Cytochrome P450 2C19 polymorphism is associated with reduced clopidogrel response in cerebrovascular disease

Purpose

Clopidogrel is a prodrug that requires transformation into an active metabolite by cytochrome P450 (CYP) in the liver in order to irreversibly inhibit the P2Y12 adenosine diphosphate platelet receptor. CYP2C19 polymorphism has been reported to correlate with reduced antiplatelet activity of clopidogrel in coronary artery disease. We assessed the association between CYP2C19 polymorphism and clopidogrel resistance in patients with cerebrovascular disease.

Materials and Methods

We retrospectively gathered data from patients who experienced cerebrovascular disease, received clopidogrel, and were tested for clopidogrel resistance and CYP2C19 polymorphism. Clopidogrel resistance was tested by the VerifyNow P2Y12 system, and the CYP2C19 polymorphism was tested by the Seeplex CYP2C19 ACE Genotyping system. Clopidogrel resistance was expressed in P2Y12 reaction units (PRU) and percent inhibition. High PRU and low percent inhibition suggests clopidogrel resistance. CYP2C19 polymorphisms were expressed as extensive, intermediate, and poor metabolizers. Clopidogrel resistance was assessed according to the subgroup of CYP2C19 polymorphism.

Results

A total of 166 patients were evaluated. The PRU values of extensive CYP2C19 metabolizers (195.0±84.9) were significantly lower than those of intermediate and poor metabolizers (237.9±88.0, 302.2±58.9). The percent inhibition of extensive metabolizers (44.6±21.8) was significantly higher than that of intermediate and poor metabolizers (30.5±21.5, 14.0±13.4).

Conclusion

Intermediate and poor metabolizing CYP2C19 polymorphism is associated with reduced clopidogrel antiplatelet activity in patients with cerebrovascular disease. The clinical implications of this finding require further investigation.     

Adjunctive Cilostazol versus High Maintenance Dose of Clopidogrel in Patients with Hyporesponsiveness to Chronic Clopidogrel Therapy

Purpose

Whether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown.

Materials and Methods

We studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35).

Results

Baseline percent inhibition of PRU and PRU was similar between 2 groups (13.0±10.2% versus 11.8±9.7%, p=0.61, and 286.3±54.7 versus 295.7±53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5±17.9% versus 28.3±16.6%, p=0.02, and 207.3±68.2 versus 241.3±76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7±8.7% to 15.8±18.4%, p=0.08, and from -18.6±58.0 to -61.9±84.3, p=0.08).

Conclusion

Adjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.     

Prospective and Systematic Analysis of Unexpected Requests for Non-Cardiac Surgery or Other Invasive Procedures during the First Year after Drug-Eluting Stent Implantation

Purpose

Unexpected requests for non-cardiac surgery requiring discontinuation of dual antiplatelet therapy (DAPT) frequently occur in daily clinical practice. The objectives of this study were to evaluate prevalence, timing and clinical outcomes of such unexpected requests for non-cardiac surgery or other invasive procedures during the first year after drug-eluting stents (DESs) implantation.

Materials and Methods

We prospectively investigated the prevalence, timing and clinical outcomes of unexpected requests for non-cardiac surgery or other procedures during the first year after DESs implantation in 2117 patients.

Results

The prevalence of requested non-cardiac surgery or invasive procedures was 14.6% in 310 requests and 12.3% in 261 patients. Among 310 requests, those were proposed in 11.3% <1 month, 30.0% between 1 and 3 months, 36.8% between 4 and 6 months and 21.9% between 7 and 12 months post-DES implantation. The rates of actual discontinuation of DAPT and non-cardiac surgery or procedure finally performed were 35.8% (111 of 310 requests) and 53.2% (165 of 310 requests), respectively. On multivariate regression analysis, the most significant determinants for actual discontinuation of DAPT were Endeavor zotarolimus-eluting stent implantation with 3-month DAPT (OR=5.54, 95% CI 2.95-10.44, p<0.001) and timing of request (OR=2.84, 95% CI 1.97-4.11, p<0.001). There were no patients with any death, myocardial infarction, or stent thrombosis related with actual discontinuation of DAPT.

Conclusion

Those unexpected requests with premature discontinuation of DAPT were relatively common and continuously proposed during the first year following DES implantation. No death, myocardial infarction or stent thrombosis occurred in patients with actual discontinuation of DAPT.     

