• One third of the Irish population aged Ն70 years were prescribed at least one potentially inappropriate medication in 2007 based on European criteria.• There was a signficant association between polypharmacy and the risk of PIP. Polypharmacy was evaluated as the number of different repeat drug classes (Ն three prescription claims) per claimant.• The most prevalent PIP drugs were: proton pump inhibitors at maximum therapeutic dosage for >8 weeks (40 mg daily omeprazole, pantoprazole and esomeprazole, 30 mg daily lansoprazole and 20 mg daily rabeprazole); non-steroidal anti-inflammatories for >3 months; long-acting benzodiazepines for >1 month and drug duplication within the same therapeutic class.• The total expenditure on potentially inappropriate drugs was €45 631 319 in 2007 which is 9% of the overall expenditure on pharmaceuticals in those aged Ն70 years in Ireland. AIMSOptimization of drug prescribing in older populations is a priority due to the significant clinical and economic costs of drug-related illness. This study aimed to: (i) estimate the prevalence of potentially inappropriate prescribing (PIP) in a national Irish older population using European specific explicit prescribing criteria; (ii) investigate the association between PIP, number of drug classes, gender and age and; (iii) establish the total cost of PIP. METHODSThis was a retrospective national population study (n = 338 801) using the Health Service Executive Primary Care Reimbursement Service (HSE-PCRS) pharmacy claims database. The HSE-PCRS uses the WHO Anatomical Therapeutic Chemical (ATC) classification system and details of every drug dispensed and claimants' demographic data are available. Thirty PIP indicators (STOPP) were applied to prescription claims for those Ն70 years in Ireland in 2007. STOPP is a physiological system based screening tool of older persons' potentially inappropriate prescriptions assessing drug-drug and drug-disease interactions, dose and duration. RESULTSIn our study population PIP prevalence was 36% (121 454 claimants).The main contributors to this were: 56 560 (17%) prescribed proton pump inhibitors at maximum therapeutic dose for >8 weeks, 29 691 (9%) prescribed non-steroidal anti-inflammatories for >3 months, 17 676 (5%) prescribed long-acting benzodiazepines for >1 month and 16 201 (5%) prescribed duplicate drugs. The main determinant of PIP was polypharmacy. The likelihood of PIP increased with a significant linear and quadratic trend (P < 0.0001) with the number of drug classes.The maximum net ingredient cost of PIP was estimated to be €38 664 640. Total PIP expenditure was estimated to be €45 631 319, 9% of the overall expenditure on pharmaceuticals in those Ն70 years in 2007.

The brachial artery pressure waveform is abnormal in smokers, but the effect of smoking on the aortic pressure waveform in both smokers and nonsmokers, particularly in the younger population, is unknown. We compared the acute and chronic effects of smoking on large-artery properties in 185 healthy young smokers and nonsmokers (mean+/-SD, 22+/-5 years). We matched 41 chronic smokers for age, height, weight, and gender with 116 nonsmokers. The augmentation index, a measure of arterial wave reflection in the aorta, was measured by applanation tonometry (Sphygmocor). We also compared augmentation index, aortic pulse wave velocity (Complior), and blood pressure in 28 subjects (11 chronic smokers) before and for 15 minutes after smoking 1 cigarette (nicotine content, 1.2 mg). Although brachial blood pressure was not different, the aortic systolic blood pressure (101+/-8 versus 97+/-9 mm Hg) and augmentation index (0.7+/-13 versus -5.7+/-14) were higher (P<0.01) in chronic smokers than in nonsmokers, whereas aortic-brachial pulse pressure amplification was reduced (13.7+/-8 versus 17.7+/-5 mm Hg, P<0.01). These effects were seen in both male and female subjects. Acutely in both groups, smoking significantly increased (P<0.01) both brachial and aortic blood pressure, augmentation index, and pulse wave velocity. No changes were seen after sham smoking. This study shows an acute increase in arterial stiffness after smoking 1 cigarette in chronic smokers and nonsmokers. Higher aortic systolic blood pressure and greater arterial stiffness, in part due to reduced pulse pressure amplification and increased arterial wave reflection, suggest that the adverse hemodynamic effects have hitherto been underestimated in young chronic smokers.

The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.

