piperidines and Coronary-Disease

High-density lipoprotein cholesterol is a potent and independent epidemiologic risk factor and is a proved antiatherosclerotic agent in animal models of atherosclerosis, acting through the principal mechanisms of accelerating cholesterol efflux and inhibiting oxidation and inflammation. Lifestyle modification increases serum levels by 5% to 15%, whereas niacin, the drug most widely used to increase high-density lipoprotein cholesterol, increases it by 25% to 35% at the highest doses. This review examines the potent methods of increasing high-density lipoprotein and/or enhancing reverse cholesterol transport, including cholesterol ester transfer protein inhibitors, apolipoprotein A-I Milano, D4F, the dual peroxisome proliferator-activated receptor agonists, and rimonabant, that are now in clinical trials. In conclusion, these new agents, used alone or in combination with existing therapies, carry the potential to markedly reduce the incidence of new coronary disease and cardiac events in this decade.

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; Cannabinoid Receptor Antagonists; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Humans; Lipoproteins, HDL; Peroxisome Proliferator-Activated Receptors; Piperidines; Pyrazoles; Rimonabant; Risk Factors

Atherogenic dyslipidemia is one of the major components of the metabolic syndrome, a complex cluster of several risk factors within a single patient that according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III includes at least 3 of the following: large waist circumference, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose levels, which are directly related to the incidence of coronary heart disease. Atherogenic dyslipidemia clinically presents as elevated serum triglyceride levels, increased levels of small dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL-C. An important component of atherogenic dyslipidemia is central obesity, which is defined as increased waist circumference and has recently been identified as a chief predictor of the metabolic syndrome in certain patients. Another recent study found that both body mass index and waist circumference were highly predictive of eventual development of the metabolic syndrome. Because atherogenic dyslipidemia usually precedes the clinical manifestation of the metabolic syndrome, strategies to treat it are the focus of pharmacologic intervention. For example, the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, commonly known as statins, benefit hypercholesterolemic patients who have atherogenic dyslipidemia that is associated with the metabolic syndrome. Pioglitazone, an antidiabetic agent that acts primarily by decreasing insulin resistance, improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. The investigational agent, rimonabant--a centrally and peripherally acting, selective cannabinoid type-1 receptor blocker--is the first therapy developed for managing several cardiovascular risk factors at one time. Rimonabant has shown promise in attacking atherogenic dyslipidemia from several vantage points by affecting glucose, HDL-C, triglycerides, and waist circumference in patients who are prone to atherogenic dyslipidemia.

Topics: Arteriosclerosis; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Diabetes Mellitus, Type 2; Drugs, Investigational; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Pioglitazone; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thiazolidinediones

Cardiovascular disease (CVD) is the leading cause of death of men and women in the United States. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing CVD and metabolic disease. Because visceral adipose tissue uniquely contributes to the pathophysiology of CVD and insulin resistance, waist circumference is now being considered as a more useful marker of potential health risks associated with overweight and obesity than body mass index. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, thereby reducing the risk of developing chronic disease and CVD.

Topics: Anti-Obesity Agents; Coronary Disease; Cyclobutanes; Exercise; Feeding Behavior; Humans; Intra-Abdominal Fat; Lactones; Metabolic Syndrome; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant

Topics: Aspirin; Biomedical Research; Coronary Disease; Drug Therapy, Combination; Drugs, Investigational; Human Experimentation; Humans; Interdisciplinary Communication; Multicenter Studies as Topic; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Professional Staff Committees; Quality of Health Care; Randomized Controlled Trials as Topic; Secondary Prevention

Despite the efficacy of intravenous glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention and those presenting with acute coronary syndromes, the application of oral glycoprotein IIb/IIIa inhibition to the chronic management of coronary artery disease has not met with the same success. To explain these results, factors related to dosing, and inadequate inhibition or activation of platelet pro-coagulant activity have been recently suggested. However, although the disparity between intravenous and oral glycoprotein IIb/IIIa experience remains largely enigmatic, the discordant effect on ischemic endpoints observed within the phase III oral glycoprotein IIb/IIIa inhibitor trials potentially implicates a mechanism unrelated to platelet function.

Topics: Administration, Oral; Alanine; Benzamidines; Coronary Disease; Humans; Integrins; Oximes; Piperidines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Randomized Controlled Trials as Topic

Numerous clinical trials have established the benefits of intravenous glycoprotein IIb/IIIa inhibition in the management of coronary artery disease. In contrast, the recent large-scale, placebo-controlled, randomized trials of the oral glycoprotein IIb/IIIa antagonists have failed to provide commensurate reductions in late composite ischemic end points despite potent inhibition of platelet aggregation.. The ORs for death, myocardial infarction, urgent revascularization, and major bleeding from the 4 large-scale, placebo-controlled, randomized trials with oral glycoprotein IIb/IIIa inhibitors were calculated and combined. Stratification by low-dose or high-dose therapy and the use of concurrent aspirin was also undertaken. In 33 326 patients followed for >30 days, a consistent and statistically significant increase in mortality was observed with oral glycoprotein IIb/IIIa therapy (OR, 1.37; 95% CI, 1.13 to 1.66; P:=0.001). This effect was evident regardless of aspirin coadministration and treatment with either low-dose or high-dose therapy. Although a reduction in urgent revascularization was observed with oral glycoprotein IIb/IIIa inhibition, pooled analysis favored an increase in myocardial infarction that did not demonstrate statistical significance.. Although we found a highly significant excess in mortality consistent across 4 trials with 3 different oral glycoprotein IIb/IIIa inhibitor agents, this was associated with a reduction in the need for urgent revascularization and no increase in myocardial infarction. These findings suggest the potential for a direct toxic effect with these agents and argue against a prothrombotic mechanism. Further investigation to elucidate the cause of this increased fatality risk is warranted.

Topics: Administration, Oral; Alanine; Aspirin; Benzamidines; Clinical Trials, Phase III as Topic; Coronary Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemorrhage; Humans; Incidence; Multicenter Studies as Topic; Myocardial Infarction; Oximes; Piperidines; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Randomized Controlled Trials as Topic

Topics: Abciximab; Antibodies, Monoclonal; Aspirin; Benzamidines; Clinical Trials as Topic; Clopidogrel; Coronary Disease; Cyclooxygenase Inhibitors; Diabetes Complications; Dipyridamole; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Endothelium, Vascular; Fibrinolytic Agents; Humans; Immunoglobulin Fab Fragments; Oximes; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prospective Studies; Randomized Controlled Trials as Topic; Stroke; Thrombosis; Thromboxane-A Synthase; Ticlopidine; Vasodilator Agents

Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of acute coronary syndromes as well as in the prevention of complications after percutaneous coronary interventions. Approximately 50,000 patients with coronary artery disease have been enrolled in randomized studies of glycoprotein IIb/IIIa inhibitors. The purpose of this article is to review the pharmacology of glycoprotein IIb/IIIa inhibitors, the results of the clinical trials using these agents, and their current use in percutaneous coronary interventions and the treatment of acute coronary syndromes.

Topics: Abciximab; Acetates; Acute Disease; Administration, Oral; Alanine; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Benzamidines; Coronary Disease; Eptifibatide; Hemorrhage; Humans; Immunoglobulin Fab Fragments; Myocardial Infarction; Oximes; Peptides; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Randomized Controlled Trials as Topic; Stents; Syndrome; Thrombocytopenia; Thrombolytic Therapy; Tirofiban; Tyrosine

Platelet aggregation plays a central role in the pathophysiology of acute coronary syndromes, and the platelet glycoprotein IIb/IIIa receptor has been identified as the critical final mediator of this process. Antagonists of this receptor used parenterally during both acute coronary syndromes and percutaneous coronary interventions reduce the likelihood of subsequent major cardiac complications. However, after the treatment period little further benefit accrues. Based on these observations and that of the significant benefit of aspirin in cardiovascular secondary prevention, oral glycoprotein IIb/IIIa receptor antagonists are being evaluated with the goal of extending the benefit of glycoprotein IIb/IIIa inhibition into chronic secondary prevention. This paper will review the results of the SYMPHONY study of one such oral agent, sibrafiban, and the current state of the oral glycoprotein IIb/IIIa inhibitor field.

Topics: Administration, Oral; Aspirin; Clinical Trials, Phase III as Topic; Coronary Disease; Humans; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic

Topics: Animals; Coronary Disease; Coronary Vessels; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Female; Humans; Piperidines; Raloxifene Hydrochloride; Tamoxifen

Serotonergic receptors have been identified in the blood vessels of the heart and in myocardial tissue. We indirectly examined the potential significance of these receptors by studying the properties of ketanserin, an S2-serotonergic antagonist. In an isolated rat heart preparation, ketanserin at 10(-6) M slowed the heart rate, whereas at 10(-5) M it also decreased the cardiac output. Because the stroke volume rose, a negative inotropic effect could be excluded. Electrophysiologically, ketanserin (10(-7) M or more) increased the action potential duration of the superfused guinea-pig papillary muscle preparation. This Class III effect may account for the antiarrhythmic action of ketanserin (5 X 10(-6) M-10(-5) M) in an ischemic-reperfused rat heart preparation. The possibility of nonspecific effects of ketanserin such as an interaction with alpha 1-adrenergic receptors merits careful evaluation, but in the case of the Class III effect, ketanserin was approximately 100 times more active than prazosin in widening the action potential duration. These data suggest that even high concentrations of ketanserin are unlikely to have harmful effects on the myocardium and might, on the contrary, have beneficial effects in the context of myocardial ischemia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Heart; Heart Rate; Humans; In Vitro Techniques; Ketanserin; Myocardial Contraction; Piperidines; Serotonin; Serotonin Antagonists; Sinoatrial Node

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Coronary Disease; Encainide; Flecainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Myocardial Infarction; Piperidines; Tachycardia; Tocainide; Ventricular Fibrillation

Topics: Administration, Oral; Anti-Arrhythmia Agents; Coronary Disease; Death, Sudden; Dose-Response Relationship, Drug; Humans; Infusions, Parenteral; Kinetics; Lidocaine; Myocardial Infarction; Piperidines; Propranolol

To demonstrate the noninferiority of alogliptin to acarbose, in terms of antidiabetic efficacy, in Chinese people with uncontrolled type 2 diabetes (T2D) and high cardiovascular risk.. ACADEMIC (NCT03794336) was a randomized, open-label, phase IV study conducted at 46 sites in China. Antidiabetic treatment-naive or metformin-treated adults with uncontrolled T2D (glycated haemoglobin [HbA1c] 58.0-97.0 mmol/mol) were randomized 2:1 to alogliptin 25 mg once daily or acarbose 100 mg three times daily for 16 weeks. All participants had a documented history of coronary heart disease or high cardiovascular risk at screening and received aspirin (acetylsalicylic acid) 100 mg daily throughout the trial. The primary endpoints were change in HbA1c versus baseline, and the incidence of gastrointestinal adverse events (AEs). Safety and tolerability were also assessed.. A total of 1088 participants were randomized. Alogliptin was noninferior to acarbose for the change in Week-16 HbA1c (least-squares mean change [standard error] -11.9 [0.4] vs. -11.4 [0.5] mmol/mol, respectively; difference between arms -0.5 [0.7] mmol/mol; 95% confidence interval -1.9 to 0.8 mmol/mol), and was associated with a lower incidence of gastrointestinal AEs (8.9% vs. 33.6%, respectively; P < 0.0001). More alogliptin than acarbose recipients achieved HbA1c <53.0 mmol/mol without gastrointestinal AEs (48.0% vs. 32.7%; P < 0.0001). Discontinuations due to treatment-related AEs were less frequent with alogliptin than acarbose (0.3% vs. 2.5%).. Glycaemic control was comparable between alogliptin and acarbose, but the gastrointestinal tolerability of alogliptin was better. More patients achieved target HbA1c without gastrointestinal AEs with alogliptin, suggesting that this agent may be preferred in clinical practice.

Topics: Acarbose; Adult; Aspirin; Coronary Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Metformin; Piperidines; Prospective Studies; Treatment Outcome; Uracil

It is skeptical about cardioprotective property of sevoflurane in patients undergoing noncardiac surgery, especially in the elderly patients with coronary heart disease. We hypothesized that long duration of sevoflurane inhalation in noncardiac surgery could ameliorate myocardial damage in such patients.. This was a randomized, prospective study. One hundred twenty-one elderly patients with coronary heart disease were randomly allocated into two groups. Maintenance of anesthesia was achieved by sevoflurane inhalation (Group S) or propofol-remifentanil respectively (Group PR). Serum cardiac troponin I (cTnI) and brain natriuretic peptide (BNP) were measured before anesthesia induction (T0), 8 h (T1) and 24 h (T2) after anesthesia respectively. The perioperative cardiac output, complications and postoperative 3-month follow-up from end of surgery were recorded.. Between the two groups, there were no statistical differences in the values of cTnI and BNP during the study. However, The area under the curve of cTnI values over 24 h after operation was less in Group S. Group PR had lower cardiac output and consumed more amount of phenylephrine during the study (P < 0.05).. Compared with the group PR, sevoflurane had no benefit in the myocardial protection for the elderly patients with CHD. However, Sevoflurane showed advantage in maintaining hemodynamic stability during the operative period.. Chinese Clinical Trial Registry, ChiCTR-IPR-16008871 , 21 July 2016.

Topics: Aged; Aged, 80 and over; Anesthetics, Inhalation; Anesthetics, Intravenous; Cardiac Output; Cardiotonic Agents; Coronary Disease; Drug Therapy, Combination; Female; Humans; Male; Methyl Ethers; Middle Aged; Natriuretic Peptide, Brain; Piperidines; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Troponin I

The baseline characteristics, complications, and survival of 489 black and 6,890 non-black patients with acute coronary syndromes were studied. Important racial differences were observed in demographic features, atherosclerosis risk factors, and treatment strategies; however, despite these differences, no independent difference was observed in clinical outcomes according to race. The 1-year mortality rate was 2.9% for black patients and 2.5% for non-black patients (p = 0.93).

