Preventing recurrent events long term after coronary artery bypass graft: Suboptimal use of medications in a population study

Background There are few population-based data on long-term management of patients after coronary artery bypass graft (CABG), despite the high risk for future major vascular events among this group. We assessed the prevalence and correlates of pharmacotherapy for prevention of new cardiac events in a large population-based series. Methods A postal survey was conducted of 2500 randomly selected survivors from a state population of patients 6 to 20 years after first CABG. Results Response was 82% (n = 2061). Use of antiplatelet agents (80%) and statins (64%) declined as age increased. Other independent predictors of antiplatelet use included statin use (odds ratio [OR] 1.6, 95% CI 1.26-2.05) and recurrent angina (OR 1.6, CI 1.17-2.06). Current smokers were less likely to use aspirin (OR 0.59, CI 0.4-0.89). Statin use was associated with reported high cholesterol (OR 24.4, CI 8.4-32.4), management by a cardiologist (OR 2.3, CI 1.8-3.0), and the use of calcium channel-blockers. Patients reporting hypertension or heart failure, in addition to high cholesterol, were less likely to use statins. Angiotensin-converting enzyme inhibitors were the most commonly prescribed agents for management of hypertension (59%) and were more frequently used among patients with diabetes and those with symptoms of heart failure. Overall 42% of patients were on angiotensin-converting enzyme inhibitors and 36% on beta-blockers. Conclusions Gaps exist in the use of-recommended medications after CABG. Lower anti-platelet and statin use was associated with older age, freedom from angina, comorbid heart failure or hypertension, and not regularly visiting a cardiologist. Patients who continue to smoke might be less likely to adhere to prescribed medications.

Cost-effectiveness of psychological and pharmacological interventions for generalized anxiety disorder and panic disorder

Objective: To assess from a health sector perspective the incremental cost-effectiveness of interventions for generalized anxiety disorder (cognitive behavioural therapy [CBT] and serotonin and noradrenaline reuptake inhibitors [SNRIs]) and panic disorder (CBT, selective serotonin reuptake inhibitors [SSRIs] and tricyclic antidepressants [TCAs]). Method: The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analyses of randomised controlled trials. An assessment on second stage filters ('equity', 'strength of evidence', 'feasibility' and 'acceptability to stakeholders') is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are calculated for a period of one year for the eligible population (prevalent cases of generalized anxiety disorder/panic disorder identified in the National Survey of Mental Health and Wellbeing, extrapolated to the Australian population in the year 2000 for those aged 18 years and older). Simulation modelling techniques are used to present 95% uncertainty intervals (UI) around the incremental cost-effectiveness ratios (ICERs). Results: Compared to current practice, CBT by a psychologist on a public salary is the most cost-effective intervention for both generalized anxiety disorder (A$6900/DALY saved; 95% UI A$4000 to A$12 000) and panic disorder (A$6800/DALY saved; 95% UI A$2900 to A$15 000). Cognitive behavioural therapy results in a greater total health benefit than the drug interventions for both anxiety disorders, although equity and feasibility concerns for CBT interventions are also greater. Conclusions: Cognitive behavioural therapy is the most effective and cost-effective intervention for generalized anxiety disorder and panic disorder. However, its implementation would require policy change to enable more widespread access to a sufficient number of trained therapists for the treatment of anxiety disorders.

Cholestanol: A serum marker to guide LDL cholesterol-lowering therapy

Statins have been the mainstay of lipid-lowering therapy since their introduction. However, as lower LDL cholesterol targets are sought, adjunct therapies are becoming increasingly important. Few patients reach new targets with statin monotherapy. We propose that the cholestanol: cholesterol ratio can be used to guide lipid-lowering therapy and result in greater numbers of patients reaching target LDL cholesterol. By determining whether a patient is mainly a synthesizer or absorber of cholesterol, customized regimens can be used and are expected to improve patient outcomes and minimize costs of treatment. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Use of methotrexate in older patients - A risk-benefit assessment