BACKGROUND.Five years of treatment provides the optimum duration of tamoxifen therapy for the prevention of breast cancer recurrence and mortality. Durations of adjuvant tamoxifen therapy less than 5 years are associated with poorer outcomes for breast cancer patients. The purpose of the study was to assess rates of tamoxifen nonpersistence (early discontinuation) in women aged 35 years or older using prescription refill data from a national prescribing database.METHODS.A cohort of 2816 women commencing tamoxifen as initial hormonal therapy was identified between January 2001 and January 2004. The cumulative tamoxifen persistence rate was calculated for these women and the relation between nonpersistence and clinical and demographic variables assessed.RESULTS.Within 1 year of commencing treatment the cumulative tamoxifen nonpersistence rate was 22.1%. This is twice the rate of treatment discontinuation observed in other studies by this time. By the end of follow‐up at 3.5 years, the cumulative nonpersistence rate had increased to 35.2%. Determinants of nonpersistence identified included age and a history of antidepressant use.CONCLUSIONS.The rate of nonpersistence with tamoxifen therapy is higher than previously reported. This study demonstrates that persistence with tamoxifen cannot be assumed and raises concerns about persistence with other oral hormonal therapies for breast cancer and oral antineoplastics in general. Oncologists need to identify those at risk of nonpersistence and develop strategies to combat this barrier to treatment success. Cancer 2007. © 2007 American Cancer Society.

Abstract-The acute phase-reactant high-sensitivity C-reactive protein, a marker of vascular inflammation and an atherosclerotic risk factor, is related to arterial stiffness in healthy subjects and in systemic vasculitis. To explore the relationship between markers of inflammation, interleukin-6 (IL-6), tumor necrosis factor-␣ (TNF-␣), and highsensitivity C-reactive protein with arterial stiffness, we studied untreated patients (nϭ78; 56% male; 47Ϯ1 years of age; meanϮSEM) with essential hypertension. After overnight fast, augmentation index and pulse wave velocity were assessed noninvasively and related to plasma levels of inflammatory markers measured by ELISA. Pulse wave velocity was significantly related to plasma high-sensitivity C-reactive protein (rϭ0.31; PϽ0.001), TNF-␣, (rϭ0.30; PϽ0.001) and IL-6 (rϭ0.21; PϽ0.05). There was also a relationship between heart rate-corrected augmentation index to high-sensitivity C-reactive protein (rϭ0.37; PϽ0.001), PϽ0.05), Pϭ0.06).High-sensitivity C-reactive protein was an independent predictor of pulse wave velocity and augmentation index in a multiple stepwise regression model. High-sensitivity C-reactive protein, a marker of systemic inflammation, is independently related to pulse wave velocity, a marker of aortic stiffness, and augmentation index, a manifestation of wave reflection, in essential hypertension. Key Words: hypertension, arterial Ⅲ arteries Ⅲ atherosclerosis Ⅲ elasticity Ⅲ endothelium A ortic stiffness, measured by carotid femoral pulse wave velocity (PWV) has been shown to be a strong independent predictor of cardiovascular morbidity in hypertension, 1 type II diabetes, 2 and of all-cause mortality in patients with hypertension 1 and end-stage renal disease. 3 The augmentation index (AIx), a composite of PWV, arterial wave reflection, and left ventricular ejection, is also an independent factor associated with poor survival in end-stage renal disease 4 and the extent of angiographic coronary artery disease (CAD) in men Ͻ60 years of age. 5 In addition to these functional hemodynamics measures, biochemical markers, particularly of vascular inflammation such as high-sensitivity C-reactive protein (hs-CRP), have been shown to be predictive of cardiovascular events. In a cross-sectional study, hs-CRP levels were found to be elevated in subjects with hypertension, 6 and increased hs-CRP levels in normotensive subjects also predicted the future development of hypertension. 6 In the hypertensive population, hs-CRP is an independent predictor of progression of atherosclerosis that is superior to either pulse pressure (PP) or systolic blood pressure (BP). 7 In healthy subjects, changes in arterial structure, assessed by carotid intima-medial thickness and presence of plaques, and in arterial stiffness, are not the compounding factors in the relationship between hs-CRP and PP. 8 The primary proinflammatory cytokines TNF-␣ and interleukin-6 (IL-6) are the main inducers for the hepatic synthesis of hs-CRP. A recent study found that hs-CRP and IL-6 are independent ...