Drug-drug interation prediction between ketoconazole and anti-liver cancer drug Gomisin G

Background

Gomisin G, isolated from herb Schisandra chinensis, exhibits anti-tumor activities. Therefore, Gomisin G is a drug candidate for anti-liver cancer therapy.

Aims

To predict the metabolic behavior and metabolism-based drug-drug interaction of gomisin G.

Methods

Molecular docking method was used. The crystal structure of CYP3A4 with the ligand ketoconazole was chosen from protein data bank (http://www.rcsb.org/pdb). Chemdraw software was used to draw the two-dimensional structure of gomisin G with standard bond lengths and angles.

Results

Gomisin G can be well docked into the activity site of CYP3A4, and distance between gomisin G the heme active site was 2.75 Å. To evaluate whether the inhibitors of CYP3A4 can affect the metabolism of gomisin G, co-docking of gomisin G and ketoconazole was further performed. The distance between ketoconazole and activity center (2.10 Å) is closer than the distance between gomisin G and activity center of CYP3A4, indicating the easy influence of CYP3A4''s strong inhibitor towards the metabolism of gomisin G.

Conclusion

Gomisin G is a good substrate of CYP3A4, and CYP3A4 inhibitors easily affect the metabolism of Gomisin G.     

Long-term prescribing of antidepressants in the older population: a qualitative study

Background

High rates of long-term antidepressant prescribing have been identified in the older population.

Aims

To explore the attitudes of older patients and their GPs to taking long-term antidepressant therapy, and their accounts of the influences on long-term antidepressant use.

Design of study

Qualitative study using in-depth semi-structured interviews.

Setting

One primary care trust in North Bradford.

Method

Thirty-six patients aged ≥75 years and 10 GPs were interviewed. Patients were sampled to ensure diversity in age, sex, antidepressant type, and home circumstances.

Results

Participants perceived significant benefits and expressed little apprehension about taking long-term antidepressants, despite being aware of the psychological and social factors involved in onset and persistence of depression. Barriers to discontinuation were identified following four themes: pessimism about the course and curability of depression; negative expectations and experiences of ageing; medicine discontinuation perceived by patients as a threat to stability; and passive (therapeutic momentum) and active (therapeutic maintenance) decisions to accept the continuing need for medication.

Conclusion

There is concern at a public health level about high rates of long-term antidepressant prescribing, but no evidence was found of a drive for change either from the patients or the doctors interviewed. Any apprehension was more than balanced by attitudes and behaviours supporting continuation. These findings will need to be incorporated into the planning of interventions aimed at reducing long-term antidepressant prescribing in older people.     

Optimal Anticoagulation during Off Pump Coronary Artery Bypass in Patients Recently Exposed to Clopidogrel

Purpose

The aim of this study was to find an optimal range of activated clotting time (ACT) during off-pump coronary artery bypass surgery (OPCAB) yielding ischemic protection without the risk of hemorrhagic complications in patients with recent exposure to dual antiplatelet therapy.

Materials and Methods

Three hundred and five patients who received aspirin and clopidogrel within 7 days of isolated multi-vessel OPCAB were retrospectively studied. Combined hemorrhagic and ischemic outcome was defined as the occurrence of 1 of the following: significant perioperative bleeding (>30% of estimated blood volume), transfusion of packed red blood cell (pRBC) ≥2 U, or myocardial infarction (MI). This was compared in relation to the tertile distribution of the time-weighted average ACT-212-291 sec (first tertile), 292-334 sec (second tertile), 335-485 sec (third tertile).

Results

The amount of perioperative blood loss was 937±313 mL, 1014±340 mL, and 1076±383 mL, respectively (p=0.022). Significantly more patients in the third tertile developed MI (4%, 4%, and 12%, respectively, p=0.034). The incidence of significant perioperative blood loss and transfusion of pRBC ≥2 U were lower in the first tertile than those of other tertiles without statistical significance. In the multivariate analysis, the first tertile was associated with a 52% risk reduction of combined hemorrhagic and ischemic outcomes (95% confidence interval: 0.25-0.92, p=0.027).

Conclusion

A lower degree of anticoagulation with a reduced initial heparin loading dose should be carefully considered for patients undergoing OPCAB who have recently been exposed to clopidogrel.     

Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

INTRODUCTION:

21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed.

OBJECTIVE:

The present study aimed to evaluate the association between polymorphic variants involved in glucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients.

METHODS:

We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels.