Topics: Acute Disease; Aged; Black or African American; Coronary Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Multivariate Analysis; Oximes; Piperidines; Platelet Aggregation Inhibitors; Prognosis; Retrospective Studies; Risk Factors

Comparison of the length of mechanical ventilation and postoperative complications after coronary surgery in elderly patients anaesthetised with propofol associated with either alfentanil or remifentanil.. Retrospective study with an historic control group.. Three hundred thirty-eight consecutive patients (75-year-old or more) undergoing isolated coronary surgery. One hundred and fifty seven patients operated between January 1998 and June 2000 received alfentanil (1 microg/kg/minute) with a manually control infusion of propofol, 181 operated between July 2000 and 2002, remifentanil 0.25 microg/kg/minute with target controlled infusion of propofol (target blood concentration: 1.5 to 2 microg/ml).. The two groups were compared for preoperative and surgical data. The length of mechanical ventilation, stay in ICU and the main postoperative complications were compared between the two groups.. Length of mechanical ventilation was significantly reduced in the remifentanil group (6 +/- 9 h vs. 13 +/- 63 h ; p <0.0001), 70% of the patients were extubated before the 6th postoperative hours against 53% in the alfentanil group (p =0.0023). This was not associated with a reduction of stay in ICU or postoperative complications. During surgery, an increased used of vasopressor was observed in the remifentanil group (40.2% vs 2.4% ; p <0.0001) with a postoperative elevation of blood concentration of CKMb (35.7 +/- 38.2 microg/l, vs. 27.7 +/- 31.9 microg/l, p =0.02).. Elderly patients undergoing coronary surgery were extubated earlier with remifentanil. However, this had no effect on duration of ICU stay but was associated with an increased used of vasopressor.

Topics: Aged; Anesthetics, Intravenous; Coronary Disease; Humans; Infusions, Intravenous; Orthopedic Procedures; Piperidines; Postoperative Complications; Propofol; Remifentanil; Stroke; Treatment Outcome

Unstable coronary artery disease (CAD) is a multifactorial disease involving both thrombotic and inflammatory processes. We have assessed the time-course and the influence of thrombin inhibitors on changes in fibrinogen and C-reactive protein levels, and their relation to myocardial ischaemia in unstable CAD.. Three hundred and twenty patients were randomized to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor, or unfractionated heparin. There were no significant differences between the treatment groups in fibrinogen or C-reactive protein levels. Overall, the fibrinogen levels were significantly increased in the first 24-96 h and still elevated at 30 days. The C-reactive protein levels showed a more pronounced increase during the first 24-96 h, but then markedly decreased over 30 days. Troponin-positive compared to troponin-negative patients had higher fibrinogen and C-reactive protein levels up to 96 h, although there was an increase compared to pre-treatment levels in both groups. A high fibrinogen level (pre-treatment top tertile) was associated with an increased rate of death or myocardial (re-)infarction at 30 days, 13% vs 5.6%, P=0.03, and increased long-term mortality. A high C-reactive protein level was related to increased 30-day mortality, 4% vs 0%, P=0.01.. Myocardial cell injury was related to a high degree of inflammation, only some of which is an acutephase response due to tissue damage. The rise in fibrinogen was sustained, which might reflect low grade inflammation with long-term risk of thrombosis. The transient elevation of C-reactive protein levels might indicate a propensity to a pronounced inflammatory response and is associated with increased mortality.

Topics: Adult; Aged; Aged, 80 and over; Antithrombins; C-Reactive Protein; Coronary Disease; Female; Fibrinogen; Follow-Up Studies; Glycine; Humans; Male; Middle Aged; Myocardial Infarction; Myocarditis; Piperidines; Survival Analysis; Troponin T

This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.. Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.. Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Aspirin; Benzodiazepines; Cerebrovascular Disorders; Coronary Disease; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Proportional Hazards Models; Risk Assessment; Treatment Outcome

We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

Topics: Acute Disease; Aspirin; Causality; Coronary Disease; Coronary Thrombosis; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Oximes; Piperidines; Platelet Aggregation Inhibitors; Postoperative Complications; Stents; Syndrome

The first Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) trial showed no benefit of 2 doses of sibrafiban over aspirin for secondary prevention after acute coronary syndromes. In 2nd SYMPHONY, we compared low-dose sibrafiban plus aspirin (LDS+A), high-dose sibrafiban (HDS), and aspirin alone.. When the first SYMPHONY results became known, enrollment in 2nd SYMPHONY was stopped prematurely at 6671 patients who had been treated for a median of 90 days. The primary end point of death, myocardial (re)infarction (MI), or severe recurrent ischemia did not differ significantly between aspirin (9.3%) and LDS+A (9.2%; OR, 0.98; 95% CI, 0.80 to 1.20) or HDS (10.5%; OR, 1.14; 95% CI, 0.9 to 1.39) patients. Secondary end points did not differ significantly between aspirin and LDS+A patients. Death or MI occurred significantly more often with HDS (OR, 1.43; 95% CI, 1.14 to 1.80), as did mortality alone (OR, 1.83; 95% CI, 1.17 to 2.88) and MI (OR, 1.32; 95% CI, 1.03 to 1.69). Major bleeding was significantly more frequent in LDS+A patients (5.7%) versus aspirin alone (4.0%) but not in HDS patients (4.6%).. Combining aspirin with LDS did not improve outcomes after acute coronary syndromes and caused more bleeding compared with aspirin alone. There was a trend toward increased mortality in this group and a significant increase in the high-dose arm.

Topics: Aged; Aspirin; Cause of Death; Coronary Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Myocardial Ischemia; Neovascularization, Physiologic; Oximes; Piperidines; Treatment Failure

The performance of the cardiovascular system depends on the interaction of the left ventricle and arterial system. An appropriate coupling of these two components is important to quantify the efficiency of myocardium, determined by Ea/Ees. The end-systolic elastance of the left ventricle (Ees) is an index of contractility which is independent of loading conditions, while the arterial end-systolic elastance (Ea) represents the properties of the arterial system. The aim of our study is to investigate the effects of a bolus of remifentanil (R) on myocardial efficiency.. In a period of 3 months we examined prospectively the effects of R in a group of 12 patients, ASA IV, 49-75 years old, submitted intraoperatively to cardiac anesthesia for revascularization of myocardium. After induction of anesthesia and before the beginning of surgery, a bolus of R (1 mg/kg/min) was administered and with the use of trans-esophageal echocardiography we determined both the left ventricle end-systolic volume and end-diastolic volume to assess, with different end-systolic arterial pressures, the ventricle elastance (Ees) and arterial elastance (Ea) before and after administration of R.. The present findings indicate that R decreases the ventricular elastance from 6.07 mmHg/ml/m2 to 4.8, with a less decrease of arterial elastance from 3.69 mmHg/ml/m2 to 3.07.. The results suggest that R preserves a good left ventricular-arterial coupling and mechanical efficiency, despite a little increase of coupling, probably because ventricular and arterial properties are so matched as to minimize the systolic work of the left ventricle.

Topics: Aged; Anesthetics, Intravenous; Aorta; Cardiovascular Agents; Combined Modality Therapy; Coronary Artery Bypass; Coronary Disease; Echocardiography, Transesophageal; Electric Impedance; Female; Heart Failure; Heart Rate; Hemorheology; Humans; Injections, Intravenous; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Oxygen Consumption; Piperidines; Propofol; Prospective Studies; Remifentanil; Stroke Volume; Thiopental; Vascular Resistance; Vecuronium Bromide; Ventricular Function, Left

Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease.. Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%.. -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

Topics: Administration, Oral; Aged; Benzodiazepines; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemorrhage; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombocytopenia; Treatment Outcome

Patients with unstable coronary syndromes are a heterogeneous group with varying degrees of ischemia and prognosis. The present study compares the prognostic value of a standard electrocardiogram (ECG) obtained at admission to the hospital with the information from 24-hour continuous electrocardiographic monitoring obtained immediately after admission. The admission ECGs and 24 hours of vectorcardiographic (VCG) monitoring from 308 patients admitted with unstable coronary artery disease were analyzed centrally regarding standard electrocardiographic ST-T changes, ST-vector magnitude (ST-VM), and ST change vector magnitude episodes. End points were death, acute myocardial infarction, and refractory angina pectoris within a 30-day follow-up period. ST-VM episodes (> or = 50 microV for > or = 1 minute) during VCG monitoring was the only independent predictor of death or acute myocardial infarction by multivariate analysis. ST-VM episodes during vectorcardiography was associated with a relative risk of 12.7 for having a cardiac event, hypertension was associated with a relative risk of 1.7, and ST depression on the admission ECG was associated with a relative risk of 5.7. Patients with ST depression at admission had an event rate (death or acute myocardial infarction) of 17% at 30-day follow-up. Patients without ST depression could further be risk stratified by 24 hours of VCG monitoring into a subgroup with ST-VM episodes at similar (8%) risk and a subgroup without ST-VM episodes at low (1%) risk (p = 0.00005). Continuous VCG monitoring provides important information for evaluating patients with unstable coronary artery disease. It is recommended that patients not initially estimated at high risk based on the admission ECG are referred for 24 hours of VCG monitoring for further risk stratification.

Topics: Aged; Angina Pectoris; Angina, Unstable; Anticoagulants; Antithrombins; Coronary Disease; Electrocardiography; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Glycine; Heparin; Humans; Hypertension; Male; Multivariate Analysis; Myocardial Infarction; Myocardial Ischemia; Patient Admission; Piperidines; Prognosis; Recurrence; Risk Assessment; Risk Factors; Survival Rate; Vectorcardiography

A multicentre study permits rapid recruitment of a large number of patients. However, there is a risk of heterogeneities in end-point evaluations, as complex definitions of criteria are interpreted by several local investigators from different hospitals. Reports discussing end-point evaluation are sparse. The TRIM trial was a multicentre trial of a thrombin inhibitor in patients with unstable angina or non-Q myocardial infarction. In this study, an independent end-point committee evaluated all the reported events of death, acute myocardial infarction and refractory angina pectoris in order to obtain uniform judgements of major end-points.. To describe the work of the end-point committee, to analyse its possible effect on the final study results and to discuss the impact on the design of future trials.. The end-point committee consisted of four members, one from each participating country. After the data were processed by the study monitors, completed case record forms and patient files for patients with reported end-points were mailed to the national member of the end-point committee for judgement. The end-point committee met regularly and made final decisions about the end-points. The work of the end-point committee was documented on a separate case record form.. The end-point committee assessed 246 events of death, acute myocardial infarction and refractory angina pectoris in 187 of the 1209 patients (15.5%) in the TRIM trial. Misinterpretation of the index event, an inclusion myocardial infarction, as an early cardiac event was found in 12 patients. After end-point committee judgements, the number of patients with acute myocardial infarction or refractory angina pectoris during 30 days of follow-up was reduced from 177 to 153 (13. 6% reduction). The classification of events was changed in 53 of 187 patients (28.3%) with death, acute myocardial infarction or refractory angina pectoris. The data assessed by the safety committee was significantly different from the final database after end-point committee judgements.. The end-point committee corrected misinterpretations in such a high proportion of cases that the final results differed significantly from the preliminary results delivered to the safety committee. End-point judgements by an end-point committee should be performed in multicentre clinical trials to improve the quality and reliability of study results.

Topics: Anticoagulants; Antithrombins; Coronary Disease; Data Collection; Double-Blind Method; Glycine; Heparin; Humans; Multicenter Studies as Topic; Outcome Assessment, Health Care; Piperidines; Randomized Controlled Trials as Topic; Survival Analysis

We investigated whether the addition of 24 h of continuous vectorcardiography ST segment monitoring (cVST) for an early (within 24 h of the latest episode of angina) determination of cardiac troponin T (cTnT) could provide additional prognostic information in patients with unstable coronary artery disease (UCAD), i.e., unstable angina and non-Q wave myocardial infarction.. Determination of cTnT at admission and cVST are individually reported to be valuable techniques for the risk assessment of patients with UCAD.. Two hundred and thirty-two patients suspected of UCAD were studied. Patients were followed for 30 days, and the occurrence of cardiac death or acute myocardial infarction (AMI) were registered.. One ST segment episode or more (relative risk [RR] 7.43, p = 0.012), a cTnT level > or = 0.20 microg/liter (RR 3.85, p = 0.036) or prestudy medication with calcium antagonists (RR 3.31, p = 0.041) were found to carry independent prognostic information after multivariate analysis of potential risk variables. By combining a cTnT determination and subsequent cVST for 24 h, subgroups of patients at high (25.8%) (n = 31), intermediate (3.1%) (n = 65) and low risk (1.7%) (n = 117) of death or AMI could be identified.. Twenty-four hours of cVST provides additional prognostic information to that of an early cTnT determination in patients suspected of having UCAD. The combination of biochemical and electrocardiographic methods provides powerful and accurate risk stratification in UCAD.

Topics: Adult; Aged; Aged, 80 and over; Angina, Unstable; Antithrombins; Coronary Disease; Death, Sudden, Cardiac; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Electrocardiography, Ambulatory; Female; Glycine; Humans; Male; Middle Aged; Myocardial Infarction; Patient Admission; Piperidines; Prognosis; Prospective Studies; Risk Assessment; Troponin T; Vectorcardiography

Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once- or twice-daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 +/- 1.0 (mean +/- SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 +/- 15 L/h, and the elimination half-life was 2.3 +/- 0.8 hours. Mean values of the steady-state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 +/- 1.7 hours; apparent clearance, 13.9 +/- 3.9 L/h; and half-life, 11.0 +/- 2.8 hours. Once-daily dosing resulted in high peak-trough excursions in active drug concentrations: trough concentrations were 21% +/- 6% of peak. Twice-daily dosing resulted in an AUC for the active drug on Day 28 that was 168% +/- 36% of that on Day 1, and steady-state trough concentrations were 54% +/- 10% of peak with sustained inhibition of platelet aggregation. Dose-adjusted steady-state active drug concentrations increased with increasing age and with decreasing renal function and body weight.