Abstract-Cigarette smoking is an important modifiable cardiovascular risk factor and pathophysiological mechanisms may include a stiff vascular tree. Although smokers have stiffer arteries, whether smoking cessation is associated with reduced arterial stiffness is not known. We compared never-treated patients with essential hypertension (nϭ554) aged 18 to 80 years (56% females) classified as current smokers (nϭ150), ex-smokers (nϭ136), and nonsmokers (nϭ268). Ex-smokers were categorized into Ͻ1 year, Ͼ1 and Ͻ10 years, and Ͼ10 years of smoking cessation. Key Words: smoking Ⅲ arterial stiffness Ⅲ pulse wave velocity Ⅲ augmentation index Ⅲ hypertension Ⅲ smoking cessation C igarette smoking is one of the most important avoidable causes of cardiovascular diseases worldwide, 1 and arterial stiffness may be one of the underlying pathophysiological mechanisms. Chronic cigarette smoking has been shown to be associated with increased arterial stiffness 2,3 and increases immediately after smoking 1 cigarette. 3 The standard measurement of arterial stiffness, aortic pulse wave velocity (PWV) in conjunction with augmentation index (AIx), an estimate of aortic wave reflection, provide a comprehensive assessment of arterial stiffness. 4 There is evidence that both PWV 5,6 and AIx 7 are independent predictors of cardiovascular events.Smoking cessation is an important lifestyle measure for the prevention of cardiovascular disease, and patients with myocardial infarction may experience as much as a 50% reduction in risk of reinfarction, sudden cardiac death, and total mortality if they quit smoking. 8 However, the speed and magnitude of risk reduction when a smoker quits is debatable, with studies quoting 3 to 20 years of smoking cessation associated with significant risk reductions in coronary artery disease. 8 Whether long-term smoking cessation is associated with a reduction in arterial stiffness compared with chronic smokers is not known. Therefore, we compared differences in arterial stiffness among nonsmokers, ex-smokers, and current smokers in a cross-sectional study. Methods SubjectsA total of 554 untreated subjects aged 18 to 80 years (47.8Ϯ0.6 years, meanϮSEM), 56% female, undergoing assessment for hypertension, were studied. None of the patients had secondary hypertension, coronary artery disease, valvular heart disorders, dysrhythmias, diabetes, heart failure, or renal impairment, and none were taking any vasoactive drugs. Current smokers were defined as those who had smoked Ͼ1 cigarette per day for Ն1 year, nonsmokers as those who had never smoked, and former or ex-smokers as those who had stopped smoking Ն1 month before examination. Ex-smokers were categorized into 3 subgroups according to smoking cessation duration: those who quit cigarette smoking for Ͻ1 year, between 1 and 10 years, and Ͼ10 years.Body weight, height, waist, and hip measurements were recorded in each patient. Body mass index (BMI) was calculated as body weight (kilograms) divided by height (meters squared), and the waist:hip ratio was calculated....

Aims St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in signi®cant reductions in trough plasma concentrations of indinavir and cyclosporin [1,2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug±drug interactions. Methods Healthy volunteers were randomized to either SJW (0.15%) 600 mg three times daily for 16 days (n=15) or placebo (n=7). Blood samples were obtained for P-glycoprotein expression and function at baseline, 16 and 32 days post treatment. Peripheral blood lymphocytes (PBMCs) were isolated by Ficoll density gradient centrifugation, ®xed and permeabilized. Cells were stained with a P-glycoprotein speci®c antibody, quanti®ed by¯ow cytometry and median¯uorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was con®rmed by RT-PCR. P-glycoprotein mediated drug ef¯ux was determined as a function of rhodamine ef¯ux in the absence and presence of ritonavir. Data are expressed as meants.d. and were subjected to nonparametric analysis. Results P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0t1.9 vs 29.5t14.3 (MFI); P<0.05). There was no effect with placebo (5.1t1.3 vs 6.0t1.9 MFI). SJW increased P-glycoprotein mediated rhodamine ef¯ux (reduced ratio) compared with baseline (0.12t0.04 vs 0.24t0.18 P<0.05).There was no change with placebo. Ritonavir (5 mM) inhibited P-glycoprotein mediated ef¯ux in both groups producing greater intracellular accumulation of rhodamine. However, this effect was attenuated following treatment with SJW (23.9t15.3% vs 75.4t16.4% P<0.05). Conclusions SJW increased expression and enhanced the drug ef¯ux function of the multi drug transporter P-glycoprotein in PBMCs of healthy volunteers. This may represent a second mechanism for the drug±herb interactions seen in clinical practice and account for the discrepancies between in vitro and in vivo data. Since P-glycoprotein and CYP3A4 have distinct though overlapping substrates, patients receiving drugs, which are P-glycoprotein substrates should be warned against self-medication with SJW as clinically signi®cant drug interactions may occur.

The results emphasise the importance of a comprehensive strategy that maximises population coverage of effective treatments, and that actively promotes primary prevention, particularly tobacco control and a cardioprotective diet.