RESULTS:

The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19%, 11.3% and 3.8% of the patients, respectively. The mean±SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9±0.8 and 19.5±3.2 mg/m²/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose.

CONCLUSION:

Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed, the CYP3A7*1C allele accounted for 20% of the variability in the cortisone acetate dose. The analysis of genes involved in glucocorticoid metabolism may be useful in the optimization of treatment of 21-hydroxylase deficiency.     

The Influence of Hypothermia on Transfusion Requirement in Patients Who Received Clopidogrel in Proximity to Off-Pump Coronary Bypass Surgery

Purpose

Hypothermia adversely affects the coagulation that could be of clinical significance in patients receiving clopidogrel. We evaluated the influence of hypothermia on transfusion requirements in patients undergoing isolated off-pump coronary artery bypass surgery (OPCAB) who continued clopidogrel use within 5 days of surgery.

Materials and Methods

Protocol-based, prospectively entered data of 369 patients were retrospectively reviewed. The time-weighted average of intraoperative temperatures and the temperature upon ICU admission (TWA-temp) was assessed. Patients were divided into normothermia (≥36℃, n=224) and hypothermia (<36℃, n=145) group. The transfusion requirement for perioperative blood loss was assessed and compared.

Results

Patients with hypothermia were older and had lower body surface area (BSA) than patients with normothermia. Age and BSA adjusted transfusion requirement was significantly larger in the hypothermia group [patients requiring transfusion: 64% versus 48%, p=0.003; number of units: 0 (0-2) units versus 2 (0-3) units, p=0.002]. In multivariate analysis of predictors of perioperative multiple transfusion requirements, hypothermia was identified as an independent risk factor along with age, female gender, BSA, chronic kidney disease, and congestive heart failure.

Conclusion

Hypothermia was associated with increased transfusion requirement in patients undergoing OPCAB who received clopidogrel in proximity to surgery. Considering the high prevalence and the possibility of hypothermia being a modifiable risk factor, aggressive measures should be undertaken to maintain normothermia in those patients.     

Correlation between prescribing quality and pharmaceutical costs in English primary care: national cross-sectional analysis

Background

Both pharmaceutical costs and quality-indicator performance vary substantially between general practices, but little is known about the relationship between prescribing costs and quality

Aim

To measure the association between prescribing quality and pharmaceutical costs among English general practices

Design and setting

Cross-sectional observational study using data from the Quality and Outcomes Framework and the Prescribing Analysis and Cost database from all 8409 general practices in England in 2005-2006

Method

Correlation between practice achievement of 26 prescribing quality indicators in eight prescribing areas and related pharmaceutical costs was examined.

Results

There was no significant association between the overall achievement of quality indicators and related pharmaceutical costs (P= 0.399). Mean achievement of quality indicators across all eight prescribing areas was 79.0% (standard deviation 4.4%). There were small positive correlations in five prescribing areas: influenza vaccination, beta blockers, angiotensin converting enzyme inhibitors, lipid lowering, and antiplatelet treatment (all P<0.001). There were small negative correlations in two prescribing areas: hypertension (P<0.001) and smoking cessation (P = 0.018).

Conclusion

Correlations between prescribing quality and pharmaceutical costs were much smallerthan expected; possible explanations forthis include a substantial variation in rates of prescribing outside evidence-based protocols, and use of expensive pharmaceuticals instead of cheaper effective alternatives. There remains considerable scope for some practices to make pharmaceutical cost savings while improving quality performance. The ratio of quality scores to related pharmaceutical costs could be developed into a performance indicator     

The Influence of Anti-Platelet Resistance on the Development of Cerebral Ischemic Lesion after Carotid Artery Stenting

Purpose

Cerebral ischemic lesions are frequently observed after carotid artery stenting (CAS), and anti-platelet agents are used to prevent stent thrombosis and peri-procedural complications. However, despite the premedication, cerebral ischemic lesions are observed, suggesting that they may rather be related to anti-platelet resistance. We, therefore, investigated the effects of anti-platelet resistance on the development of cerebral ischemic lesions after CAS.

Materials and Methods

We retrospectively reviewed patients who received CAS and selected patients for whom brain MRI was performed within 24 hours after CAS and for whom anti-platelet resistance was checked. Anti-platelet resistance was examined by the VerifyNow system. We analyzed the correlation between anti-platelet resistance and cerebral ischemic lesions detected on follow-up MRI.