Topics: Acute Disease; Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Amidines; Area Under Curve; Body Weight; Coronary Disease; Double-Blind Method; Female; Glomerular Filtration Rate; Heterocyclic Compounds; Humans; Male; Metabolic Clearance Rate; Middle Aged; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prodrugs; Syndrome

In a prospective, randomized study, sevoflurane-remifentanil (Group SR) was compared with fentanyl-etomidate (Group FE) for induction of anaesthesia in patients with ischaemic heart disease. Cardiovascular stability, heart rate, mean arterial pressure, rate pressure product, rescue medications and associated myocardial ischaemia were measured. For Group SR (n = 20), anaesthesia was induced with vital capacity breaths of sevoflurane 5% in oxygen. After loss of consciousness, the inspired sevoflurane was reduced to 3% and remifentanil was administered as a 0.5 microgram.kg-1 bolus over 90 seconds (0.33 microgram.kg-1.min-1) followed by a 0.025 microgram.kg-1.min-1 infusion. After intubation, the inspired sevoflurane was reduced to 2%. For Group FE (n = 20), anaesthesia was induced with fentanyl 10.5 micrograms.kg-1 and etomidate 0.2 mg.kg-1 given 60 seconds later. Isoflurane 1% in oxygen was administered after loss of consciousness. Both groups received rocuronium and the trachea was intubated two minutes later. Sevoflurane gaseous induction was smooth, with cardiovascular stability comparable to fentanyl-etomidate. Significantly more patients in Group SR (P < 0.05) were on beta-blocking medication, and, overall, the HR and RPP was lower pre-intubation in Group SR. Remifentanil administration was associated with severe bradycardia in three patients and asystole in a fourth. All four patients were on beta-blocking medication and three of the four were on diltiazem. The study was terminated due to the high incidence of bradycardic/asystolic complications in Group SR.

Topics: Adrenergic beta-Antagonists; Analgesics, Opioid; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Coronary Artery Bypass; Coronary Disease; Etomidate; Female; Fentanyl; Heart Rate; Humans; Intubation, Intratracheal; Male; Methyl Ethers; Middle Aged; Piperidines; Prospective Studies; Remifentanil; Sevoflurane

Aims Direct thrombin inhibitors have failed to prove superiority over unfractionated heparin in several clinical trials of unstable coronary artery disease. We have investigated the relationship between activated partial thromboplastin time levels and adverse clinical events, i.e. death, myocardial (re-)infarction or refractory angina. Methods and Results One thousand two hundred and nine patients with unstable coronary artery disease were randomized to 72 h infusion with inogatran, a low molecular mass direct thrombin inhibitor, or unfractionated heparin. During 30 days follow-up there was no significant difference between inogatran and unfractionated heparin treatment as regards clinical outcome. 11.6% of the 464 inogatran treated patients with activated partial thromboplastin time above the median at 6 h (44 s) had a clinical event in 7 days, and 6.6% of the 423 patients with activated partial thromboplastin time below the median (P=0.01). After 30 days the event rate was still 41% higher in the inogatran patients with activated partial thromboplastin time above the median (P=0.06). Activated partial thromboplastin time in quartiles indicated a direct relationship between higher activated partial thromboplastin time and worse outcome. In contrast, during heparin infusion there was a trend for improved clinical outcome with activated partial thromboplastin time above the median, but this benefit was lost after cessation of treatment.. Higher activated partial thromboplastin time levels during inogatran treatment are related to increased risk of death, myocardial infarction or refractory angina. This might, at least in part, be explained by differences in anticoagulant mechanisms between direct thrombin inhibitors and heparin, and further emphasizes the poorly defined optimal activated partial thromboplastin time range during treatment with direct thrombin inhibitors in unstable coronary artery disease.

Topics: Adult; Aged; Aged, 80 and over; Angina, Unstable; Antithrombins; Cause of Death; Coronary Disease; Dose-Response Relationship, Drug; Female; Glycine; Heparin; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Piperidines; Survival Rate; Thrombin; Treatment Outcome

Inhibitors of the platelet glycoprotein IIb/IIIa receptor given intravenously have been shown to be effective in reducing ischemic complications after coronary angioplasty and in unstable angina, making this a promising new class of agents for the treatment and prevention of ischemic events in patients with acute coronary syndromes. Sibrafiban (Ro 48-3657) is an oral, peptidomimetic, selective antagonist of the glycoprotein IIb/IIIa receptor.. The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 329 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibition were achieved: mean peak values ranged from 47% to 97% inhibition of 20 micromol/L ADP-induced platelet aggregation on day 28 across the seven doses. Twice-daily dosing provided more sustained platelet inhibition (mean inhibition, 36% to 86% on day 28), whereas platelet inhibition returned to baseline levels by 24 hours with once-daily dosing. Major hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined "minor" bleeding, usually mucocutaneous, occurred in 0% to 32% of patients in the various sibrafiban groups and in none of the patients treated with aspirin. Minor bleeding was related to total daily dose (P=.002), once- versus twice-daily dosing (P<.0001), renal function (P<.0001), and presentation with unstable angina (P<.01).. The oral glycoprotein IIb/IIIa antagonist sibrafiban achieved effective, long-term platelet inhibition with a clear dose-response but at the expense of a relatively high incidence of minor bleeding. Oral IIb/IIIa inhibition deserves further study as a new treatment strategy in patients after acute coronary syndromes.

Topics: Acute Disease; Administration, Oral; Aged; Cohort Studies; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemorrhage; Humans; Male; Middle Aged; Oximes; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recurrence

Studies have demonstrated that troponin T is a strong independent indicator of a poor prognosis in patients with unstable coronary artery disease. Up to the present, no study has compared the prognostic value of troponin T with that of troponin I in the same cohort of patients.. Patients (n=516) suspected of having unstable coronary artery disease were investigated. Follow-up was done after 30 days, and the occurrences of cardiac death, acute myocardial infarction, refractory angina pectoris, and recurrent angina pectoris were registered. Elevated levels of troponin T (> or = 0.10 microg/L) were associated with an increased risk of cardiac death at 30 days compared with patients with normal levels, 3.2% versus 0.4% (P=.014). Troponin I values above the chosen cutoff (2.0 microg/L) were similarly found to be an indicator of increased risk of cardiac death, 3.2% versus 0.7% (P=.026). With regard to the composite end point of cardiac death/acute myocardial infarction, the troponins were strong independent indicators of adverse outcome.. In patients suspected of having unstable coronary artery disease, both troponin T and troponin I provide independent prognostic information with regard to cardiac death and acute myocardial infarction.

Topics: Adult; Aged; Antithrombins; Cohort Studies; Coronary Disease; Female; Glycine; Heparin; Humans; Male; Middle Aged; Multivariate Analysis; Myocardium; Outcome Assessment, Health Care; Piperidines; Prognosis; Prospective Studies; Troponin; Troponin I; Troponin T

The present study was designed to evaluate the potential anti-ischaemic activity of R 56865 in patients with coronary artery disease, scheduled to undergo percutaneous transluminal coronary angioplasty (PTCA). At baseline a complete haemodynamic profile, including cardiac output and coronary sinus blood flow (CSBF) was obtained. In addition, left ventricular pressure and contractility parameters were measured. These parameters were also measured before and after additional balloon inflations, preceded by placebo and R 56865 i.v. R 56865 was infused intravenously at three different dosages, namely: 20 mg (n = 8), 30 mg (n = 2), 40 mg (n = 2). No significant differences were observed between placebo and R 56865 (20 mg) concerning time to onset and duration of ST-segment changes and symptomatic angina pectoris, respectively. The other parameters did not show differences compared with the baseline values when R 56865 (20 and 30 mg) was infused. However, the two patients receiving a dose of 40 mg R 56865 developed a dramatic decrease in systolic and diastolic blood pressure, left ventricular (LV) systolic pressure, peak positive dP/dt and the CSBF (ranging from 30-50%), while the LV end-diastolic pressure increased by 100%. The two patients who received this dose became pale and cyanotic and did not respond to verbal commands. In summary, no anti-ischaemic effects of R 56865 were observed under these conditions, whereas at the highest dose (40 mg) R 56865 induced hypotension and a reduction in cardiac contractile force.

Topics: Angioplasty, Balloon, Coronary; Benzothiazoles; Blood Gas Analysis; Blood Pressure; Calcium Channel Blockers; Cardiac Output; Coronary Circulation; Coronary Disease; Female; Humans; Male; Myocardial Contraction; Piperidines; Thiazoles; Ventricular Function, Left

The haemodynamic effects of roxatidine were investigated in 12 patients with congestive heart failure (New York Heart Association class II) in a placebo-controlled, double-blind, randomized, cross-over study. Impedance and mechanocardiography were determined following successive 7-day treatment periods with placebo and roxatidine 150 mg once daily. Comparison with placebo values showed roxatidine to significantly increase the preejection period (109.7 +/- 2.7 ms versus 117.3 +/- 2.7 ms, 1.5 h after administration). Heart rate and blood pressure remained the same. In contrast to other, newer H2-receptor antagonists, which decrease stroke volume and/or cardiac output, roxatidine did not reduce these parameters but increased the preejection period and the ratio of the preejection period to the left ventricular ejection time, indicating a slight negative influence on cardiac performance.

Topics: Blood Pressure; Cardiac Output; Coronary Disease; Double-Blind Method; Electrocardiography; Heart Failure; Heart Rate; Hemodynamics; Histamine H2 Antagonists; Humans; Middle Aged; Piperidines; Stroke Volume

The acute haemodynamic effects of pirmenol, a new Class 1 antiarrhythmic agent, were investigated in a double-blind comparison with lidocaine and placebo. Three groups of 10 patients each received either pirmenol as a 50 mg intravenous injection followed by a 2.5 mg min-1 infusion, or lidocaine as a 75 mg injection followed by a 3 mg min-1 infusion, or placebo. Mean plasma pirmenol concentrations during the 30 min infusion period were 2.3-2.5 mg l-1, and were considered to be therapeutically effective. Compared to measurements taken during a baseline phase of 15 min duration, pirmenol increased heart rate by 10 beats min-1 (P less than 0.001) and mean arterial pressure (MAP) by 5 mmHg (P less than 0.001). It also increased systemic vascular (P less than 0.05) and pulmonary arterial resistances (P less than 0.01). Left ventricular end-diastolic pressure (LVEDP) was not increased significantly. Cardiac index and left ventricular work index remained unchanged. Lidocaine induced a comparable increase in MAP (6 mmHg; P less than 0.001) and elevated LVEDP (2.8 mmHg; P less than 0.05) and did not affect left ventricular work index. Echocardiographic left ventricular ejection fraction was reduced more by pirmenol (-0.05; P less than 0.001) than by lidocaine (-0.03; P less than 0.05), but the greater reduction may partly be explained by the increase in heart rate. Primenol did not induce excessive circulatory responses or side-effects in any patient. Intravenous administration of pirmenol results in increased heart rate and afterload but has little effect on preload. The myocardial depressant effect is relatively slight, and comparable to that of lidocaine.

Topics: Adult; Analysis of Variance; Anti-Arrhythmia Agents; Clinical Trials as Topic; Coronary Disease; Double-Blind Method; Female; Hemodynamics; Humans; Lidocaine; Male; Middle Aged; Myocardial Infarction; Piperidines

We assessed the antiarrhythmic effectiveness, therapeutic plasma concentrations and adverse effects of pirmenol in 16 patients with frequent (mean 933 h-1) premature ventricular complexes (PVC). Progressive increase in dose to a maximum of 200 mg twice daily suppressed PVC in a majority of patients. By preset criteria 11 patients (69%) exhibited an effective suppression of PVCs whereas in 5 patients (31%) the suppression was inadequate despite therapeutic plasma concentrations. The responders exhibited an 87% mean reduction of PVCs and a 97% reduction in repetitive PVC. This therapeutic effectiveness was verified against placebo by repetitive 24-hour ECG monitorings recorded in a double-blind cross-over fashion. The plasma trough concentration during the effective dose averaged 1.31 +/- 0.67 mg-1 (SD). The efficacy was maintained with the twice daily regimen despite an elimination half life of 6.3 +/- 1.7 h (SD) but a slight decrease in PVC suppression was observed towards the end of the administration interval. Pirmenol was well tolerated but aggravation of the arrhythmia occurred in one patient who shared an associated excessive prolongation of the Q-T interval, a feature observed with quinidine-like class I agents.

Topics: Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Electrocardiography; Female; Humans; Kinetics; Male; Myocarditis; Piperidines; Tachycardia

Flecainide, a new antiarrhythmic agent with poorly defined hemodynamic actions, was studied in 22 patients with coronary artery disease. Intravenous infusions of 1 mg/kg and 2 mg/kg resulted in respective increases in right atrial pressure (12%, p less than 0.05; 15%, p less than 0.01), mean pulmonary artery pressure (27%, p less than 0.01; 28%, p less than 0.01), and pulmonary capillary wedge pressure (44%, p less than 0.05; 33%, p less than 0.01). Cardiac index decreased 8% (p less than 0.05) after 1 mg/kg flecainide and 12% (p less than 0.05) after the 2 mg/kg dose. The mean left ventricular ejection fraction decreased by 15% (p less than 0.01) and 16% (p less than 0.01), respectively, 10 minutes after 1 mg/kg and 2 mg/kg of flecainide. Minimal increases in the heart rate (less than 5%) and no significant change in arterial pressure occurred 5 to 10 minutes after flecainide and were associated with borderline and variable increases in pulmonary and systemic vascular resistances. Flecainide diluent did not induce changes in pulmonary capillary wedge pressure or left ventricular ejection fraction. Thus, flecainide exerts a moderate but significant negative inotropic effect which may be clinically significant in patients with severely compromised ventricular function.

