 34.1% and 26.3% antidepressants, 13.2% and 4.1% anxiolytics and 18.4% and 8.3% hypnotics. The slopes for monthly use of antipsychotics were positive in the year leading up to AChEI and memantine use; after treatment initiation the slope for AChEI users continued to increase but at a reduced rate whereas antipsychotic use declined for memantine users. CONCLUSIONS: The marked reduction in antipsychotic use in dementia is to be welcomed while there was a steady increase in antidepressant use. There was a decline in antipsychotic use after the initiation of memantine.

Fracture outcomes related to persistence and compliance with oral bisphosphonates.

The effects of low persistence on fracture risk have not been fully addressed. The objectives of this study were to describe the persistence and compliance with bisphosphonates and to evaluate the association with fracture risk. The General Practice Research database was used to identify patients >or=18 yr of age prescribed alendronate or risedronate. The follow-up was divided into periods of current and past use. Time-dependent Cox regression was used. The study population included 44,531 patients; 58.3% of the patients continued bisphosphonate treatment for >1 yr and 23.6% for >5 yr. The risk of hip/femur fracture (adjusted relative rate [RR], 0.78; 95% CI, 0.64-0.94) and osteoporotic fracture (RR, 0.85; 95% CI, 0.76-0.94) were lower with current compared with past bisphosphonate use. The largest reduction in hip/femur and osteoporotic fracture risk was observed in patients treated for at least 6 mo and no reduction in those treated for <6 mo. The risks of hip/femur and osteoporotic fractures followed the pattern of nonosteoporotic fractures in the first 6 mo but then started to reduce after 6-12 mo of treatment. Increased risks of osteoporotic and hip/femur fractures were found in patients with low compliance. Use of bisphosphonates was associated with fracture risk reductions after 6-12 mo of treatment, but only 58% of the patients were treated for at least 1 year. Improvement in long-term persistence to bisphosphonate treatment may be important to reduce the impact of osteoporosis-related fractures.

Patterns of treatment for restless legs syndrome in primary care in the United Kingdom.

BACKGROUND: The dopamine agonists pramipexole and ropinirole are licensed for the treatment of moderate to severe idiopathic restless legs syndrome (RLS) in Europe and the United States. In addition, various drugs that are not approved for this indication have been used for symptomatic treatment of RLS, including analgesics, quinine, and anxiolytics. OBJECTIVE: The purpose of this analysis was to describe patterns of treatment of newly diagnosed RLS, including treatment effectiveness and resource utilization, in primary care in the United Kingdom. METHODS: This was a cohort study that employed the UK General Practice Research Database. Two cohorts were assembled, one consisting of patients with an initial diagnosis of RLS between 1990 and 2004 and the other consisting of patients without RLS matched to cases in a 10:1 ratio by general practice, year of birth, sex, and registration with the practice on the case index date (date of the RLS diagnosis). The frequency of RLS-specific symptoms was estimated based on records of prescriptions for sleep medications and antidepressants, and reported cramps and leg problems other than RLS. Rates of resource use in the 2 years before and after the index date were estimated for both cohorts based on the numbers of total prescriptions, referrals to secondary care, and laboratory tests. RESULTS: The RLS cohort comprised 8621 patients and the matched cohort 85,087 patients. Age and sex distributions were comparable between groups. The annual frequency of prescriptions for sleep medications in the RLS cohort increased significantly from 19.8% and 21.6% in the 2 years before the diagnosisof RLS to 27.4% in the first year after the diagnosis and 25.2% in the second year (all comparisons, P < 0.001). A similar pattern was observed for antidepressants in the RLS cohort (23.5%, 26.7%, 31.0%, and 29.6%, respectively; P < 0.001). Prescription rates were nearly constant in the matched cohort. The frequency of cramps and other leg problems was highest in the year before the diagnosis of RLS, declined in the first year after the diagnosis, and increased thereafter. Compared with the matched cohort, rates of prescriptions, referrals, and laboratory tests ranged from 49.7% to 59.0% higher in the RLS cohort in the 2 years before the diagnosis of RLS and from 63.4% to 91.4% higher in the 2 years after the diagnosis (all comparisons, P < 0.001). CONCLUSION: In patients with newly diagnosed RLS in this UK primary care cohort, use of medications that are not approved for the treatment of RLS was not associated with a reduction in clinical symptoms or health care resource utilization between 1990 and 2004.

Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study.

OBJECTIVE: To compare the risk of non-fatal self harm and suicide in patients taking selective serotonin reuptake inhibitors (SSRIs) with that of patients taking tricyclic antidepressants, as well as between different SSRIs and different tricyclic antidepressants. DESIGN: Nested case-control study. SETTING: Primary care in the United Kingdom. PARTICIPANTS: 146,095 individuals with a first prescription of an antidepressant for depression. MAIN OUTCOME MEASURES: Suicide and non-fatal self harm. RESULTS: 1968 cases of non-fatal self harm and 69 suicides occurred. The overall adjusted odds ratio of non-fatal self harm was 0.99 (95% confidence interval 0.86 to 1.14) and that of suicide 0.57 (0.26 to 1.25) in people prescribed SSRIs compared with those prescribed tricyclic antidepressants. We found little evidence that associations differed over time since starting or stopping treatment. We found some evidence that risks of non-fatal self harm in people prescribed SSRIs compared with those prescribed tricyclic antidepressants differed by age group (interaction P = 0.02). The adjusted odds ratio of non-fatal self harm for people prescribed SSRIs compared with users of tricylic antidepressants for those aged 18 or younger was 1.59 (1.01 to 2.50), but no association was apparent in other age groups. No suicides occurred in those aged 18 or younger currently or recently prescribed tricyclic antidepressants or SSRIs. CONCLUSION: We found no evidence that the risk of suicide or non-fatal self harm in adults prescribed SSRIs was greater than in those prescribed tricyclic antidepressants. We found some weak evidence of an increased risk of non-fatal self harm for current SSRI use among those aged 18 or younger. However, preferential prescribing of SSRIs to patients at higher risk of suicidal behaviour cannot be ruled out.

Simultaneous determination of aceclofenac and three of its metabolites in human plasma by high-performance liquid chromatography.

Aceclofenac [[2-(2',6'-dichlorophenyl)amino]phenylacetoxyacetic acid] is a phenylacetic acid derivative with potent analgesic and anti-inflammatory properties and an improved gastro-intestinal tolerance. In the present study, a liquid-liquid extraction-based reversed-phase HPLC method with UV detection was validated and applied for the analysis of aceclofenac and three of its metabolites (4'-hydroxy-aceclofenac, diclofenac, 4'-hydroxy-diclofenac) in human plasma. The analytes were separated using an acetonitrile-phosphate buffer gradient at a flow rate of 1 mL/min, and UV detection at 282 nm. The retention times for aceclofenac, diclofenac, 4'-hydroxy-aceclofenac, 4'-hydroxy-diclofenac and ketoprofen (internal standard) were 69.1, 60.9, 46.9, 28.4 and 21.2 min, respectively. The validated quantitation range of the method was 10-10000 ng/mL for aceclofenac, 4'-hydroxy-aceclofenac and diclofenac, and 25-10000 ng/mL for 4'-hydroxy-diclofenac. The developed procedure was applied to assess the pharmacokinetics of aceclofenac and its metabolites following administration of a single 100 mg oral dose of aceclofenac to three healthy male volunteers.