Methotrexate is eliminated almost entirely by the kidneys. The risk of methotrexate toxicity is therefore increased in patients with poor renal function, most likely as a result of drug accumulation. Declining renal function with age may thus be an important predictor of toxicity to methotrexate. Up to 60% of all patients who receive methotrexate for rheumatoid arthritis (RA) discontinue taking it because of adverse effects, most of which occur during the first year of therapy. Gastrointestinal complications are the most common adverse effects of methotrexate, but hepatotoxicity, haematological toxicity, pulmonary toxicity, lymphoproliferative disorders and exacerbation of rheumatic nodules have all been reported, Decreased renal function as a result of disease and/or aging appears to be an important determinant of hepatic, lymphoproli ferative and haematological toxicity, Concomitant use of low doses of folic acid has been recommended as an approach to limiting toxicity. Interactions between methotrexate and several nonsteroidal anti-inflammatory drugs have been reported, but they may not be clinically significant. However, caution is advised in the use of such combinations in patients with reduced renal function. More serious toxicities (e.g. pancytopenia) may result when other inhibitors of folate utilisation [e.g. cotrimoxazole (trimethoprim-sulfamethoxazole)] or inhibitors of renal tubular secretion (e.g. probenecid) are combined with methotrexate. Before starting low dose methotrexate therapy in patients with RA, a full blood count, liver function tests, renal function tests and chest radiography should be performed. Blood counts and liver function tests should be repeated at regular intervals. Therapeutic drug monitoring of methotrexate has also been suggested as a means of limiting toxicity. Patients with RA usually respond very favourably to low dose methotrexate therapy, and the probability of patients continuing their treatment beyond 5 years is greater than for other slow-acting antirheumatic drugs. Thus, given its sustained clinical utility and relatively predictable toxicity profile, low dose methotrexate is a useful addition to the therapy of RA.

Short-term and long-term cardiovascular actions of different doses of perindopril in the rabbit

Short-term (one week) and chronic (six week) cardiovascular effects of orally administered perindopril were examined in the rabbit to demonstrate if short-term results can predict chronic outcomes. In short-term treatment, five doses of perindopril were examined in random order separated by a one week recovery period in each of six rabbits. Two doses of perindopril which resulted in a moderate hypotensive effect (-14 mmHg) and no hypotensive effect, respectively, were then selected for long-term treatment. Each rabbit in the short-term study received perindopril in doses of 0.01, 0.06, 0.32, 1.8 and 10 mg kg(-1) day(-1) for a week at a time. Rabbits on long-term treatment received either 0.3 or 0.01 mg kg(-1) day(-1) perindopril for six weeks. All rabbits had their mean arterial blood pressure (MAP) and heart rate recorded throughout treatment. Plasma angiotensin I (AngI), perindoprilat, angiotensin converting enzyme (ACE) inhibition were also assayed. Perindopril treatment for one week produced a dose-dependent hypotensive effect with the threshold dose, 0.06 mg kg(-1) day(-1), producing a 6.5+/-1.8 mmHg fall in MAP. The highest dose (10.0 mg kg(-1) day(-1)) produced a large fall in blood pressure of -29.6+/-4.2 mmHg. The 0.01 and 0.06 mg kg(-1) day(-1) doses of perindopril produced an average 2.65 fold increase in plasma AngI levels compared to the initial control. The three higher doses (0.32-10.0 mg kg(-1) day(-1)) of perindopril produced an equivalent 5.7 fold increase in plasma AngI levels compared to the initial controls. However, over six weeks 0.01 mg kg(-1) day(-1) perindopril induced a similar decrease in MAP as the 30 fold higher dose (-9.3 mmHg compared to -11.7 mmHg,). This was in spite of a 3 fold difference in plasma perindoprilat concentrations between the high and low dose perindopril groups. Plasma ACE inhibition was >80% with both doses of perindopril. The results indicate that while perindopril decreases MAP in a dose-dependent manner in short-term (one week) periods, over longer treatment times (six weeks) low concentrations of perindopril, non-hypotensive with shortterm treatment, may be as anti-hypertensive as considerably higher doses. (C) 1996 The Italian Pharmacological Society.

Structure of TcpG, the DsbA protein folding catalyst from Vibrio cholerae

The efficient and correct folding of bacterial disulfide bonded proteins in vivo is dependent upon a class of periplasmic oxidoreductase proteins called DsbA, after the Escherichia coli enzyme. In the pathogenic bacterium Vibrio cholerae, the DsbA homolog (TcpG) is responsible for the folding, maturation and secretion of virulence factors. Mutants in which the tcpg gene has been inactivated are avirulent; they no longer produce functional colonisation pill and they no longer secrete cholera toxin. TcpG is thus a suitable target for inhibitors that could counteract the virulence of this organism, thereby preventing the symptoms of cholera. The crystal structure of oxidized TcpG (refined at a resolution of 2.1 Angstrom) serves as a starting point for the rational design of such inhibitors. As expected, TcpG has the same fold as E. coli DsbA, with which it shares similar to 40% sequence identity. Ln addition, the characteristic surface features of DsbA are present in TcpG, supporting the notion that these features play a functional role. While the overall architecture of TcpG and DsbA is similar and the surface features are retained in TcpG, there are significant differences. For example, the kinked active site helix results from a three-residue loop in DsbA, but is caused by a proline in TcpG (making TcpG more similar to thioredoxin in this respect). Furthermore, the proposed peptide binding groove of TcpG is substantially shortened compared with that of DsbA due to a six-residue deletion. Also, the hydrophobic pocket of TcpG is more shallow and the acidic patch is much less extensive than that of E. coli DsbA. The identification of the structural and surface features that are retained or are divergent in TcpG provides a useful assessment of their functional importance in these protein folding catalysts and is an important prerequisite for the design of TcpG inhibitors. (C) 1997 Academic Press Limited.

