Clinical trials update: highlights of the scientific sessions of The American College of Cardiology 2002: LIFE,DANAMI 2, MADIT-2, MIRACLE-ICD,OVERTURE, OCTAVE,ENABLE 1 & 2, CHRISTMAS,AFFIRM, RACE,WIZARD, AZACS,REMATCH, BNP trial and HARDBALL

This article continues a series of reports updating recent research developments of particular interest to personnel involved in the treatment and management of patients with heart failure. This is a summary of selected presentations made at the American College of Cardiology 51st Annual Scientific Session held in Atlanta on 17-20 March 2002. Reports of the following clinical studies are included: LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL.     

Electrochemical Recovery and Behaviors of Rare Earth (La,Ce, Pr,Nd, Sm,Eu, Gd,Tb, Dy,Ho, Er,Tm, and Yb) Ions on Ni Sheets

The electrochemical behaviors of rare earth (RE) ions have extensively been studied because of their high potential applications to the reprocessing of used nuclear fuels and RE-containing materials. In the present study, we fully investigated the electrochemical behaviors of RE(III) (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, and Yb) ions over a Ni sheet electrode in 0.1 M NaClO₄ electrolyte solution by cyclic voltammetry between +0.5 and −1.5 V (vs. Ag/AgCl). Amperometry electrodeposition experiments were performed between −1.2 and −0.9 V to recover RE elements over the Ni sheet. The successfully RE-recovered Ni sheets were fully characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and photoluminescence spectroscopy. The newly reported recovery data for RE(III) ions over a metal electrode provide valuable information on the development of the treatment methods of RE elements.     

Biliary microlithiasis,sludge,crystals,microcrystallization,and usefulness of assessment of nucleation time

BACKGROUND:The process of microcrystallization,its sequel and the assessment of nucleation time is ignored.This systematic review aimed to highlight the importance of biliary microlithiasis,sludge,and crystals,and their association with gallstones,unexplained biliary pain,idiopathic pancreatitis, and sphincter of Oddi dysfunction.DATA SOURCES:Three reviewers performed a literature search of the PubMed database.Key words used were"biliary microlithiasis","biliary sludge","bile crystals","cholesterol crystallisation","bile microscopy","microcrystal formation of bile","cholesterol monohydrate crystals","nucleation time of cholesterol","gallstone formation","sphincter of Oddi dysfunction"and"idiopathic pancreatitis".Additional articles were sourced from references within the studies from the PubMed search.RESULTS:We found that biliary microcrystals account for almost all patients with gallstone disease,7%to 79%with idiopathic pancreatitis,83%with unexplained biliary pain, and 25%to 60%with altered biliary and pancreatic sphincter function.Overall,the detection of biliary microcrystals in gallstone disease has a sensitivity ranging from 55%to 87%and a specificity of 100%.In idiopathic pancreatitis,the presence of microcrystals ranges from 47%to 90%.A nucleation time less than 10 days in hepatic bile or ultra-filtered gallbladder bile has a specificity of 100%for cholesterol gallstone disease.CONCLUSIONS:Biliary crystals are associated with gallstone disease,idiopathic pancreatitis,sphincter of Oddi dysfunction, unexplained biliary pain,and post-cholecystectomy biliary pain.Pathways of cholesterol super-saturation,crystallisation, and gallstone formation have been described with scientificsupport.Bile microscopy is a useful method to detect microcrystals and the assessment of nucleation time is a good method of predicting the risk of cholesterol crystallisation.     

Antibacterial activity of cefpodoxime in comparison with cefixime,cefdinir, cefetamet,ceftibuten, loracarbef,cefprozil, BAY 3522, cefuroxime,cefaclor and cefadroxil