Results

Among 76 patients, 45 (59.2%) developed new ischemic lesions after CAS. Twelve (15.8%) patients showed aspirin resistance and 50 (65.8%) patients showed clopidogrel resistance. Patients with a new ischemic lesion demonstrated a significantly greater frequency of clopidogrel resistance than those who had no new ischemic lesion (82.2% versus 41.9%, p=0.001). The frequency of aspirin resistance was not significantly different between the groups of patients with and without new ischemic lesions (20.0% versus 9.7%, p=0.340). In multivariate analysis, clopidogrel resistance was a significant risk factor for post-procedural cerebral ischemia.

Conclusion

Anti-platelet resistance can be used to predict new ischemic lesions after CAS. Anti-platelet resistance should be evaluated in all patients prior to CAS to prevent ischemic complications related to CAS.     

Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation

Background

Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. However, the use of this common agent is fraught with complications and little is known regarding inter‐individual variation in warfarin response.

Objective

We tested for association between single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin dose required to maintain patients at their desired anticoagulation target.

Methods

The sample consisted of 93 European‐American patients from anticoagulation clinics at the University of North Carolina at Chapel Hill. Data on mean weekly warfarin dose were collected over a mean treatment period of 20.6 months. ANCOVA models were used and haplotype analysis was performed.

Results

Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001). The mean weekly dose by genotype ranged from approximately 27 to 47 mg. There was no evidence for an association between either of the two CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for VKORC1*1173.

Conclusions

These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin''s actions.     

Use of Drugs that Act on the Cytochrome P450 System in the Elderly

OBJECTIVES:

The objective of this study was to analyze medications that act on the cytochrome P450 (CYP450) enzymatic system and are used daily by non-institutionalized elderly individuals.

METHODS:

A cross-sectional population-based study of elderly individuals (≥ 60 years old) was conducted. All continuously used medications with hepatic metabolism via CYP450 that are classified as substrates, inducers or inhibitors were considered. For the analysis, elderly individuals were stratified according to age groups, and hepatic metabolism activity due to daily alcohol consumption and smoking were considered.

RESULTS:

Elderly individuals (396 in total: 222 women and 174 men) between 60 and 95 years of age (mean: 72.1) were assessed. Use of drugs that act on CYP450 was identified in 61.6% of the subjects. Drug use was observed among 16.2% of the subjects: three drugs among 9.8% and four or more among 6.3% of the subjects. The metabolic activities of the drugs used were classified as substrates (58.8%), inhibitors (14.9%), and inducers (4.3%). The main drugs used were beta-blockers and statins (as substrates), proton pump inhibitors and fluoxetine (as inhibitors), and prednisone and carbamazepine (as inducers).

CONCLUSIONS:

The results demonstrate that the elderly use high levels of medications that act on CYP450, thereby increasing the risk of drug interactions in a group that is already vulnerable to adverse drug effects.     

Physical activity attenuates neuropsychiatric disturbances and caregiver burden in patients with dementia

INTRODUCTION:

A significant benefit from physical activity has recently been described in some patients who suffer from neurodegenerative diseases.

OBJECTIVE:

To assess the effects of physical activity on neuropsychiatric disturbances in demented patients and on the mental burden of their caregivers.

METHODS:

Assisted by a public geriatric psychiatry clinical unit, we studied 59 patients with dementia. Patients were divided into three groups according to their diagnosis and level of physical activity. Data were assessed through a semi-structured interview. Patients were evaluated with the Neuropsychiatric Inventory, the Mini-Sleep Questionnaire and the Baecke Questionnaire. The data were statistically analyzed using the Mann-Whitney U test and linear regression, with the level of significance set at 5%.

RESULTS:

Patients with Alzheimer''s or vascular dementia who engaged in physical activity had fewer neuropsychiatric symptoms than those who did not. When compared to the control group, the caregivers of patients with vascular dementia who engaged in physical activity had a reduced burden.

CONCLUSION:

The regular practice of physical activity seems to contribute to a reduction in neuropsychiatric symptoms in dementia patients and to attenuate the burden of the caregivers of those patients.     

Efficacy and Safety of 6-Month Nightly Ramelteon Administration in Adults with Chronic Primary Insomnia

Study Objectives:

Long-duration ( ≥ 6 months) polysomnographic studies of insomnia medications are lacking. This study evaluated the long-term efficacy of ramelteon, a selective MT₁/MT₂ melatonin-receptor agonist used for insomnia treatment.

Design:

Six-month, randomized, double-blind, placebo-controlled study.

