This paper examines whether there is a switch in total (originator and generic) consumption after generic entry from molecules that face generic competition towards other molecules of the same class, which are still in-patent. Data from six European countries for the time period 1991 to 2006 are used to study the cases of angiotensin-converting enzyme inhibitors and proton pump inhibitors. Empirical evidence shows that patent expiry of captopril and enalapril led to a switch in total (off-patent originator and generic) consumption towards other in-patent angiotensin-converting enzyme inhibitors, whereas patent expiry of omeprazole led to a switch in consumption towards other proton pump inhibitors. This phenomenon makes generic policies ineffective and results in an increase in pharmaceutical expenditure due to the absence of generic alternatives in the market of in-patent molecules. Copyright © 2013 John Wiley & Sons, Ltd.

We have used a set of four local properties based on semiempirical molecular orbital calculations (the electron density (ρ), hydrogen bond donor field (HDF), hydrogen bond acceptor field (HAF) and molecular lipophilicity potential (MLP)) for 3D-QSAR studies to overcome the limitations of the current force-field based molecular interaction fields (MIFs). These properties can be calculated rapidly and are thus amenable to high-throughput industrial applications. Their statistical performance was compared with that of conventional 3D-QSAR approaches using nine datasets (angiotensin converting enzyme inhibitors (ACE), acetylcholinesterase inhibitors (AchE), benzodiazepine receptor ligands (BZR), cyclooxygenase-2 inhibitors (COX2), dihydrofolate reductase inhibitors (DHFR), glycogen phosphorylase b inhibitors (GPB), thermolysin inhibitors (THER), thrombin inhibitors (THR) and serine protease factor Xa inhibitors (fXa)). The 3D-QSAR models generated were tested thoroughly for robustness and predictive ability. The average performance of the quantum mechanical molecular interaction field (QM-MIF) models for the nine datasets is better than that of the conventional force-field-based MIFs. In the individual datasets, the QM-MIF models always perform better than, or as well as, the conventional approaches. It is particularly encouraging that the relative performance of the QM-MIF models improves in the external validation. In addition, the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation. QM-MIF contour maps reproduce the features important for ligand binding for the example dataset (factor Xa inhibitors), demonstrating the intuitive chemical interpretability of QM-MIFs.

Background:

Treating non-diabetic proteinuric patients with advanced renal disease with an angiotensin-converting enzyme (ACE) inhibitor is still subject to discussion. This study aims to determine the cost-effectiveness of ACE inhibitor therapy in this patient population in the Netherlands.

Methods:

We compared two strategies: first, treating patients with advanced renal disease with an ACE inhibitor and no-treatment. A lifetime Markov decision model was developed simulating the progression of renal disease and using published data on costs and health outcomes. A health care perspective was adopted.

Results:

In the base-case analysis, treatment with ACE inhibitors leads to higher benefits and lower costs and dominates the no-treatment strategy. Sensitivity analysis shows that the probability of savings is 83%.

Conclusion:

ACE inhibitor treatment for non-diabetic patients with advanced renal disease in the Netherlands is highly cost-effective and should therefore be considered.

In the June 2011 issue of the New England Journal of Medicine, the BEAM (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) trial investigators rekindled new interest and also some controversy regarding the concept of renoprotection and the role of renoprotective agents, when they reported significant increases in the mean estimated glomerular filtration rate (eGFR) in diabetic chronic kidney disease (CKD) patients with an eGFR of 20-45 ml/min/1.73 m(2) of body surface area at enrollment who received the trial drug bardoxolone methyl versus placebo. Unfortunately, subsequent phase IIIb trials failed to show that the drug is a safe alternative renoprotective agent. Current renoprotection paradigms depend wholly and entirely on angiotensin blockade; however, these agents [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)] have proved to be imperfect renoprotective agents. In this review, we examine the mechanistic limitations of the various previous randomized controlled trials on CKD renoprotection, including the paucity of veritable, elaborate and systematic assessment methods for the documentation and reporting of individual patient-level, drug-related adverse events. We review the evidence base for the presence of putative, multiple independent and unrelated pathogenetic mechanisms that drive (diabetic and non-diabetic) CKD progression. Furthermore, we examine the validity, or lack thereof, of the hyped notion that the blockade of a single molecule (angiotensin II), which can only antagonize the angiotensin cascade, would veritably successfully, consistently and unfailingly deliver adequate and qualitative renoprotection results in (diabetic and non-diabetic) CKD patients. We clearly posit that there is this overarching impetus to arrive at the inference that multiple, disparately diverse and independent pathways, including any veritable combination of the mechanisms that we examine in this review, and many more others yet to be identified, do concurrently and asymmetrically contribute to CKD initiation and propagation to end-stage renal disease (ESRD) in our CKD patients. We conclude that current knowledge of CKD initiation and progression to ESRD, the natural history of CKD and the impacts of acute kidney injury on this continuum remain in their infancy and call for more research. Finally, we suggest a new classification scheme for renoprotective agents: (1) the single-pathway blockers that block a single putative pathogenetic pathway involved in CKD progression, as typified by ACE inhibitors and/or ARBs, and (2) the multiple-pathway blockers that are able to block or antagonize the effects of multiple pathogenetic pathways through their ability to simultaneously block, downstream, the effects of several pathways or mechanisms of CKD to ESRD progression and could therefore concurrently interfere with several unrelated upstream pathways or mechanisms. We surmise that maybe the ideal and truly renoprotective agent, clearly a multiple-pathway blocker, is on the horizon. This calls for more research efforts from all.