Solution structure of the sodium channel antagonist conotoxin GS: A new molecular caliper for probing sodium channel geometry

Background: The venoms of Conus snails contain small, disulfide-rich inhibitors of voltage-dependent sodium channels. Conotoxin GS is a 34-residue polypeptide isolated from Conus geographus that interacts with the extracellular entrance of skeletal muscle sodium channels to prevent sodium ion conduction. Although conotoxin GS binds competitively with mu conotoxin GIIIA to the sodium channel surface, the two toxin types have little sequence identity with one another, and conotoxin GS has a four-loop structural framework rather than the characteristic three-loop mu-conotoxin framework. The structural study of conotoxin GS will form the basis for establishing a structure-activity relationship and understanding its interaction with the pore region of sodium channels. Results: The three-dimensional structure of conotoxin GS was determined using two-dimensional NMR spectroscopy. The protein exhibits a compact fold incorporating a beta hairpin and several turns. An unusual feature of conotoxin GS is the exceptionally high proportion (100%) of cis-imide bond geometry for the three proline or hydroxyproline residues. The structure of conotoxin GS bears little resemblance to the three-loop mu conotoxins, consistent with the low sequence identity between the two toxin types and their different structural framework. However, the tertiary structure and cystine-knot motif formed by the three disulfide bonds is similar to that present in several other polypeptide ion channel inhibitors. Conclusions: This is the first three-dimensional structure of a 'four-loop' sodium channel inhibitor, and it represents a valuable new structural probe for the pore region of voltage-dependent sodium channels. The distribution of amino acid sidechains in the structure creates several polar and charged patches, and comparison with the mu conotoxins provides a basis for determining the binding surface of the conotoxin GS polypeptide.

Plasminogen activator system in osteoclasts

To determine which genes of the plasminogen activator (PA) system were expressed in osteoclasts, RNA extracted from microisolated mouse osteoclasts was used as template for reverse transcribed polymerase chain reaction (RT-PCR) with gene-specific primer pairs, Using this approach, the expression of RNAs for tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protease nexin, and urokinase receptor isoform 1 (uPAR1) were detected in mouse osteoclasts. The expression of uPAR RNA in osteoclasts was confirmed by in situ hybridization with a uPAR1 probe, RNA encoding the uPAR isoform 2 was not detected in mouse osteoclasts, but a novel unspliced uPAR RNA variant was detected in these cells, The novel uPAR variant and uPAR1 RNA were also detected in mouse calvarial osteoblasts, kidney, muscle, and the mouse macrophage cell line J774A.1 by RT-PCR The presence of RNAs for most of the components of the PA system in osteoclasts suggests that it may have a functional role in this cell type.

Characterisation of the recently cloned rat noradrenaline transporter - Comparison with bovine and human transporters

The aims of this study were to characterize the recently cloned rat norepinephrine transporter (NET) in more detail and in particular to study possible species differences in its pharmacological properties compared with the human and bovine NETs. The study was carried out by measuring the uptake of [3H]norepinephrine in COS-7 cells expressing the NET after transient transfection with rat, human, or bovine NET cDNA. There were small but significant differences between the rat NET and the human or bovine NETs with respect to the affinities of sodium ions (greater for rat than for bovine) of the substrates norepinephrine, epinephrine, and 1-methyl-4-phenylpyridinium (greater for human than for rat), and of the inhibitor cocaine (greater for human and bovine than for rat), whereas the affinities of dopamine and of most inhibitors, including tricyclic antidepressants, showed no species differences. The fact that the affinities for some substrates, cocaine and sodium ions exhibited small but significant interspecies differences among the rat, human, and bovine NETs suggests that ligand recognition, the translocation process, and sodium ion dependence are influenced differentially by just a few amino acid exchanges in the primary sequences of the transporters. On the other hand, the lack of any major differences in the pharmacological properties of the rat, human, and bovine NETs in this study suggests that data obtained in previous studies on rat tissues and bovine cells can be extrapolated, in all except the most quantitative analyses, to the properties of the human NET.