Setting:

Forty-six investigative sites in the United States, Europe, Russia, and Australia.

Participants:

Four hundred fifty-one adults (age ≥ 18 years) with chronic primary insomnia.

Interventions:

Ramelteon, 8 mg, or placebo 30 minutes before bedtime nightly for 6 months.

Measurements:

Sleep was evaluated by polysomnography and morning questionnaires on the first 2 nights of Week 1; the last 2 nights of Months 1, 3, 5, and 6; and Nights 1 and 2 of the placebo run-out. Next-morning residual effects as well as adverse effects and vital signs were recorded at each visit. Rebound insomnia and withdrawal effects were evaluated during placebo run-out.

Results:

Over the 6 months of treatment, ramelteon consistently reduced latency to persistent sleep compared with baseline and with placebo; significant decreases were observed at Week 1 and Months 1, 3, 5, and 6 (P < 0.05). Ramelteon significantly reduced subjective sleep latency relative to placebo at Week 1, Month 1, and Month 5 (P < 0.05), with reductions nearing statistical significance at Months 3 and 6 (P ≤ 0.08). No significant next-morning residual effects were detected during ramelteon treatment. No withdrawal symptoms or rebound insomnia were detected after ramelteon discontinuation. Most adverse events were mild or moderate in severity.

Conclusions:

In adults with chronic insomnia, long-term ramelteon treatment consistently reduced sleep onset, with no next-morning residual effects or rebound insomnia or withdrawal symptoms upon discontinuation.

Citation:

Mayer G; Wang-Weigand S; Roth-Schechter B; Lehmann R; Staner C; Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. SLEEP 2009;32(3):351–360.     

The Inhibitory Activity of the Extracts of Popular Medicinal Herbs on CYP1A2, 2C9, 2C19 and 3A4 and the Implications for Herb-Drug Interaction

Background

Studies have suggested an increasing practice of concurrent herb-drug consumption. One of the major clinical risks of such concomitant herb-drug use is pharmacokinetic herb-drug interaction (HDI). This is brought about by the ability of phytochemicals to inhibit or induce the activity of metabolic enzymes. The aim of this study was to investigate the potential of the crude aqueous extracts of three popular medicinal herbs used in South Africa to inhibit major cytochrome P450 (CYP) enzymes.

Materials and Methods

The extracts of Bowiea volubilis, Spirostachys africana and Tulbaghia violacea were incubated with human liver microsomes (HLM) to monitor the phenacetin O-deethylation, diclofenac 4′-hydroxylation, S-mephenytoin 4′-hydroxylation and testosterone 6β-hydroxylation as respective probe reactions for CYP1A2, CYP2C9, CYP2C19 and CYP3A4. The inhibitory activity, where observed, was profiled against the extract concentration.

Results

Extracts of Bowiea volubilis inhibited the metabolic activity of CYP1A2 and CYP3A4 with IC₅₀ values of 92.3 ± 5.5 µg/mL and 8.1 ± 0.6 µg/mL respectively. Similar observation with Spirostachys africana showed inhibitory activity against CYP1A2 and CYP3A4 with respective IC₅₀ values of 14.3 ± 0.6 µg/mL and 47.4 ± 2.4 µg/mL. Tulbaghia violacea demonstrated relatively weak inhibitory activity against CYP1A2 (767.4 ± 10.8 µg/mL) and CYP2C9 (921 ± 15.3 µg/mL).

Conclusion

The results suggest the potential for HDI between the herbs and the substrates of the affected enzymes, if sufficient in vivo concentration is attained.     

Platelet Function and Genotype after DES Implantation in East Asian Patients: Rationale and Characteristics of the PTRG-DES Consortium

PurposePlatelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel.Materials and MethodsSearching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them.ResultsNine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (^*2 or ^*3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively.ConclusionThe PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT04734028","term_id":"NCT04734028"}}NCT04734028.     

Improving anticoagulation in atrial fibrillation: observational study in three primary care trusts

Background

Atrial fibrillation (AF) is a cause of stroke, and undertreatment with anticoagulants is a persistent issue despite their effectiveness.

Aim

To increase the proportion of people with AF treated appropriately using anticoagulants, and reduce inappropriate antiplatelet therapy.

Design of study

Cross-sectional analysis.

Setting

Electronic patient health records on 4604 patients with AF obtained from general practices in three inner London primary care trusts between April 2011 and 2013.