Topics: Adult; Aged; Blood Pressure; Coronary Disease; Double-Blind Method; Flecainide; Heart; Heart Rate; Hemodynamics; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Pulmonary Wedge Pressure; Radionuclide Imaging; Stroke Volume; Vascular Resistance

This study was designed to test the hypothesis of a possible role of serotonin in the pathogenesis of myocardial ischemia in patients with pure vasospastic angina, since serotonin is known to cause contraction in isolated coronary arteries. This effect, as well as serotonin-induced platelet aggregation, is reversed by ketanserin, a specific S2-receptor blocker. Five male patients (49 to 68 years old) with more than six episodes/day of myocardial ischemia at rest as characterized by ST segment elevation on the electrocardiogram (ECG) were selected for the study after a 2 day run-in period of continuous ECG Holter monitoring in the absence of any therapy except that with sublingual nitrates. In a double-blind crossover protocol they received consecutive infusions of 6 hr each of ketanserin (2 mg/hr iv, preceded by a 10 mg bolus in three patients) and placebo in the following sequence: ketanserin-placebo-ketanserin-placebo in the first and placebo-ketanserin-placebo-ketanserin in the second 24 hr period. The efficacy of the infused drug was tested by exposing platelet-rich plasma, obtained from the study patients at a fixed morning time before and during ketanserin infusions, to a series of serotonin concentrations from 10(-5) to 10(-8)M in a conventional aggregometer. A complete suppression of aggregation curves in the range of serotonin concentrations tested resulted during administration of ketanserin. The efficacy of the drug in preventing ischemic episodes was assessed by computing the ischemic episodes (recorded by Holter monitoring) and nitroglycerin consumption in each 6 hr ketanserin period and in the corresponding placebo period. A total of 171 ischemic episodes were recorded, 33 of which (19%) were symptomatic.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Angina Pectoris, Variant; Coronary Disease; Coronary Vasospasm; Double-Blind Method; Drug Evaluation; Hemodynamics; Humans; Ketanserin; Male; Middle Aged; Piperidines; Placebos; Platelet Aggregation; Serotonin; Serotonin Antagonists

In 12 patients with coronary artery disease, 11 of them with previous myocardial infarction, the antiarrhythmic effects of orally administered flecainide (F.), mexiletine (M.) and propafenone (P.) were examined. The doses amounted to 400 mg F., 600 mg M., and 900 mg P. daily. The administration was made randomized with a change between placebo and verum periods with a duration of 3 respectively 4 days. The 3 antiarrhythmic agents reduced significantly the number of ventricular premature beats (VPB), the reduction of VPB amounted to 94.2% (F.), 80.2% (P.), and 52.8% M.). Repetitive VPB were reduced about 98.8 % (F.), 96.8% (P.) and 83.33% (M.). The Lown-Index diminished by about 1.45 classes (F.) 1.18 classes (P.) respectively 0.55 classes (M.). A complete suppression of VPB was obtained only in one patient under medication with F. F. and P. lengthened the duration of P, PQ and QRS, whereas M. did not affect these parameters. Heart rate and QT remained unchanged. Subjective side-effects of the 3 agents were similar. Without of the influence on the ECG, objective side effects were missed. The long plasma half-life of F. (19.0 +/- 5.2 h) guarantees an antiarrhythmic effect over a period of 24 hours if the substance is administered twice daily. The large variance of plasma half-life can cause some difficulties in the finding of individually required dose of F.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Complexes, Premature; Coronary Disease; Electrocardiography; Flecainide; Half-Life; Heart Rate; Heart Ventricles; Humans; Mexiletine; Middle Aged; Myocardial Infarction; Piperidines; Propafenone; Propiophenones

In a blind cross-over study, 12 patients with ventricular arrhythmias (VPC's; Lown Grades II-IVB) resistant to a daily dose of quinidine 1.2 g, disopyramide 0.8 g, N-propyl-ajmaline 0.1 g were randomly given, each dose for one week, placebo (PL), mexiletine (MEX; 400, 600, 800 mg daily) and lorcainide (LOR; 200, 300, 400 mg daily). On the last day of each treatment period, patients were evaluated by 24-h continuous ambulatory monitoring, 6-channel surface ECG, plasma concentrations and side-effects. During PL I (before) and PL II (after drug treatment), the mean number of VPCs per hour was 670 and 701. VPCs were reduced in 5 of the 12 patients with MEX by 43% (400 mg), 74% (600 mg) and 91% (800 mg). VPCs were reduced in 10 patients with LOR by 60% (200 mg), 78% (300 mg) and 93% (400 mg). Log. lin. plasma conc. effect relationships were constructed for MEX and LOR. Vomiting, nausea, and abdominal pain were seen in 2 patients with MEX; insomnia and feeling heat in 10 patients with LOR. At the end of the LOR-treatment, these side-effects were less in 5 and absent in 5 patients. In this study, LOR seems superior to MEX in refractory ventricular arrhythmias.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Coronary Disease; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Failure; Heart Ventricles; Humans; Male; Mexiletine; Middle Aged; Mitral Valve Prolapse; Piperidines; Propylamines; Random Allocation

Topics: Aged; Anti-Arrhythmia Agents; Clinical Trials as Topic; Coronary Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines

Topics: Angina Pectoris; Clinical Trials as Topic; Coronary Disease; Humans; Perhexiline; Physical Exertion; Piperidines; Placebos

In 15 patients with angiographically proven coronary heart disease and reproducible exercise induced ischemic ST-segment depression the antianginal effect of Perhexilinmaleat was tested in a cross-over randomized double-blind trial. The patients were treated 4 weeks with a placebo, 2 weeks with 200 mg and 2 weeks with 400 mg/day Perhexilinmaleat. The exercise-induced ischemic ST-segment depression was significantly reduced (p less than 0.001) by Perhexilinmaleat. This calcium-antagonist drug also prolonged the PQ-interval and reduced the heart rate during exercise. Some liver specific enzymes were slightly elevated. These and other side effects more often occurred at the higher dose of 400 mg/day.

Topics: Coronary Disease; Electrocardiography; Heart Rate; Humans; Liver; Male; Perhexiline; Physical Exertion; Piperidines

Topics: Administration, Oral; Aged; Alanine Transaminase; Angina Pectoris; Animals; Arrhythmias, Cardiac; Aspartate Aminotransferases; Clinical Trials as Topic; Coronary Disease; Dose-Response Relationship, Drug; Drug Evaluation; Electrocardiography; Female; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Contraction; Nitroglycerin; Oxygen Consumption; Perhexiline; Piperidines; Prognosis

Topics: Adult; Aged; Angina Pectoris; Clinical Trials as Topic; Coronary Disease; Female; Humans; Male; Maleates; Middle Aged; Perhexiline; Piperidines; Vasodilator Agents

Topics: Adult; Aged; Benzoates; Body Weight; Cholesterol; Clinical Trials as Topic; Coronary Disease; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Middle Aged; Piperidines; Sulfonic Acids; Triglycerides; Uric Acid

Topics: Adult; Aged; Clinical Trials as Topic; Coronary Disease; Female; Humans; Male; Middle Aged; Nitroglycerin; Perhexiline; Piperidines; Prenylamine; Vasodilator Agents

Topics: Aged; Clinical Trials as Topic; Coronary Disease; Female; Humans; Male; Middle Aged; Nitroglycerin; Perhexiline; Piperidines; Vasodilator Agents

Topics: Angina Pectoris; Clinical Trials as Topic; Coronary Disease; Female; Humans; Male; Perhexiline; Piperidines; Vasodilator Agents

Topics: Angina Pectoris; Clinical Trials as Topic; Coronary Disease; Enzyme Induction; Enzymes; Humans; Perhexiline; Piperidines; Time Factors; Vasodilator Agents

Topics: Aged; Arrhythmias, Cardiac; Clinical Trials as Topic; Coronary Disease; Electrocardiography; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Vasodilator Agents

Topics: Adult; Aged; Coronary Disease; Electrocardiography; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Placebos; Vasodilator Agents

Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may inhibit glucose uptake. The objective of the study was to investigate if ET (selective ET(A) and dual ET(A)+ET(B)) receptor blockade improves insulin sensitivity in patients with insulin resistance and coronary artery disease.. Seven patients (aged 58 +/- 2 years) with insulin resistance and coronary artery disease completed three hyperinsulinemic-euglycemic clamp protocols: a control clamp (saline infusion), during ET(A) receptor blockade (BQ123), and during combined ET(A) (BQ123) and ET(B) receptor blockade (BQ788). Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by infusions of cardiogreen and p-aminohippurate.. Total-body glucose uptake (M) differed between the clamp protocols with the highest value in the BQ123+BQ788 clamp (P < 0.05). The M value corrected by insulin was higher in the BQ123+BQ788 than in the control clamp (P < 0.01) or the BQ123 clamp (P < 0.05). There was no difference between the control clamp and the BQ123 clamp. Mean arterial pressure did not change during the control clamp, whereas it decreased during both the BQ123 (P < 0.01) and BQ123+BQ788 (P < 0.05) clamps. RBF increased and renal vascular resistance decreased in the BQ123+BQ788 clamp (P < 0.05) but not in the BQ123 clamp. There was no change in SBF in either clamp.. Dual ET(A)+ET(B) receptor blockade acutely enhances insulin sensitivity in patients with insulin resistance and coronary artery disease, indicating an important role for endogenous ET-1.

Topics: Antihypertensive Agents; Blood Glucose; Blood Pressure; Coronary Disease; Diabetes Mellitus, Type 2; Endothelin Receptor Antagonists; Glucose Clamp Technique; Glucose Intolerance; Heart Rate; Humans; Insulin; Insulin Resistance; Middle Aged; Obesity; Oligopeptides; Peptides, Cyclic; Piperidines

Recent trials reveal no benefit and possible harm from chronic hormone replacement therapy (HRT). Less is known about intermediate-term outcomes associated with HRT use in the setting of acute coronary syndromes (ACS).. To examine the prevalence of HRT use and relationships with intermediate-term outcomes among women with ACS, we classified as HRT users or nonusers 4029 postmenopausal women (age > 50 years or postmenopausal by case report form) randomized in the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) and 2nd SYMPHONY trials. Outcomes included 90-day and 1-year death and 90-day stroke, death, or myocardial infarction (MI); death, MI, or stroke; and death, MI, or severe recurrent ischemia (SRI).. HRT use was 13% overall and varied by region (Asia, 0%; Eastern Europe, 0.2%; Latin America, 0.8%; Western Europe, 4%; Australia/New Zealand, 12%; Canada, 14%; United States, 24%); estrogen-only regimens were most common (90%). HRT users were younger, had higher estimated creatinine clearance, more frequently were smokers and had prior revascularization, but less frequently had diabetes, prior angina, or heart failure. Unadjusted 90-day and 1-year mortality rates were lower among HRT users (hazard ratios [95% CI] 0.48 [0.23-0.98] and 0.35 [0.18-0.68], respectively) but after multivariable adjustment, were not significantly different. Ninety-day stroke and composite end points did not differ between HRT users and nonusers.. HRT use (predominantly estrogen-only) was low among patients with ACS but varied by region and was not associated with improved intermediate-term outcomes. These results are consistent with the absence of benefit from HRT use (combination or estrogen only) in previous studies in more stable populations.

Topics: Aged; Aspirin; Attitude to Health; Coronary Disease; Estrogen Replacement Therapy; Female; Global Health; Humans; Middle Aged; Myocardial Infarction; Odds Ratio; Oximes; Piperidines; Platelet Aggregation Inhibitors; Postmenopause; Prevalence; Randomized Controlled Trials as Topic; Surveys and Questionnaires; Survival Analysis; Time Factors; Treatment Outcome; Women's Health

To determine the myocardial and vascular effects of remifentanil and fentanyl in human atria and saphenous veins.. In vitro, prospective with repeated measures.. University research laboratory.. The direct effects of remifentanil and fentanyl on the electrical stimulation-induced contraction of nonfailing human atrium and saphenous veins contracted with 5-hydroxytryptamine were studied.. In human atrial trabeculae, cumulative (10(-9)-10(-5) mol/L) added remifentanil had no effect on contractile force, compared with untreated muscles (p > 0.05). The force of contraction was significantly less than control values with concentrations of fentanyl ranging from 10(-8) to 10(-5) mol/L (p < 0.05). At the highest concentration (10(-5) mol/L), the inhibition by fentanyl of the electrical stimulation-induced contraction was 40.6% +/- 6.32%. In human saphenous vein strips preconstricted with 5-hydroxytryptamine, remifentanil (10(-8)-10(-5) mol/L) and fentanyl (10(-8)-10(-5) mol/L) produced "concentration-dependent" relaxation when compared with the control contraction value (p < 0.05). The IC(50) was similar with remifentanil and fentanyl and the E(max) of fentanyl was significantly higher than remifentanil (p < 0.05). The venodilatory effects of remifentanil and fentanyl were similar on veins with or without endothelium (p > 0.05).. Remifentanil has no direct effect on the contraction of myocardium. Fentanyl inhibits the electrical stimulation-induced contraction in human right atrial muscles in vitro. Remifentanil and fentanyl produce "concentration-dependent" relaxation in human saphenous vein strips independent from the endothelium.

Topics: Adult; Aged; Analgesics, Opioid; Coronary Artery Bypass; Coronary Disease; Dose-Response Relationship, Drug; Electric Stimulation; Endothelium, Vascular; Female; Fentanyl; Free Radical Scavengers; Heart Atria; Humans; Male; Middle Aged; Myocardial Contraction; Piperidines; Prospective Studies; Remifentanil; Reproducibility of Results; Saphenous Vein; Serotonin; Stroke Volume; Time Factors; Treatment Outcome; Vasodilation

The success of intravenous platelet glycoprotein (GP) IIb/IIIa receptor blockers as potent antithrombotic therapies has ignited interest in the research and development of oral agents with the intention of extending the initial clinical benefits proven with intravenous GP IIb/IIIa blockers to long-term care with the use of oral agents. Nonetheless, results of the recently published Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial support the disappointing results of the earlier published studies, which revealed that the use of oral GP IIb/IIIa inhibitors was associated with an unacceptable increased mortality. Further research to elucidate the mechanism of this increased fatality risk is warranted before any further clinical studies with the oral GP IIb/IIIa inhibitors can be ethically justified.