BACKGROUND:

Most hypertensive patients need more than one agent to achieve blood pressure (BP) control. The fixed dose combinations can provide effective 24-h BP control, which is essential in hypertension management.

AIMS:

The primary objectives of the PErindopril/Amlodipine Reduction of blood pressure Level (PEARL) ABPM substudy were to assess the effect of a perindopril/amlodipine fixed-dose combination on mean 24-h BP, daytime BP, and nighttime BP in a subgroup of PEARL patients. Secondary objectives included assessment of office BP, metabolic parameters (blood glucose and lipids), heart rate, and safety and tolerability.

METHODS:

PEARL was a 3-month observational study with a perindopril/amlodipine fixed-dose combination for treatment of outpatients with essential hypertension uncontrolled by prior treatment (office BP ≥140/90 mmHg or ≥130/80 mmHg in those at high/very high cardiovascular risk). In this ABPM substudy of PEARL, treatment efficacy was assessed by 24-h ABPM. At inclusion, previous angiotensin-converting enzyme (ACE) inhibitors and/or calcium channel blockers (CCBs) were replaced by a perindopril/amlodipine fixed-dose combination at a dosage (5/5, 5/10, 10/5, or 10/10 mg) chosen by the physician and uptitrated at month 1, if required. ABPM and office BP measurements were assessed at inclusion, month 1, and month 3. Metabolic effects, heart rate, and adverse events were also monitored.

RESULTS:

Mean age of the 262 ABPM patients (144 males) was 60.4 ± 11.7 years, and mean baseline office brachial systolic BP/diastolic BP was 159.8 ± 16.0/94.3 ± 10.3 mmHg. After 3 months, the perindopril/amlodipine fixed-dose combination reduced mean 24-h ambulatory BP from 146.1/84.3 to 127.6/75.9 mmHg (p < 0.001). Mean office BP decreased to 131.1/80.0 mmHg (p < 0.001). Results were consistent in subgroups, defined by cardiovascular comorbidities or previous treatments. Favorable metabolic and heart rate effects were observed, and no serious adverse events were reported.

CONCLUSIONS:

Further effective, safe, and sustained 24-h ambulatory BP and office BP reductions were obtained by switching from ACE inhibitors and/or CCBs to a perindopril/amlodipine fixed-dose combination in outpatients with uncontrolled essential hypertension in a practice setting. For this type of patient, the use of a perindopril/amlodipine fixed-dose combination can be considered an effective and safe option to normalize BP.

Carotid artery intima-media thickness (IMT) is a biomarker for cardiovascular disease that also predicts the risk of cardiovascular mortality. Angiotensin-converting enzyme (ACE) inhibition is a unique therapeutic modality because it both treats hypertension and improves arterial health and cardiovascular disease outcomes. Controversy exists regarding the role of ACE inhibitors and angiotensin receptor blockers (ARBs) in IMT regression. Our article provides an update on how ACE inhibitors and ARBs could play a role in decreasing IMT.

Aims Angiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. Main methods Diabetes was induced in spontaneously-hypertensive rats (~210g) by streptozotocin (50mg/kg). Thirty days later, animals received ramipril 15μg/kg/day (R, n=10), or amlodipine 10mg/kg/day (A, n=8,) or water (C, n=10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF-β1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). Key findings After treatments, body weight (p=0.77) and glycaemia (p=0.22) were similar among the groups. Systolic BP was similarly reduced (p<0.001) in A and R vs. C (172.4±3.2; 186.7±3.7 and 202.2±4.3mmHg; respectively). ACE activity (C: 0.903±0.086; A: 0.654±0.025, and R: 0.389±0.057mU/mg), albuminuria (C: 264.8±15.4; A: 140.8±13.5 and R: 102.8±6.7mg/24h), and renal cortex GLUT1 content (C: 46.81±4.54; A: 40.30±5.39 and R: 26.89±0.79AU) decreased only in R (p<0.001, p<0.05 and p<0.001; respectively). Significance We concluded that the blockade of the renin-angiotensin system with ramipril reduced early markers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels.