Method

The Anticoagulant Programme East London (APEL) sought to achieve its aims through an intervention with three components: altering professional beliefs using new clinical guidance and related education; facilitating change using computer software to support clinical decisions and patient review optimising anticoagulation; motivating change through evaluative feedback showing individual practice performance relative to peers.

Results

From April 2011 to April 2013, the proportion of people with CHA₂DS₂-VASc ≥1 on anticoagulants increased from 52.6% to 59.8% (trend difference P<0.001). The proportion of people with CHA₂DS₂-VASc ≥1 on aspirin declined from 37.7% to 30.3% (trend difference P<0.001). Comparing the 2 years before the intervention with the 2 years after, numbers of new people on the AF register almost doubled from 108 to 204.

Conclusions

The APEL programme supports improvement in clinical managing AF by a combined programme of education around agreed guidance, computer aids to facilitate decision-making and patient review and feedback of locally identifiable results. If replicated nationally over 3 years, such a programme could result in approximately 1600 fewer strokes every year.     

Type 2 diabetes and dog walking: patients' longitudinal perspectives about implementing and sustaining physical activity

Background

Physical activity is particularly important for people with type 2 diabetes, as evidence suggests that any reduction in sedentary time is good for metabolic health.

Aim

To explore type 2 diabetes patients'' talk about implementing and sustaining physical activity.

Design of study

Longitudinal, qualitative study using repeat in-depth interviews with 20 patients over 4 years following clinical diagnosis.

Setting

Patients were recruited from 16 general practices and three hospitals across Lothian, Scotland.

Results

Discussion, and salience, of physical activity was marginal in patient accounts of their diabetes management. Patients claimed to have only received vague and non-specific guidance about physical activity from health professionals, and emphasised a perceived lack of interest and encouragement. Aside from walking, physical activities which were adopted tended to attenuate over time. Patients'' accounts revealed how walking a dog assisted this kind of activity maintenance over time. Three main themes are highlighted in the analysis: 1) incidental walking; 2) incremental physical activity gains; and 3) augmenting physical activity maintenance. The problems arising from walking without a dog (for example, lack of motivation) are also examined.

Conclusion

Asking patients about pet preferences might seem tangential to medical interactions. However, encouraging dog walking or identifying another interest that promotes a regular commitment to undertake physical activity may yield long-term health benefits.     

Synthesis, characterization and biological activities of substituted cinnoline culphonamides

Background

The Cinnoline moiety and Sulphonamide moiety both have good antimicrobial properties.

Methods

In the present study both the moieties were condensed to synthesize substituted cinnoline sulphonamide derivatives using intramolecular cyclization followed by diazotization in order to get synergistic activity.

Results

These derivatives particularly halogen substituted cinnoline derivatives showed potent antimicrobial activity.

Conclusion

Further investigations are required to find out possible mechanism of action.     

The spectrum of liver diseases in HIV infected individuals at an HIV treatment clinic in Kampala, Uganda

Background

Liver diseases are common in patients with HIV due to viral hepatitis B and C co-infections, opportunistic infections or malignancies, antiretroviral drugs and drugs for opportunistic infections.

Objective

To describe the spectrum of liver diseases in HIV-infected patients attending an HIV clinic in Kampala, Uganda.

Method

Consecutive patients presenting with jaundice, right upper quadrant pain with fever or malaise, ascites and/or tender hepatomegaly were recruited and underwent investigations to evaluate the cause of their liver disease.

Results

Seventy-seven consecutive patients were recruited over an eleven month period. Of these, 23 (30%) had increased transaminases because of nevirapine (NVP) and/or isoniazid (INH) hepatotoxicity. Although 14 (61%) patients with drug-induced liver disease presented with jaundice, all recovered with drug discontinuation. Hepatitis B surface antigen was positive in 11 (15%) patients while anti-hepatitis C antibody was reactive in only 2 (3%). Probable granulomatous hepatitis due to tuberculosis was diagnosed in 7 (9%) patients and all responded to anti-TB therapy. Other diagnoses included alcoholic liver disease, AIDS cholangiopathy, hepatocellular carcinoma, schistosomiasis, haemangioma and hepatic adenoma. Twelve (16%) patients died during follow-up of which 7 (9%) died because of liver disease.

Conclusion

Drug history, liver enzyme studies, ultrasound, and hepatitis B and C investigations identified the probable etiology in 60 (78%) of 77 patients with HIV infection presenting with symptoms and/or signs of liver disease.