Summary The new oral cephalosporins cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten demonstrate enhanced activity against Enterobacteriaceae susceptible to the established compounds as well (e.g. cefuroxime, cefaclor, cefadroxil). In addition, cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten include in their spectrum species hitherto resistant to oral cephalosporins (Proteus vulgaris, Providencia spp.,Yersinia enterocolitica). Besides, the majority of these compounds demonstrate relevant activity (MIC₅₀ equal to or below 2 mg/l) againstEnterobacter spp.,Citrobacter freundii, Serratia spp. andMorganella morganii. Ceftibuten is the most potent oral cephalosporin against most of the Enterobacteriaceae. Non-fermentative bacilli (Acinetobacter spp.,Pseudomonas spp.) remain completely resistant to oral cephalosporins (except someAcinetobacter species against cefdinir andPseudomonas cepacia against ceftibuten). Antistaphylococcal activity for oral cephalosporins is highest for cefdinir followed by BAY 3522, cefprozil, cefuroxime and cefpodoxime. Loracarbef, cefaclor and cefadroxil are about equally active, while the other compounds are only weakly active (cefixime) or inactive (cefetamet, ceftibuten). Enterococci are insensitive to new generation oral cephalosporins as they have been to established compounds. The most active oral cephalosporins against hemolytic streptococci are cefdinir and cefprozil.Streptococcus pneumoniae, Streptococcus milleri andStreptococcus mitior are most susceptible to cefpodoxime, cefdinir, cefuroxime and BAY 3522. Penicillin resistant pneumococci have to be regarded as resistant to all oral cephalosporins. Fastidious pathogens likeHaemophilus spp.,Moraxella catarrhalis andNeisseria gonorrhoeae are more susceptible to cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten than to the other oral cephalosporins. The activity of oral cephalosporins is only weak againstListeria spp.,Helicobacter pylori and anaerobic pathogens (except BAY 3522).Bordetella pertussis remains resistant to all absorbable cephalosporins. Progress in antibacterial activity of oral cephalosporins was mainly achieved by cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten against Enterobacteriaceae and the fastidious pathogens and against staphylococci and the nonenterococcal streptococci by cefdinir, BAY 3522, cefprozil and cefpodoxime.

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Antibakterielle Aktivität von Cefpodoxim im Vergleich mit anderen oralen Cephalosporinen

Zusammenfassung Die neuen oralen Cephalosporine Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten zeigen eine verstärkte Aktivität auch gegen solche Enterobacteriaceae, die gegen etablierte Substanzen empfindlich sind (z.B. Cefuroxim, Cefaclor, Cefadroxil). Zusätzlich schließt das Spektrum von Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten Spezies ein, die gegen die bisherigen oralen Cephalosporine resistent waren (Proteus vulgaris, Providencia spp.,Yersinia enterocolitica). Daneben zeigt die Mehrheit der neuen Substanzen erhöhte Aktivität (MHK₅₀<2 mg/l) gegenEnterobacter spp.,Citrobacter freundii, Serratia spp. undMorganella morganii. Gegen die meisten Enterobacteriaceae ist Ceftibuten das wirksamste orale Cephalosporin. Non-Fermenter (Acinetobacter spp.,Pseudomonas spp.) bleiben gegenüber oralen Cephalosporinen vollständig resistent (mit Ausnahme einigerAcinetobacter-Spezies gegen Cefdinir undPseudomonas cepacia gegen Ceftibuten). Die Antistaphylokokken-Aktivität oraler Cephalosporine ist am höchsten bei Cefdinir, gefolgt von BAY 3522, Cefprozil, Cefuroxim und Cefpodoxim. Loracarbef, Cefaclor und Cefadroxil sind etwa gleich aktiv, während die anderen Substanzen nur schwach aktiv (Cefixim) oder inaktiv sind (Cefetamet, Ceftibuten). Enterokokken sind gegenüber der neuen Generation oraler Cephalosporine ebenso unempfindlich wie gegenüber den etablierten Substanzen. Die aktivsten oralen Cephalosporine gegen hämolysierende Streptokokken sind Cefdinir und Cefprozil.Streptococcus pneumoniae, Streptococcus milleri undStreptococcus mitior sind am empfindlichsten gegen Cefpodoxim, Cefdinir, Cefuroxim und BAY 3522. Penicillin-resistente Pneumokokken müssen als resistent gegenüber allen oralen Cephalosporinen betrachtet werden. Anspruchsvolle Erreger wieHaemophilus spp.,Moraxella catarrhalis undNeisseria gonorrhoeae sind gegen Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten empfindlicher als gegen die anderen oralen Cephalosporine. Die Aktivität oraler Cephalosporine gegenListeria spp.,Helicobacter pylori und Anaerobier (Ausnahme BAY 3522) ist nur schwach.Bordetella pertussis bleibt gegen alle resorbierbaren Cephalosporine resistent. Der Fortschritt in der antibakteriellen Aktivität oraler Cephalosporine wurde gegen Enterobacteriaceae und anspruchsvolle Erreger hauptsächlich durch Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten erlangt, gegen Staphylokokken und Streptokokken (außer Enterokokken) durch Cefdinir, BAY 3522, Cefprozil und Cefpodoxim.

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Supported by Luitpold-Werk, a company of the Sankyo group.     