Topics: Administration, Oral; Benzodiazepines; Coronary Disease; Humans; Piperidines; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Stroke

The expansion of coronary surgery on the beating heart without cardiopulmonary bypass has led to increasing interest in ultra-fast track anesthesia, allowing extubation of the patient in the operating theater. The techniques described to date combined general anesthesia with thoracic epidural analgesia. We report the routine application of a technique that allows immediate extubation in the majority of patients undergoing off-pump coronary artery bypass grafting without thoracic epidural analgesia.. Fast-track anesthesia using an ultra-shortacting opiate remifentanil, without epidural catheter insertion, was used in 160 unselected patients undergoing off-pump coronary artery bypass grafting (aged 43 to 83 years, mean 65 years). There were an average of 2.2 bypass procedures per patient, with the left internal mammary artery used in 93%. Contraindications to immediate extubation were (except for failure to meet standard extubation criteria) hemodynamic instability and persistent bleeding at the end of operation. Satisfactory postoperative pain control was achieved by continuous remifentanil (0.0125 to 0.05 microg x kg(-1) x min(-1)).. Operating theater extubation within 10 minutes of the end of operation was feasible in 150 patients (94%). Five patients (3%) were extubated within 2 hours, and the remaining 5 patients (3%) were converted to standard anesthesia. There were no deaths during hospitalization. Major complications included myocardial infarction and transient ischemic attacks (2 patients each). No pulmonary complications were seen. Episodes of atrial fibrillation occurred in 21% of the patients undergoing operation.. Immediate extubation is possible in most patients after off-pump coronary artery bypass grafting even without thoracic epidural analgesia. We believe this type of less invasive cardiac anesthesia is safe and promising.

Topics: Adult; Aged; Aged, 80 and over; Analgesia, Epidural; Anesthesia Recovery Period; Anesthetics, Intravenous; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Feasibility Studies; Female; Hospital Mortality; Humans; Intubation, Intratracheal; Male; Middle Aged; Outcome and Process Assessment, Health Care; Piperidines; Remifentanil; Survival Rate; Time and Motion Studies

Topics: Acetylcholine; Bosentan; Coronary Artery Bypass; Coronary Disease; Endothelin Receptor Antagonists; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Male; Mammary Arteries; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Sulfonamides; Vasodilation; Vasodilator Agents

Remifentanil may be an alternative to conventional opioids for minimally invasive direct coronary artery bypass surgery because of its extremely short duration of action. The aim of this study was to investigate the effects of remifentanil on myocardial blood flow, metabolism and systemic haemodynamic variables in patients with coronary artery disease. After approval by the local ethics committee, 12 male patients were investigated before elective coronary artery bypass grafting. Systemic haemodynamic variables, myocardial blood flow and metabolism were measured when patients were awake and when they were anaesthetized with high-dose remifentanil (2.0 micrograms kg-1 min-1), or with remifentanil 0.5 microgram kg-1 min-1 combined with propofol (target-controlled infusion aiming at a plasma concentration of 2.0 micrograms ml-1). Myocardial blood flow was measured using a modified Kety-Schmidt technique. High-dose remifentanil anaesthesia significantly reduced cardiac index (CI) (-25%) as a consequence of a decrease in stroke volume index (SVI) (-14%) and heart rate (-13%). Mean arterial pressure (MAP) was 30% lower than that in the awake patient. Myocardial blood flow and myocardial oxygen uptake (MVO2) decreased by 30% and 42%, respectively. In contrast to high-dose remifentanil anaesthesia, systemic vascular resistance index (-14%) during remifentanil/propofol anaesthesia was significantly lower than that in the awake patient. Other haemodynamic variables, and myocardial blood flow and MVO2, did not significantly differ from the high-dose remifentanil period. In conclusion, high-dose remifentanil reduces SVI, heart rate, MAP, myocardial blood flow and MVO2 and its effects do not differ from those of remifentanil/propofol anaesthesia.

Topics: Aged; Anesthetics, Intravenous; Blood Pressure; Coronary Circulation; Coronary Disease; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Narcotics; Oxygen Consumption; Piperidines; Propofol; Regional Blood Flow; Remifentanil; Stroke Volume

1. The NHE1 isoform of the Na(+)/H(+) exchanger plays an important role in the regulation of intracellular pH and in cardiac cell injury caused by ischaemia and reperfusion. SL 59.1227 is a novel imidazolypiperidine Na(+)/H(+) antiport inhibitor which is structurally unrelated to previously described acylguanidine inhibitors such as cariporide. 2. Recovery of pH(i) following an intracellular acid load was measured in CCL39-derived PS120 variant cells, selectively expressing either NHE1 or NHE2 isoforms of the Na(+)/H(+) exchanger. pH(i) recovery was potently and selectively slowed by SL 59.1227 in NHE1-expressing cells (IC(50) 3.3+/-1.3 nM) versus NHE2-expressing cells (2.3+/-1.0 microM). The respective IC(50) values for cariporide were 103+/-28 nM (NHE1) and 73+/-46 microM (NHE2). 3. In anaesthetized rats following left coronary artery occlusion (7 min) and reperfusion (10 min) SL 59.1227 (10 - 100 microg kg(-1) min(-1) i.v.) inhibited ischaemia-mediated ventricular tachycardia (71 - 100%) and reperfusion-induced ventricular fibrillation (75 - 87%) and prevented mortality. Bolus i.v. administration of SL 59.1227 (1 mg kg(-1)) produced anti-arrhythmic effects when administered either before or during ischaemia. 4. Cardiac infarct size was determined in anaesthetized rabbits following left coronary artery occlusion (30 min) and reperfusion (120 min). Infarct size measured as a percentage of the area at risk was 36.2+/-3.4% (control group) versus 15.3+/-3.9% (SL 59.1227 0.6 mg kg(-1) i.v.). 5. SL 59.1227 is the first example of a potent and NHE1-selective non-acylguanidine Na(+)/H(+) exchanger inhibitor. It possesses marked cardioprotective properties.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Coronary Disease; Guanidines; Heart Rate; Heart Ventricles; Hydrogen-Ion Concentration; Imidazoles; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Piperidines; Rabbits; Rats; Rats, Sprague-Dawley; Sodium-Hydrogen Exchangers; Sulfones

Topics: Angina, Unstable; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Coronary Disease; Humans; Inflammation; Methylprednisolone; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic

Topics: Benzamidines; Clinical Trials as Topic; Coronary Disease; Humans; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex

Alendronate sodium and raloxifene hydrochloride were recently approved for the prevention of postmenopausal osteoporosis, but data on their clinical efficacy are limited. We compared these drugs with hormone replacement therapy (HRT) to help women and physicians guide postmenopausal treatment decisions.. To help physicians understand how they can best help women choose the most beneficial therapy after menopause based on their individual risk profile.. We developed a decision analytic Markov model to compare the effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip fracture, coronary heart disease (CHD), breast cancer, and life expectancy. Regression models linked individual risk factors to future disease risks and were modified by drug effects on bone density, lipid levels, and associated breast cancer effects.. Hormone replacement therapy, alendronate therapy, and raloxifene therapy have similar predicted efficacies in preventing hip fractures (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone replacement therapy should be more than 10 times more effective than raloxifene therapy in preventing CHD, but raloxifene therapy may not induce breast cancer. Women at low risk for hip fracture, CHD, and breast cancer do not benefit significantly from any treatment. Among women at average risk, HRT was preferred unless raloxifene therapy could reduce the risk of breast cancer by at least 66%, compared with a 47% increase for HRT. Women at high risk for CHD benefit most from HRT; women at high risk for breast cancer but low risk for CHD benefit most from raloxifene therapy, but only if it lowers the risk of breast cancer.. Because of significant differences in the impact of these drugs, treatment choice depends on an individual woman's risk for hip fracture, CHD, and breast cancer.

Topics: Alendronate; Bone Density; Breast Neoplasms; Coronary Disease; Decision Support Techniques; Estrogen Replacement Therapy; Estrogens; Estrogens, Conjugated (USP); Female; Hip Fractures; Humans; Life Expectancy; Lipids; Markov Chains; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Risk; Risk Factors; Sensitivity and Specificity

Topics: Animals; Coronary Disease; Estrogens; Female; Humans; Male; Piperidines; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Sex Distribution

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Coronary Disease; Estrogen Antagonists; Female; Humans; Menopause; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Tamoxifen; Uterine Neoplasms

Carotid endarterectomy (CEA) and coronary artery bypass grafting (CABG) as a combined procedure is occurring with increasing frequency. CEA-CABG incurs the morbidity of both procedures, and considerations for this procedure include anesthetic techniques that provide hemodynamic stability and prompt emergence from anesthesia. We present, to our knowledge, the first reported use in a combined CEA-CABG of the novel opioid remifentanil as a component of the anesthetic technique to achieve these goals. Remifentanil allows for early neurologic evaluation without sacrificing the hemodynamic stability of traditional, high-dose opioid techniques.

Topics: Analgesics, Opioid; Anesthesia Recovery Period; Anesthetics, Intravenous; Blood Pressure; Carotid Stenosis; Coronary Artery Bypass; Coronary Disease; Endarterectomy, Carotid; Heart Rate; Humans; Infusions, Intravenous; Injections, Intravenous; Intubation, Intratracheal; Ischemic Attack, Transient; Male; Middle Aged; Morphine; Neurologic Examination; Piperidines; Propofol; Remifentanil

Topics: Breast Neoplasms; Coronary Disease; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Humans; Molecular Structure; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Receptors, Estrogen; Structure-Activity Relationship; Tamoxifen

Topics: Coronary Disease; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Humans; Medroxyprogesterone; Meta-Analysis as Topic; Piperidines; Postmenopause; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Women's Health

Topics: Acute Disease; Antithrombins; Coronary Disease; Glycine; Heparin; Hirudin Therapy; Humans; Piperidines; Syndrome

We investigated the antiarrhythmic effects of bidisomide (SC-40230), a new class I antiarrhythmic drug, in early-phase ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats. The effects of bidisomide were compared with those of mexiletine (MXT) and disopyramide (DSP), established class I antiarrhythmic drugs. Drugs were administered intravenously, 5 min before induction of coronary occlusion. Bidisomide (5 mg/kg) reduced the number of premature ventricular complexes and the incidence of ventricular tachycardia and ventricular fibrillation similarly to MXT and DSP in rats with ventricular arrhythmias induced by coronary artery occlusion. In rats with ventricular arrhythmias induced by coronary artery reperfusion following a 5-min coronary occlusion, the antiarrhythmic effects of 5 mg/kg of bidisomide were similar to those of the same doses of MXT and DSP. All three drugs significantly slowed the heart rate. Our results suggest that bidisomide may effectively reduce the severity of life-threatening ventricular arrhythmias that occur during acute coronary syndrome.

Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Cardiac Complexes, Premature; Coronary Disease; Disopyramide; Heart Rate; Male; Mexiletine; Myocardial Reperfusion Injury; Piperidines; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation

Topics: Analgesics, Opioid; Coronary Disease; Drug Combinations; Humans; Length of Stay; Pancuronium; Piperidines; Propofol; Remifentanil; Retrospective Studies

Previous studies in guinea pig heart cells have shown pharmacologically and kinetically distinct components of the classical delayed rectifier current (IK), generally referred to as IKr (rapid IK) and IKs (slow IK). This study was designed to determine whether the human heart contains corresponding components.. The whole cell voltage clamp technique was used to study IK in single myocytes isolated from human right atrial appendages removed at the time of aortocoronary artery bypass surgery.. The activation of IK was best fitted by a biexponential relation, with time constants averaging 204(SEM 20) and 1080(197) ms at +10 mV. IK was inhibited by the specific IKr blocker E-4031 (5 microM), with the drug sensitive and drug resistant components having markedly different kinetic properties. The E-4031 sensitive current activated rapidly, while the drug resistant component activated more slowly, and the activation time courses of E-4031 sensitive and resistant currents paralleled the rapid and slow components of IK between -20 and +50 mV. The E-4031 sensitive component showed strong inward rectification, a half activation voltage (V 1/2) of -14.0(3.3) mV and a slope factor (k) of 6.5(1.5) mV, while the E-4031 resistant current had a linear current-voltage relationship, and values of +19.9(4.2) mV and 12.7(2.5) mV for V 1/2 and k respectively. The envelope of tails analysis showed a time dependent change in IKtail/IKstep under control conditions, and E-4031 strongly reduced the time dependent variation, suggesting that the E-4031 resistant current consisted of one dominant component.. (1) IK in human atrium shows kinetically distinguishable rapid and slow components. (2) These components correspond to E-4031 sensitive and resistant currents. (3) The kinetics and voltage dependence of the rapid (E-4031 sensitive) and slow (E-4031 resistant) components correspond to properties previously described in guinea pig myocytes. These findings have important potential implications for understanding the mechanisms of human atrial repolarisation and its regulation by the autonomic nervous system and antiarrhythmic drugs.

Topics: Arrhythmias, Cardiac; Cells, Cultured; Coronary Disease; Heart Atria; Humans; Membrane Potentials; Middle Aged; Patch-Clamp Techniques; Piperidines; Potassium Channels; Pyridines

The aim was to study the combined effect of DV-7028, a selective 5-hydroxytryptamine2 receptor antagonist, and aspirin or heparin on cyclic flow reductions in the canine coronary artery.. Anaesthetised open chest beagle dogs under artificial respiration were used. Cyclic flow reductions were induced by partial occlusion of the left anterior descending coronary artery at the site of endothelial injury. After induction of cyclic flow reductions, test drugs were given to the animals intravenously.. DV-7028 (0.1 mg.kg-1) reduced the frequency of cyclic flow reductions by 77% and improved the nadir of coronary blood flow velocity that indicated the severity of cyclic flow reductions. Also, aspirin (1 or 3 mg.kg-1) or heparin (200 U.kg-1) attenuated the cyclic flow reductions. In experiments with drug combinations, DV-7028 was given to animals that had already received aspirin (1 mg.kg-1) or heparin (200 U.kg-1). DV-7028 (0.1 mg.kg-1) completely abolished the cyclic flow reductions remaining after aspirin treatment in three of four animals. Heparin inhibited the cyclic flow reductions in one of five animals and the addition of DV-7028 abolished the remaining cyclic flow reductions in the other four animals. After combined injection of DV-7028 with aspirin or heparin, the coronary blood flow with cyclical reductions returned to the baseline.. The 5-HT2 receptor antagonist DV-7028 can inhibit the cyclic flow reductions that are resistant to aspirin or heparin. The combined regimen of DV-7028 and aspirin or heparin in treatment of acute coronary stenosis is more effective than that of aspirin or heparin alone.