The mechanisms underlying the anti-inflammatory and anti-hypertensive effects of long chain ω-3 polyunsaturated fatty acids (PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid (epoxyeicosatrienoic acids; EETs) also exhibit anti-hypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may lower blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for three weeks in a murine model of angiotensin-II dependent hypertension. Also, since EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of a sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II increased blood pressure, further increased renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (i.e. prostaglandins and MCP-1), down-regulated an epithelial sodium channel and up-regulated Angiotensin converting enzyme-2 message (ACE-2) and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering SBP and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by up-regulation of ACE-2 in angiotensin-II dependent hypertension.

Two professional athletes in the US National Basketball Association required surgery for aortic root dilation in 2012. These cases have attracted attention in sports medicine to the importance of aortic root disease in athletes. In addition to aortic root dilation, other forms of aortic disease include anomalous coronary artery, bicuspid aortic valve, and Marfan's syndrome. In this review, electronic database literature searches were performed using the terms "aortic root" and "athletes." The literature search produced 122 manuscripts. Of these, 22 were on aortic root dilation, 21 on anomalous coronary arteries, 12 on bicuspid aortic valves, and 8 on Marfan's syndrome. Aortic root dilation is a condition involving pathologic dilation of the aortic root, which can lead to life-threatening sequelae. Prevalence of the condition among athletes and higher risk athletes in particular sports needs to be better delineated. Normative parameters for aortic root diameter in the general population are proportionate to anthropomorphic variables, but this has not been validated for athletes at the extremes of anthropomorphic indices. Although echocardiography is the favored screening modality, computed tomography (CT) and cardiac magnetic resonance imaging (MRI) are also used for diagnosis and surgical planning. Medical management has utilized beta-blockers, with more recent use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and statins. Indications for surgery are based on comorbidities, degree of dilation, and rate of progression. Management decisions for aortic root dilation in athletes are nuanced and will benefit from the development of evidence-based guidelines. Anomalous coronary artery is another form of aortic disease with relevance in athletes. Diagnosis has traditionally been through cardiac catheterization, but more recently has included evaluation with echocardiography, multislice CT, and MRI. Athletes with this condition should be restricted from participation in competitive sports, but can be cleared for participation 6 months after surgical repair. Bicuspid aortic valve is another form of aortic root disease with significance in athletes. Although echocardiography has traditionally been used for diagnosis, CT and MRI have proven more sensitive and specific. Management of bicuspid aortic valve consists of surveillance through echocardiography, medical therapy with beta-blockers and ARBs, and surgery. Guidelines for sports participation are based on the presence of aortic stenosis, aortic regurgitation, and aortic root dilation. Marfan's syndrome is a genetic disorder with a number of cardiac manifestations including aortic root dilation, aneurysm, and dissection. Medical management involves beta-blockers and ARBs. Thresholds for surgical management differ from the general population. With regard to sports participation, the most important consideration is early detection. Athletes with the stigmata of Marfan's syndrome or with family history should be tested. Further research should determine whether more aggressive screening is warranted in sports with taller athletes. Athletes with Marfan's syndrome should be restricted from activities involving collision and heavy contact, avoid isometric exercise, and only participate in activities with low intensity, low dynamic, and low static components. In summary, many forms of aortic root disease afflict athletes and need to be appreciated by sports medicine practitioners because of their potential to lead to tragic but preventable deaths in an otherwise healthy population.

Abstract Cutaneous adverse drug reactions (ADRs) to antihypertensive drugs have been frequently reported. We describe a peculiar clinical pattern of cutaneous ADR, represented by an eczematous reaction induced by certain antihypertensive drugs that we observed in elderly patients. The case series consisted of 23 hypertensive patients aged 66-87 years; 19 of them were taking another drug in addition to the suspected antihypertensive medication and 15 were on polytherapy with three or more drugs to treat multiple comorbidities. The antihypertensive culprit agents were angiotensin-converting enzyme (ACE) inhibitors in 9 patients, ACE-inhibitors combined to hydrochlorothiazide (HCT) in 7 subjects, angiotensin II receptor blockers alone in 2 patients and associated with HCT in 5 cases. The cutaneous ADR was characterized by an eczematous rash that was generalized in 16 patients and localized in 7 cases, with predominant involvement of lower limbs. Such lesions developed after a latency of 4-30 months and were associated with moderate-to-severe itch, usually unresponsive to oral antihistamines. Histopathological diagnosis was available for 9 cases, confirming the presence of a spongiotic dermatitis with possible associated psoriasiform skin changes.