Clinical trials update from the American College of Cardiology 2008: CARISMA, TRENDS, meta-analysis of Cox-2 studies, HAT, ON-TARGET, HYVET, ACCOMPLISH, MOMENTUM, PROTECT, HORIZON-HF and REVERSE

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American College of Cardiology. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. CARISMA investigated the use of implantable loop recorders for detecting life-threatening arrhythmias in patients with LVSD after MI and found that brady- and ventricular tachy-arrhythmias predicted an adverse prognosis. The TRENDS study showed that the burden of atrial fibrillation detected by pacemakers or defibrillators predicted the risk of embolic events but not with sufficient precision to justify changes in anti-thrombotic management. A meta-analysis of six trials reported an increased cardiovascular risk associated with celecoxib, particularly for heart failure, which was related to dose and baseline cardiovascular risk. The HAT study failed to show a benefit of providing post-MI patients with a home defibrillator. MOMENTUM, a study of a device designed to augment aortic blood flow, was stopped early due to increased bleeding risk. Results from PROTECT support the use of rolofylline 30 mg/day in acute heart failure, a definitive study is now underway. Istaroxime, an agent that appears to have both inotropic and lusitropic effects, improved haemodynamics when added to standard therapy in patients stabilised after admission with heart failure in HORIZON-HF. The REVERSE study suggested that CRT improves ventricular function and reduces morbidity even in patients with few or no symptoms of heart failure and may delay or prevent worsening heart failure.     

Prevalence,Self-Awareness,Treatment, and Control of Hypertension in Lhasa,Tibet

To investigate the prevalence, self-awareness, and treatment of hypertension in Lhasa, Tibet, a total of 1370 native Tibetan aged ≥18 years were selected, using stratified proportional sampling. The study showed that the prevalence of hypertension was 51.2%, significantly higher in men (56.0%) than in women (48.0%) (P = .004). The hypertension prevalence increased with increasing age (77.8% in 60–74 y and 82.5% in ≥75 y groups) and was higher in urban, suburban, or agricultural area than in pastoral area (P < .001). The self-awareness, treatment, and control rate of hypertension were 63.5%, 24.3% and 7.7%, respectively. In multivariable regression analysis, age, urban residence, amount of daily intake of fat and oil, and body mass index <18.5 kg/m² were independently associated with hypertension. In conclusion, hypertension was highly prevalent among native Tibetan people in Lhasa, and the rates of self-awareness, treatment, and control of hypertension were low.     

Current status of pulmonary thromboembolism--incidence, diagnosis, classification, pathogenesis, and treatment

The incidence of pulmonary thromboembolism in the total autopsied cases and the actual reported cases of pulmonary thromboembolism in Japan has gradually increased. Since there is no part of the history, physical examination or noninvasive laboratory findings that is specific, a tentative criteria for diagnosis of pulmonary thromboembolism is proposed based a scoring system. Pulmonary thromboembolism can be classified into 5 different types: (1) massive pulmonary thromboembolism, (2) recurrent or occult pulmonary thromboembolism, (3) diffuse pulmonary microthromboembolism, (4) submassive pulmonary thromboembolism, (5) pulmonary infarction. We have carried out a series of model experiments in order to clarify the mechanism of the development of pulmonary microthromboembolism and the production of pulmonary infarction. On the basis of this data, we suspect that hyperfibrinolysis, endothelial damages and activated permeability factors lead to the interstitial and alveolar edema in pulmonary microthromboembolism or severe hemorrhage in pulmonary infarction. The combination therapy of UK (480,000 units) and DS (3,000 mg) had two advantages: (1) inhibition of shortening of APTT, (2) economy of UK dosage. Laboratory monitoring for effective UK therapy showed a markedly reduced alpha 2PI to under 50% of normal levels and fibrinolysis associated with fibrinogenolysis. The therapeutic effects of heparin were assessed by prolonged APTT (45-250 sec) and elevated Anti-FXa activity (0.2-1.2 u/ml of plasma heparin concentration) as an indicator for the evaluation of anticoagulation activity and by normalized FPA, Fbg, FDP, Plg and AT III as an indicator for evaluation of antithrombolic activity.     

Lysis of venous, pulmonary, prosthetic valvular, arterial, and ventricular clots

Thrombolysis has been used for the treatment of diverse thrombotic conditions for almost 50 years. Treatment of deep venous thrombosis and pulmonary embolism have been extensively studied, and benefit has been demonstrated in some subgroups. More recently thrombolysis has been investigated for the treatment of prosthetic valvular, arterial, and ventricular mural thrombi.     

Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American College of Cardiology meeting in March 2007. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. The ALPHA study suggested that patients with heart failure (HF) due to idiopathic dilated cardiomyopathy who have a negative T-wave alternans test have a good prognosis and are unlikely to benefit from ICD therapy. EVEREST provides some evidence of short-term symptom benefit of tolvaptan in patients with acute decompensated HF but no clinically important long-term benefit. FUSION II failed to show a benefit of nesiritide in patients with chronic decompensated HF. Reducing blood pressure in hypertensive patients improved diastolic dysfunction in VALIDD. Eplerenone did not improve left ventricular remodelling in mild to moderate chronic HF. Selecting HF patients for revascularisation using FDG-PET imaging did not significantly improve outcome. Crataegus extract added to standard HF therapy did not reduce morbidity or mortality in SPICE. The COURAGE study, conducted in patients without HF or major cardiac dysfunction, showed that PCI did not reduce cardiac morbidity or mortality and can be safely deferred in patients with stable coronary disease on optimal medical therapy. The COACH study failed to show that HF nurse-intervention could reduce hospitalisations but did show trends to lower mortality, especially amongst patients with reduced ejection fraction; however, the smaller REMADHE study suggested striking benefits on morbidity and mortality. A large study of BNP provided additional information on its ability to distinguish cardiac and pulmonary breathlessness. The importance of dietary intervention in post-MI patients was highlighted by the findings of THIS-diet study.     

Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese, adolescent girls: effect of flutamide

Functional ovarian hyperandrogenism, a variant of polycystic ovary syndrome, is often associated with hyperinsulinism and dyslipidemia. The mechanisms interlinking this triad are poorly understood; both hyperandrogenism and hyperinsulinism have been proposed as factors involved in the pathogenesis of the dyslipidemia. Precocious pubarche (PP) in girls is a risk factor for subsequent anovulation, ovarian and adrenal hyperandrogenism, hyperinsulinism and dyslipidemia. Flutamide, a nonsteroidal antiandrogen, is known to be effective in reducing hirsutism in patients with ovarian hyperandrogenism. However, the effects of flutamide on the endocrine-metabolic correlates of hyperandrogenism are uncertain. We assessed the effects of low dose flutamide treatment (250 mg daily for 18 months) on hormonal and metabolic variables in 18 nonobese adolescent girls (age, 16.8 +/- 0.3 yr) with functional ovarian hyperandrogenism (diagnosis by GnRH agonist test) after PP. Flutamide treatment was accompanied by a marked decrease in the hirsutism score, free androgen index, and testosterone, androstenedione, and dehydroepiandrosterone levels and by an increase in sex hormone-binding globulin concentrations. However, there were no substantial changes in the pattern of menstrual cycles, gonadotropin, estradiol, or dehydroepiandrosterone sulfate concentrations, and there was no detectable effect on the 17-hydroxyprogesterone response to GnRH agonist. Serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels decreased markedly during flutamide therapy, whereas high-density lipoprotein cholesterol, fasting glycemia/insulinemia, and the insulin response to a glucose load remained unchanged. Flutamide was well tolerated. In conclusion, low dose flutamide treatment was found to be an effective and safe approach to reduce hirsutism and circulating androgen, low-density lipoprotein cholesterol, and triglyceride levels in girls with functional ovarian hyperandrogenism after PP. However, flutamide failed to increase high-density lipoprotein cholesterol levels or decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease.     

Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin,atenolol, enalapril,phenytoin, rosiglitazone,and sitagliptin

Aims

Drug interactions with bile acid sequestrants are primarily due to the potential of these agents to bind to concomitant drugs. Six clinical studies were performed to determine the effects of colesevelam on the pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin.

Methods

All six studies enrolled healthy subjects aged 18–45 years. The phenytoin study used a single-dose, three-period crossover design (phenytoin alone, phenytoin simultaneously with colesevelam, and phenytoin 4 h before colesevelam). The other studies used a two-period crossover design (test drug alone and test drug simultaneously with colesevelam). Colesevelam (3750 mg once daily) was dosed throughout the pharmacokinetic sampling period. After each single dose of the test drug, serial blood samples were collected for determination of plasma drug concentrations and calculation of pharmacokinetic parameters.

Results

For all six test drugs, 90% CIs for geometric least-squares mean ratios of AUC and C_max for the measured analytes were within specified limits, indicating no interaction between the test drug and colesevelam.

Conclusions

Aspirin, atenolol, enalapril, rosiglitazone, and sitagliptin may be taken with colesevelam. Although the phenytoin study indicated no pharmacokinetic interaction, phenytoin should continue to be taken ≥4 h before colesevelam in accordance with current prescribing information.     

The pathology of acute myocardial infarction: definition, location, pathogenesis, effects of reperfusion, complications, and sequelae

This article reviews the definition, locations, and pathogenesis of acute myocardial infarction and provides a review of the pathology of acute reperfusion therapy. Various complications and sequelae of acute myocardial infarction are also surveyed.