Topics: Animals; Aspirin; Blood Pressure; Coronary Circulation; Coronary Disease; Disease Models, Animal; Dogs; Drug Synergism; Heart Rate; Heparin; Piperidines; Serotonin Antagonists; Triazines; Ventricular Function, Left

The threshold dose of ouabain necessary to induce ventricular fibrillation is decreased in sensitized guinea-pigs signalizing an enhanced arrhythmogenicity. Esculetine or WEB 2170 antagonists of histamine and PAF, respectively and especially a combination of both can increase the threshold dose of ouabain-induced fibrillation demonstrating an antiarrhythmic effect. BN 52256 a substance with multi-antagonistic properties shows antiarrhythmic effect in this method, too. WEB 2170 and BN 52256 decrease the incidence of ventricular fibrillation after coronary ligation in rats.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Azepines; Clemastine; Coronary Disease; Coronary Vessels; Guinea Pigs; Organoselenium Compounds; Ouabain; Piperidines; Platelet Activating Factor; Propranolol; Rats; Triazoles; Umbelliferones; Ventricular Fibrillation

Veratridine-induced Na+ and Ca2+ uptake was used as a simulation of ischemia-induced Na+ and Ca2+ uptake. Therefore, electrically driven (1 Hz) isolated left atria of the rat were intoxicated with veratridine and the 45Ca2+ uptake was determined. Veratridine (10(-4) mol/l) increased the 45Ca2+ uptake from 575 +/- 13 to 2320 +/- 86 dpm/mg ww (n = 20). The total tissue content of 45Ca was elevated from 4328 +/- 132 to 5136 +/- 303 dpm/mg ww (n = 13). The veratridine-induced 45Ca2+ uptake was completely suppressed by tetrodotoxin (10(-7) and 10(-6) mol/l), whereas amiloride (6.10(-6) mol/l) and phentolamine (10(-6) and 10(-5) mol/l) exhibited no effect on the veratridine-induced 45Ca2+ uptake. Nifedipine (10(-7) and 10(-6) mol/l) was ineffective on veratridine-induced 45Ca2+ uptake. Verapamil (10(-5) mol/l) suppressed the veratridine-induced 45Ca2+ uptake, but the 45Ca2+ uptake in the absence of veratridine was also suppressed by verapamil (10(-6) and 10(-5) mol/l). The novel anti-ischemic compounds R 56865 (10(-8)-10(-5) mol/l) and R 59494 (10(-8)-10(-5) mol/l) totally abolished veratridine-induced 45Ca2+ uptake. It is speculated that Ca2+ enters the cell via a Na+ channel which changes its selectivity upon veratridine treatment. Consequently, R 56865 and R 59494 could display their protective effect by either inhibiting the modified Na+ channel or preventing the transition of the normal Na+ channel to its altered state.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Function, Left; Benzothiazoles; Calcium; Coronary Disease; Dose-Response Relationship, Drug; Heart; In Vitro Techniques; Male; Piperidines; Pyrroles; Rats; Sodium; Sodium Channels; Thiazoles; Veratridine

We examined the role of calcium in the pathogenesis of ischemic cardiac cell death in the isolated working rabbit heart subjected to normothermic global ischemia followed by reperfusion. Apart from measurements of cardiodynamic function and ultrastructural examination, we also used a cytochemical procedure to localize exchangeable calcium pools at the ultrastructural level. The effects of verapamil (1.5 x 10(-8) M, 3 x 10(-8) M) (high affinity for L-type calcium channels) were compared with those of R 56 865 (4 x 10(-7) M) (Ca2+ overload blocker with low affinity for the L-type calcium channels). A severe depression of cardiac function was observed after solvent or verapamil pretreatment and 25 min of ischemia followed by reperfusion. R 56 865 treatment resulted in a significantly improved postischemic recovery when compared to solvent and verapamil treatment groups. The ultrastructural and cytochemical results corroborated the hemodynamic findings. In solvent and verapamil-treated hearts, irreversible damage was observed mainly in mid- and endocardial areas. Ultrastructural changes were accompanied by shifts in calcium localization: i.e. loss of sarcolemmal calcium binding capacity, accumulation of calcium precipitate in the mitochondria. In the R 56 865 treatment group, damage was limited to some cells scattered in the midcardial areas. In conclusion, R 56 865, which has little affinity for the slow channels was highly effective in protecting against ischemic damage, indicating that, in this experimental set-up, the calcium responsible for cellular Ca2+ overload is not entering via L-type calcium channels.

Topics: Animals; Benzothiazoles; Calcium; Calcium Channels; Cell Death; Coronary Disease; Female; Hemodynamics; In Vitro Techniques; Male; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Perfusion; Piperidines; Rabbits; Subcellular Fractions; Thiazoles; Verapamil

The Class III agent E-4031 was evaluated for its antiarrhythmic and antifibrillatory actions in conscious dogs 3-5 days after anterior myocardial infarction that were responsive to the induction of tachyarrhythmia by programmed electrical stimulation. The administration of E-4031 as an intravenous loading dose (100 micrograms/kg) followed by an infusion for 90 min (10 micrograms/kg/min) suppressed the induction of ventricular tachycardia by programmed electrical stimulation in 6 of 12 dogs and prolonged the cycle length of the induced arrhythmia in 5 of the 6 remaining animals. Continued administration of E-4031 in a dose regimen of 1,000 microgram/kg every 2 h provided significant protection (8 of 10 dogs) against the development of ventricular fibrillation (sudden coronary death) within the first hour after the onset of myocardial ischemia in a region of the ventricle remote from the infarct-related vessel. The incidence of sudden coronary death was 80% in a comparable control group of electrically inducible postinfarcted dogs. Increases in ventricular myocardial refractoriness in the paced QT and QTc intervals suggest that Class III electrophysiologic actions contribute to the antiarrhythmic and antifibrillatory actions of E-4031. The findings suggest that E-4031 may be of clinical utility in the prevention of life-threatening arrhythmias in the setting of myocardial ischemia in the postinfarcted heart.

Topics: Animals; Anti-Arrhythmia Agents; Coronary Disease; Death, Sudden; Dogs; Electric Stimulation; Electrocardiography; Electrophysiology; Heart Rate; Male; Piperidines; Pyridines; Ventricular Fibrillation

The effects of R 56,865, a compound with unusual calcium antagonistic properties, on altered left ventricular (LV) diastolic properties were studied during pacing-induced ischemia in dogs with coronary stenosis. Severe coronary artery stenosis was produced on both the left anterior descending (LAD) and circumflex (Cx) coronary arteries in anesthetized beta-blocked dogs. The right atrium was paced at 200 beats/min for 3 min. In the post-pacing period and before drug intervention, the most characteristic observation was a significant increase in LV end-diastolic pressure (LVEDP) and in the time constant of (tau) LV pressure decrease; after return of LV hemodynamics to baseline values (15 min), R 56,865 (0.16 mg.kg-1) or solvent (control) was injected and four subsequent pacing runs were performed at 30-min intervals. In the postpacing period of these four subsequent runs, there was a steep increase in LVEDP and tau-values while HR returned more slowly to baseline values. After R 56,865 infusion, the increase in LVEDP and tau-values was significantly lower than in the pretreatment run and all LVEDP values were significantly lower than in the control group. We conclude that R 56,865 effectively attenuates ischemia-induced changes in LV diastolic stiffness.

Topics: Animals; Benzothiazoles; Blood Pressure; Cardiac Pacing, Artificial; Coronary Disease; Coronary Vessels; Diastole; Dogs; Female; Heart Rate; Hemodynamics; Male; Piperidines; Propranolol; Thiazoles; Ventricular Function, Left

The ATP-sensitive potassium channel opener, cromakalim, protects ischemic hearts and its effect can be reversed by glyburide. It is presently unknown if glyburide can abolish the anti-ischemic effects of mechanistically different agents or if blockers of other potassium channels can abolish the protective effects of cromakalim. Thus, the effect of glyburide on previously reported cardioprotective agents was tested in globally ischemic/reperfused isolated rat hearts. Calcium antagonists, sodium channel blockers and calmodulin antagonists were found to significantly improve postischemic contractile function and reduce lactate-dehydrogenase release after 25 min of global ischemia and 30 min of reperfusion. Glyburide did not reverse their cardioprotective effects. 5-(N,N-dimethyl)amiloride, an inhibitor of Na+/H+ exchange, significantly reduced lactatedehydrogenase release without improving postischemic contractile function, and glyburide did not reverse this. The potassium channel opener, cromakalim, protected ischemic rat hearts (improved recovery of contractile function and reduced enzyme release) and this was abolished by glyburide. Charybdotoxin blocks both calcium-activated potassium channels and voltage-gated potassium channels and E-4031 the delayed rectifier potassium channels. Neither was found to effect the action of the potassium channel opener, cromakalim. These data indicate that glyburide is selective in that it only blocks the anti-ischemic effects of potassium channel openers and not other cardioprotective compounds. In addition, cromakalim is unaffected by blockers of other potassium channels, further indicating selectivity of glyburide for ATP-sensitive potassium channels.

Topics: Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Benzopyrans; Coronary Circulation; Coronary Disease; Cromakalim; Glyburide; Lidocaine; Male; Piperidines; Potassium Channels; Pyridines; Pyrroles; Rats; Rats, Inbred Strains

The antiarrhythmic effects of R56865 were characterized both in vivo and in vitro. Four groups (n = 12 per group) of anesthetized rats, subjected to 5- or 30-min coronary artery ligation and reperfusion, were studied: saline, dimethyl sulfoxide (DMSO) carrier, and R56865 (0.5 or 2 mg/kg) were administered as an intravenous (i.v.) bolus before ligation. After 5 min of ischemia, the incidences of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF), which were high in the saline (100 and 75%, respectively) and DMSO (100 and 82%, respectively) control groups, were abolished with both doses of R56865. With 30 min of ischemia, R56865 (2 mg/kg) significantly reduced the incidences of ischemia-induced VT and VF (from 100 and greater than 50% to 25 and 8%, respectively). For in vitro studies, five groups (n = 12 per group) of isolated rat hearts subjected to 10- or 30-min coronary ligation and reperfusion were studied: unmodified buffer and buffer containing DMSO or R56865 (10(-7), 10(-8), 10(-9) M). After 10 min of ischemia, R56865 (10(-7) M) decreased reperfusion-induced VT and VF (from 100 and 75% in buffer controls to 42 and 8%, respectively) when administered throughout the experiment. With 30 min of ischemia, R5685 (10(-7) M) reduced the incidences of ischemia-induced VT and VF (from 75 and 67% in the buffer controls to 25 and 25%, respectively). Although reperfusion after 30 min of ischemia did not induce VF in any of the groups studied, VT and other arrhythmias did occur and their incidences were reduced significantly by R56865. To investigate whether calcium overload might mediate the effects of R56865, hearts were perfused aerobically with a high-calcium/low-sodium medium. VT and VF occurred in 80% of control hearts; R56865 (10(-7) M) did not prevent these arrhythmias. In conclusion, R56865 exerts a potent effect against ischemia- and reperfusion-induced arrhythmias through a mechanism which appears to operate during ischemia.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Benzothiazoles; Calcium; Coronary Disease; Hemodynamics; In Vitro Techniques; Male; Myocardial Reperfusion; Piperidines; Potassium; Rats; Rats, Inbred Strains; Thiazoles

The aim of the study was to test the hypothesis that platelet serotonin 5HT2 receptors are important in the genesis of thrombosis in stenosed coronary arteries.. The specific serotonin 5HT2 receptor antagonist, ritanserin was used as a pharmacological tool to examine the effect of removal of the participation of the 5HT2 receptors on thrombus growth, in a paired statistical design.. The study involved 10 open chest anaesthetised dogs, with constrictors of critical diameter applied to the left circumflex coronary artery.. Blood flow was monitored in the left circumflex coronary arteries, distal to the critical stenosis. Flow reductions occurred that have previously been shown to be caused by the accumulation of platelet thrombi. By embolising the thrombi, the process could be monitored cyclically (cyclic flow reductions). The specific serotonin 5HT2 receptor antagonist, ritanserin, abolished cyclic flow reductions at a dose of 0.5 mg.kg-1. There was no effect on blood pressure or heart rate on administration of ritanserin at any dose. The serotonin blockade by ritanserin also prevented the reestablishment of cyclic flow reductions by adrenaline infusion (0.4 micrograms.kg-1.min-1), but required ritanserin doses up to 1.5 mg.kg-1. Ex vivo aggregation of platelets was reduced in blood taken from the dogs after ritanserin administration.. These results constitute further evidence of the possible importance of serotonin as a mediator of platelet thrombosis in stenosed coronary arteries.

Topics: Animals; Coronary Disease; Coronary Thrombosis; Dogs; Dose-Response Relationship, Drug; Epinephrine; Female; Male; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Serotonin; Ritanserin; Serotonin Antagonists

1. The cardioprotective effects of antiarrhythmic agents classified as class III, amiodarone, sotalol and E-4031, were investigated in anaesthetized dogs. 2. The left anterior descending coronary artery was occluded for 2 h. 3. Heart mitochondria were prepared from both the ischaemic and non-ischaemic areas, and their function was estimated polarographically. 4. Activities of the lysosomal enzymes, N-acetyl-beta-glucosaminidase and beta-glucuronidase, were measured in each fraction. 5. Two hour occlusion induced ventricular arrhythmias, and amiodarone, sotalol and E-4031 greatly suppressed the development of arrhythmias. 6. Amiodarone, sotalol and E-4031 significantly protected mitochondria against ischaemia, and prevented ischaemia-induced leakage of lysosomal enzymes. 7. Antiarrhythmic agents classified as class III show cardioprotective effects, which might participate in their antiarrhythmic effect.

Topics: Acetylglucosaminidase; Amiodarone; Anesthesia; Animals; Anti-Arrhythmia Agents; Blood Pressure; Coronary Disease; Coronary Vessels; Dogs; Electrocardiography; Female; Heart Rate; In Vitro Techniques; Lysosomes; Male; Mitochondria, Heart; Piperidines; Pyridines; Sotalol

The hemodynamic effects of intravenous pirmenol were studied in 21 subjects instrumented with peripheral arterial, pulmonary artery, and left ventricular catheters. Baseline measurements of heart rate, cardiac output, pulmonary artery pressure, systemic arterial pressure, left ventricular end-diastolic pressure, left ventricular stroke work, and ejection fraction were obtained. An infusion of pirmenol hydrochloride was administered and hemodynamic measurements were repeated an average of 16.1 minutes following the start of the infusion after a new stable hemodynamic state was achieved. Significant increases in heart rate and systemic arterial pressure were noted. There were no significant changes in cardiac output, pulmonary arterial pressure, or left ventricular end-diastolic pressure. Significant reductions in left ventricular stroke work and ejection fraction were demonstrated. The amount of decrease in the ejection fraction was not related to the plasma pirmenol level achieved or to the baseline level of ventricular function. These findings suggest a negative inotropic effect of acute infusions of pirmenol and suggest caution should be used in its administration to patients with compromised left ventricular performance.

Topics: Adult; Angina Pectoris; Anti-Arrhythmia Agents; Coronary Disease; Depression, Chemical; Drug Evaluation; Female; Heart Ventricles; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Piperidines; Stroke Volume; Time Factors

The data obtained in this study demonstrate that the concentration of serotonin is markedly elevated (18- to 27-fold) at the site of a coronary arterial stenosis in open-chest, anesthetized dogs with cyclic flow variations. Cyclic flow variations in this experimental preparation were abolished by ketanserin, a 5-hydroxytryptamine antagonist, but serotonin concentration at the site of the coronary stenosis remained elevated. The intra-atrial administration of serotonin (0.16 to 1 mg/min) restored cyclic flow variations after they had been abolished by ketanserin. Taken together, these data suggest that serotonin may be one of the important mediators of cyclic flow variations in this experimental preparation.

Topics: Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Hemodynamics; Ketanserin; Male; Periodicity; Piperidines; Serotonin

The efficacy and electrophysiologic effects of pirmenol were evaluated in 21 patients with a history of sustained ventricular tachycardia (VT) and coronary artery disease. Intravenous pirmenol (0.7- to 1.1-mg/kg bolus, followed by a 35- to 40-micrograms/kg/min infusion) significantly prolonged the PR, QRS, QT and corrected QT intervals, HV interval and right ventricular effective refractory period, and shortened the sinus cycle length and atrioventricular nodal block cycle length. All 21 patients had inducible VT (20 sustained, 1 nonsustained) during programmed stimulation in the control state. After intravenous pirmenol, 5 patients (24%) no longer had inducible VT. In those in whom VT was still inducible, the VT cycle length was prolonged significantly. The 5 patients who responded to intravenous pirmenol were given oral pirmenol (200 to 250 mg every 8 hours) for 1 to 3 days and retested with programmed stimulation. In 4 of these 5, VT could not be induced with oral pirmenol administration; in 1 patient sustained VT was induced and pirmenol therapy was discontinued. Oral pirmenol suppressed recurrent VT during a follow-up of 315 +/- 133 days in 4 patients. However, pirmenol therapy was discontinued in 2 patients because of possible deleterious effects (worsened heart failure in 1 patient and elevated liver function test results in 1). Thus, pirmenol, a type IA antiarrhythmic drug, had an overall efficacy of approximately 19% in patients with sustained VT secondary to coronary artery disease.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Coronary Disease; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Tachycardia

Thirty-two patients received flecainide acetate for nonsustained ventricular tachycardia after having had unsuccessful treatment with a mean of four antiarrhythmic drugs. The mean left ventricular ejection fraction was 41% in 27. Thirty-one patients had organic heart disease, and 22 patients had arrhythmia-related symptoms. Total suppression of ventricular tachycardia occurred in 22 patients. Thirty patients were discharged from the hospital receiving flecainide at a mean (+/- SD) dosage of 315 +/- 76 mg/d and 26 of these patients attained a mean trough plasma drug level of 567 +/- 254 ng/mL. One patient had proarrhythmia and 3 had worsening of heart failure. Twenty-two patients remained in the trial for a mean follow-up of 13 +/- 7 months. Five patients died (1 suddenly) during the follow-up period. Our data indicate that flecainide suppresses refractory nonsustained ventricular tachycardia in 69% of patients who have organic heart disease. Serious adverse effects were minimized by initiation of treatment in the hospital and careful surveillance of electrocardiograms and plasma drug levels.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Coronary Disease; Electrocardiography; Female; Flecainide; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Tachycardia

The effect of flecainide acetate, a class 1c antiarrhythmic agent, was examined in 15 patients with recurrent ventricular tachycardia. Intravenous flecainide was administered in a dose of 2 mg/kg at the time of intracardiac stimulation and recording studies. Oral flecainide was given to 10/15 patients and retesting was undertaken using an indwelling electrode. Intravenous flecainide terminated sustained stable tachycardia in 8/11 patients and prevented reinitiation of tachycardia in 5/10 patients. Oral therapy prevented induction of tachycardias in only 2/10 patients. Five patients had non-sustained tachycardia and three had slower sustained tachycardia. "New" non-clinical tachycardias could be induced in six patients after flecainide but five of these had had more than one type of induced tachycardia. Four of 10 patients remained free of tachycardias during follow-up. Withdrawal of oral treatment was necessary in three patients, one of whom had severe proarrhythmic effects. Two patients required additional antiarrhythmic therapy. Long-term suppression could not be predicted from the results of oral therapy, but testing after intravenous drug seemed to be a more useful prognostic indicator. In summary, intravenous flecainide is effective for slowing and termination of stable ventricular tachycardia. Oral therapy is also effective but caution should be exerted in patients with multimorphic tachycardias.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Aneurysm; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Recurrence; Tachycardia

Twenty-two patients with coronary artery disease and spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) underwent intracardiac electrophysiologic evaluation and, when possible, ambulatory monitoring before and after therapy with flecainide (mean dose 418 +/- 87 mg [mean +/- standard deviation]). An average of 4 antiarrhythmic agents were used and were unsuccessful before therapy with flecainide was begun. During 64 +/- 16 hours of control Holter monitoring in 16 patients, all had 1 or more salvos of VT, as well as ventricular premature complexes (VPCs). Programmed stimulation during the control period induced VT in 17 of 22 patients. After flecainide therapy, Holter monitoring showed elimination of all forms of VT in all but 1 patient, as well as significant reduction of paired VPCs by 95% (p less than 0.03) and single VPCs by 70% (p less than 0.005). Electrophysiologic study during flecainide therapy showed significant increases in AH, HV, PR, QRS and QTc intervals, and the ventricular effective refractory period. Programmed stimulation in 17 patients taking flecainide, with a mean plasma level of 1,075 +/- 521 ng/ml, showed ablation of inducible VT in only 2 patients, a worsening in 5 and continued VT inducibility in 10. Adverse effects that required drug withdrawal were infrequent and encountered in patients who received higher drug levels: 1 patient with congestive heart failure and 1 with severe sinus bradycardia. Thus, although flecainide suppresses complex ventricular arrhythmias on Holter recordings, it rarely alters the response to programmed stimulation. Caution is recommended in its use for recurrent sustained VT or VF and in the interpretation of electrophysiologic studies until the predictive value of programmed stimulation with flecainide therapy is established.

Topics: Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Coronary Disease; Electrocardiography; Female; Flecainide; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Tachycardia; Ventricular Fibrillation

The haemodynamic effects of flecainide were compared in three different subsets of patients with documented coronary disease. Ten patients (A) had no heart failure, 5 patients were on beta blockers (B) and 5 patients had overt heart failure (C). Flecainide was associated with negative inotropic effects that were relatively more pronounced in patients with left ventricular dysfunction: pulmonary wedge pressure increased by 27% in A, by 31% in B and by 42% in C; left ventricular stroke volume and stroke work decreased respectively by 10 and 12% in A, 21 and 19% in B, 26 and 28% in C. Ejection fraction decreased by 9% in A, 13% in B and 20% in C, in relation with an increase in end systolic volume (+9% in A, +10% in B and +5% in C). Absolute changes, however, were not significantly different from one group to another except for the increase of systemic vascular resistance which was more pronounced in C as compared with the other groups. The myocardial depression was also confirmed by the fall in dP/dt that was maximal at the end of injection; dP/dt remained depressed 15 min later despite some improvement. Flecainide thus exerts negative inotropic effects that are maximal at the end of infusion and may be of importance in patients with established left ventricular dysfunction.

Topics: Adult; Aged; Blood Pressure; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Piperidines; Stroke Volume; Vascular Resistance

Platelets possess alpha 2-adrenergic and serotonergic (5-hydroxytryptamine) receptors which are thought to mediate the in vitro proaggregatory effects of epinephrine and serotonin, respectively. However, their importance in platelet aggregation in vivo is uncertain. In the present study, we evaluate the ability of yohimbine and ketanserin, relatively selective alpha 2-adrenergic and serotonin antagonists, respectively, to alter cyclic flow reductions in stenosed coronary arteries in open-chest, anesthetized dogs. These cyclic flow reductions, characterized by progressive declines in coronary blood flow interrupted by abrupt and, often spontaneous, restorations of flow, were produced by cylindrical constrictors placed on the left anterior descending coronary artery. A pulsed Doppler flow probe, placed proximal to the constrictor, was used to measure coronary blood flow. Regional myocardial blood flow was measured with 15-micron radiolabeled microspheres before coronary constriction and when coronary blood flow appeared to be at its nadir and zenith during cyclic flow reductions. After the cyclic flow reductions had been observed for 1 hour, yohimbine (1-2 mg/kg), ketanserin (0.25 or 0.5 mg/kg), or saline was given, and coronary blood flow and hemodynamics were monitored for another hour. The frequency of cyclic flow reductions and the mean of the three lowest nadirs of coronary blood flow (mean +/- SE) were compared between the first and second hours. Ketanserin, at doses of 0.25 and 0.50 mg/kg, virtually abolished cyclic flow reductions in all dogs tested. Yohimbine [1 mg/kg ( n = 14)] was partially effective in reducing the frequency (9.6 vs. 5.5 cyclic flow reductions/hr) and severity of cyclic flow reductions (nadirs of coronary blood flow = 6.2 +/- 2.4 vs. 20.9 +/- 6.1% of control). A higher dose of yohimbine [2 mg/kg (n = 7)] was no more effective. The frequency (9.3 +/- 0.9 vs. 9.3 +/- 1.0 CFR/hr) and severity (17.4 +/- 5.4 vs. 12.4 +/- 3.9% of control coronary blood flow) of cyclic flow reductions were not changed by saline. The relatively selective alpha 1-adrenergic antagonist, prazosin (0.01 mg/kg, iv), and the beta-adrenergic antagonist, propranolol (1-2 mg/kg, iv), did not affect the frequency or severity of cyclic flow reductions. Thus, the abilities of yohimbine to inhibit and ketanserin to abolish cyclic flow reductions in stenosed canine coronary arteries suggest that serotonin and, possibly, alpha 2-adrenergic agonists may influence cycli

Topics: Adenosine Diphosphate; Animals; Blood Flow Velocity; Coronary Circulation; Coronary Disease; Dogs; Female; Heart Rate; Hemodynamics; Ketanserin; Male; Piperidines; Platelet Aggregation; Prazosin; Propranolol; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Yohimbine

Flecainide has unusual electrophysiologic properties and a high potency for the suppression of ventricular tachyarrhythmias. Little is known about its inotropic and hemodynamic actions. In isolated rabbit papillary muscle, it produced a concentration-dependent depression of contractile force, the threshold concentration being 1.0 micrograms/ml. In patients undergoing coronary angiography for ischemic heart disease and given 1 (n = 11) and 2 mg/kg (n = 11) of flecainide acetate i.v., there was no change in heart rate or mean arterial pressure. The vehicle in which i.v. flecainide was suspended had no significant effects in 6 patients in whom it was tested. Both doses produced comparable hemodynamic effects irrespective of the level of the left ventricular ejection fraction. The mean right atrial pressure increased by 12% (p less than 0.05) after 1 mg/kg and by 15% (p less than 0.01) after 2 mg/kg of the drug. The corresponding increases in mean wedge pressure were 44% (p less than 0.05) and 33% (p less than 0.05), in mean pulmonary artery pressure 27% (p less than 0.01) and 28% (p less than 0.05), in systemic vascular resistance 10% (p less than 0.05) and 9% (not significant [NS]) and in pulmonary vascular resistance 6% (NS) and 49% (p less than 0.05). Significant decreases in cardiac index (8 and 12%, p less than 0.05), stroke volume index (11 and 15%, p less than 0.01) and stroke work index (12%, p less than 0.05, and 21%, p less than 0.01) as well as in left ventricular ejection fraction (15 and 16%, p less than 0.01) were also induced by the 2 doses of flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Animals; Anti-Arrhythmia Agents; Cardiac Catheterization; Coronary Disease; Female; Flecainide; Heart; Heart Failure; Hemodynamics; Humans; In Vitro Techniques; Male; Middle Aged; Piperidines; Rabbits; Retrospective Studies; Tachycardia

Class 1 antiarrhythmic drugs have been subdivided into 1a, 1b and 1c according to their effect on the action potential duration. The effects on the surface electrocardiogram of one drug from each subgroup were investigated in nine patients. Electrocardiographic recordings were taken during sinus rhythm and at identical atrial and ventricular paced rates. Disopyramide (1a) significantly prolonged the QT interval during sinus rhythm and at the identical paced rates, by increasing both the QRS duration and JT interval. Lignocaine (1b) significantly reduced the QT interval during sinus rhythm and at the identical paced rates, by reducing the JT interval. Lignocaine had no effect on the QRS duration. Flecainide (1c) significantly prolonged the QRS duration during sinus rhythm, but not the QTc. However the QT interval at the paced rates prolonged significantly, due entirely to an increase of the QRS duration. Flecainide had no effect on the JT interval. These characteristic electrocardiographic differences support the differentiation of class 1 drugs into three separate subgroups.

Topics: Action Potentials; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Coronary Disease; Disopyramide; Electrocardiography; Female; Flecainide; Humans; Lidocaine; Male; Middle Aged; Piperidines

Topics: Amiodarone; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Complexes, Premature; Coronary Disease; Disopyramide; Electrocardiography; Humans; Lidocaine; Mexiletine; Piperidines; Propafenone; Propiophenones; Tachycardia; Tocainide

The hemodynamic effects of flecainide acetate, a new class I antiarrhythmic agent, were studied in 10 patients with coronary heart disease. The drug was injected intravenously at a dose of 2 mg/kg over 30 minutes. The mean drug plasma level achieved was 394 ng/ml (range 329 to 470). The heart rate did not change, but a significant increase (p less than 0.001) in P-R (+17%), QRS (+15%), and Q-T (+7%) duration occurred after drug administration. Negative inotropic effects also were observed and consisted of an increase (p less than 0.01) in pulmonary wedge pressure (+27%) and a decrease (p less than 0.01) in stroke index (-10%), left ventricular stroke work index (-12%), and left ventricular ejection rate (-11%). No significant change in mean aortic pressure or systemic and pulmonary vascular resistance occurred. Left ventriculography performed after drug infusion revealed a significant increase (p less than 0.01) in systolic volume (+9%) and a decrease in ejection fraction (-9%) and mean velocity of circumferential fiber shortening (Vcf) (-13%). A progressive and significant decrease of dP/dt was observed during drug infusion, but 15 minutes after the injection, dP/dt had returned to near basal values. Thus, flecainide acetate has slight, but significant negative inotropic effects, particularly conspicuous during drug infusion. The drug should be administered with caution in patients with poorly compensated heart.

Topics: Adult; Anti-Arrhythmia Agents; Cardiac Output; Coronary Disease; Depression, Chemical; Electrocardiography; Female; Flecainide; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Piperidines; Pulmonary Wedge Pressure; Vascular Resistance

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Blood Pressure; Bundle of His; Cardiac Pacing, Artificial; Coronary Disease; Electrophysiology; Female; Flecainide; Heart Rate; Humans; Male; Middle Aged; Piperidines; Sinoatrial Node; Tachycardia; Time Factors

Flecainide acetate has been shown to be a potent antiarrhythmic agent which is active for more than 8 h, whether given intravenously or orally. However, the negative inotropic effect demonstrated in animal studies could hamper the potential clinical utility of the drug. Ten patients with coronary artery disease but without cardiac failure were given intravenous flecainide (2 mg/kg). Stroke index (SI), left ventricular systolic pressure (LVP), end diastolic pressure (EDP) and LV contractility indices (max dP/dt, VCE 40 mm Hg, peak VCE, Vmax from total pressure (TP] were measured immediately before and 10 min after flecainide, under resting conditions and during atrial pacing with heart rates up to 133 +/- 4.2 beats/min (mean +/- s.e. mean). It is demonstrated that flecainide has a negative inotropic effect, not only under resting conditions, but also less apparently during pacing-induced tachycardia. The effect appears to be dose-related and may result in a reduction of cardiac performance.

Topics: Adult; Anti-Arrhythmia Agents; Blood Pressure; Cardiac Pacing, Artificial; Coronary Disease; Female; Flecainide; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines; Time Factors

After an initial pilot study in five patients, the effect of flecainide on chronic ventricular arrhythmias was tested during 48-hour oral administration of 250 mg twice a day in nine further patients with previously drug-resistant chronic, stable ventricular arrhythmias. Mean age was 45.9 +/- 14.9 years; seven patients were male. Three patients had coronary artery disease, whereas the diagnoses in the remaining patients were congestive cardiomyopathy, aortic stenosis or no apparent heart disease. Continuous Holter monitoring with quantitative evaluation was performed in all patients for 24 hours before and during a two days' period of treatment. The mean number of ventricular ectopic beats decreased from 20.3 +/- 6.4 beats/min during hour six of treatment and further to 3.1 +/- 7.7 beats/min during hour 25 to 48 after onset of treatment. In either of nine patients, the mean decrease in ventricular ectopic rate was 97.5%. In only one patient, therapy was ineffective, Ventricular couplets were completely suppressed in six of eight cases. Looking at the spontaneous variability of ventricular ectopic beats during the control period, eight of nine patients showed a decrease which considerably exceeded the statistically necessary one. Headache of moderate degree was reported in one case in the pilot study. Therapy had to be stopped after the first dose because of QRS widening in another patient. In conclusion, this short-term study suggests that flecainide may be an effective drug for the management of ventricular arrhythmias.

Topics: Adult; Anti-Arrhythmia Agents; Aortic Valve Stenosis; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Chronic Disease; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

Topics: Coronary Disease; Electrocardiography; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia; Time Factors

13 patients (54 +/- 11.8 years) with either spontaneously occurring ventricular tachycardia (N = 12) or recurrent syncope (n = 1) probably due to ventricular tachycardia were studied electrophysiologically. In all patients, ventricular tachycardia could be initiated by programmed right ventricular stimulation during the control study. Ventricular tachycardia was sustained in eleven patients and non-sustained in the remaining two. After several days of oral administration of flecainide (400 to 500 mg per day) sustained ventricular tachycardia could still be initiated in seven cases that had to be interrupted by overdrive stimulation in five cases, and by cardioversion in the remaining two. In six cases, short, self-terminating episodes of ventricular tachycardia were induced. In four patients, induction of ventricular tachycardia was unchanged or made easier, whereas in seven cases ventricular tachycardia was more difficult to induce (i.e. later during the step-like stimulation program). The mean rate of induced ventricular tachycardia decreased from 215 +/- 59.4/min (+/- S.D.) to 169 +/- 44.1/min during flecainide (p less than 0.025). The interval between the tachycardia-initiating beat and the first beat of tachycardia increased from 323 +/- 61.1 ms to 438 +/-148.3 ms (P less than 0.02). The effective refractory period of the right ventricle was prolonged from 240 +/- 20.5 ms t 279 +/- 37.3 ms (P less than 0.005). The plasma concentration of flecainide at the time of stimulation was 995 +/- 238 ng/ml. Thus, flecainide exerts a marked effect on the rate of induced ventricular tachycardia, whereas the mode of induction did not change considerably. The prophylactic effect of long-term therapy with flecainide in patients with recurrent ventricular tachycardia needs further studies.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Failure; Heart Rate; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Tachycardia

11 patients (mean age 52 +/- 16.3 years) with recurrent ventricular tachycardia (VT), in whom VT could be initiated by programmed ventricular stimulation, were studied before and after lorcainide, a new antiarrhythmic agent. Lorcainide was either injected intravenously at a dose of 2 mg/kg within five to ten minutes (n = 3) or infused at a rate of 0.1 mg/kg/min up to the same total dose. After intravenous administration, there was no change in inducibility of VT in three patients, whereas in seven patients VT was either more difficult to induce requiring two instead of one premature beat (n = 2) or a higher rate of basic pacing (n = 2) or VT was no longer inducible (n = 3). In one case, VT was easier to induce. In patients with still inducible VT, the rate of VT decreased from 220 +/- 33 b.p.m. to 186 +/- 49.1 b.p.m. (non-significant). The echo zone for initiation of VT did not show any consistent change. The coupling interval between the last stimulated complex and the first beat of VT increased from 327 +/- 66.8 ms to 390 +/- 98.6 ms (p less than 0.05). The effective refractory period of the right ventricle increased slightly though not significantly. In three cases paradoxical side effects, probably due to lorcainide, were observed. The blood level of lorcainide at the end of injection or infusion immediately before right ventricular stimulation was 0.69 +/- 0.48 micrograms/ml (range 0.11 to 1.74 micrograms/ml). No N-dealkylated metabolite of lorcainide was detected after intravenous injection. Thus far, lorcainide is effective in preventing initiation of VT in some patients making it more difficult to induce in others. However, long-term efficacy and tolerance to the drug cannot be predicted from the data of this study though the data suggest that the drug might be effective on the long-term run against ventricular tachyarrhythmias.

Topics: Benzeneacetamides; Cardiac Pacing, Artificial; Coronary Disease; Heart Failure; Heart Rate; Piperidines; Tachycardia; Ventricular Fibrillation

Topics: Aconitine; Action Potentials; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Epinephrine; Female; Heart Conduction System; Hemodynamics; Male; Ouabain; Piperidines; Time Factors; Ventricular Fibrillation

Topics: Acetanilides; Anesthetics, Local; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Pressure; Cardiomegaly; Coronary Disease; Depression, Chemical; Mitral Valve Insufficiency; Piperidines; Stroke Volume

Ten new cases of perhexiline induced peripheral neuropathies are reported. The authors emphasize the possible association of other neurological disorders: cerebellar symptoms in one case, complex tremor in two other cases, marked decrease of photomotor reflexes in one case and disgeusia in another one. The pharmacocinetic study of 4 cases revealed the presence of a low metabolism of the drug in one of them. Polymorphous inclusions have been seen in Schwann cell and endothelial cell cytoplasm in the three patients with electron microscopic study of the nerves. The pathological study of one case showed the demyelination of spinal cord posterior columns. In another case, who died from hepatic coma, the biochemical study of cerebral lipids revealed the low values of cerebrosides and sulfatides in cerebellum and cerebral white matter.

Topics: Cerebellar Diseases; Coronary Disease; Demyelinating Diseases; Endothelium; Humans; Inclusion Bodies; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Piperidines; Schwann Cells; Spinal Cord Diseases

1. A phosphodiesterase inhibitor, UK 14,275 (Pfizer) was administered intravenously to six patients with suspected coronary artery disease under-going diagnostic cardiac catheterisation to assess its inotropic activity. 2. Intracardiac haemodynamic measurements included pulmonary and systemic arterial pressure. Left ventricular end diastolic pressure and left ventricular dP/dtmax were also measured, in addition to cardiac output using the indocyanine green dye technique. 3. UK 14,275 resulted in a significant increase in LV dP/dtmax and cardiac output. 4. No chronotropic action was observed using this agent. 5. This agent may have potential therapeutic value in the management of cardiovascular failure associated with low cardiac output.

Topics: Aged; Cardiac Output; Coronary Disease; Electrocardiography; Hemodynamics; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperidines; Quinazolines; Vascular Resistance

Topics: Coronary Disease; Humans; Nifedipine; Perhexiline; Physical Exertion; Piperidines; Practolol; Pyridines; Spirometry

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Electrocardiography; Exercise Test; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Placebos; Verapamil

Topics: Aged; Chemical and Drug Induced Liver Injury; Coronary Disease; Female; Humans; Liver; Male; Middle Aged; Perhexiline; Piperidines; Transaminases

Topics: Balneology; Coronary Disease; Cyclohexanes; Health Education; Health Facilities; Health Resorts; Humans; Physical Therapy Modalities; Piperidines

Topics: Aged; Coronary Disease; Female; Humans; Male; Middle Aged; Myocardial Infarction; Papilledema; Perhexiline; Piperidines

Topics: Aged; Chemical and Drug Induced Liver Injury; Coronary Disease; Cytoplasm; Gangliosides; Gangliosidoses; Humans; Liver; Male; Middle Aged; Perhexiline; Piperidines

Topics: Coronary Disease; Female; Glucose-6-Phosphatase; Humans; Hypoglycemia; Liver; Liver Glycogen; Middle Aged; Perhexiline; Piperidines

The improvement in the electrocardiographic signs of coronary insufficiency under the influence of perhexiline maleate is the object of an ergometric study in 28 patients. Ergometric tests repeated at regular over an average period of 8.3 months show a rapid ECG improvement, sustained over the period of the study. The heart rate, registered while at rest, which diminshes between that noted at the beginning of the study and that noted at the first registration under treatment, remains stable during the three following registrations. At the end of the effort, on the other hand, a significant reduction in tachycardia is observed during all the registrations.

Topics: Coronary Disease; Drug Evaluation; Electrocardiography; Exercise Test; Female; Heart Conduction System; Humans; Male; Middle Aged; Perhexiline; Piperidines

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Placebos

Topics: Aged; Blood Pressure; Coronary Disease; Electrocardiography; Female; Hand; Heart Rate; Humans; Isometric Contraction; Male; Middle Aged; Perhexiline; Physical Exertion; Piperidines; Placebos; Propranolol

1 The chronotropic and inotropic properties of U.K. 14275, a phosphodiesterase inhibitor were assessed in patients with coronary heart disease. 2 Left ventricular function was assessed in eight patients with acute myocardial infarction using the non-invasive measurement of systolic time intervals. 3 Twelve patients with angina pectoris were studied during diagnostic coronary arteriography. Left ventricular function was assessed using a high fidelity catheter tipped transducer in the left ventricle. 4 In both groups of patients U.K. 14275 infused intravenously in doses of 32, 64, 128 and 256 microgram kg-1 bodyweight min-1 enhanced the contractile state of the left ventricle without altering the heart rate.

Topics: Coronary Disease; Hemodynamics; Humans; Male; Myocardial Contraction; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperidines; Quinazolines

Topics: Adult; Coronary Disease; Hemodynamics; Humans; Middle Aged; Perhexiline; Piperidines; Spirometry

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Drug Tolerance; Female; Humans; Male; Maleates; Middle Aged; Palliative Care; Perhexiline; Piperidines

Topics: Coronary Disease; Female; Humans; Long-Term Care; Middle Aged; Perhexiline; Piperidines; Polyradiculopathy

Intravenous perhexiline maleate in a canine preparation with fixed coronary flow increases coronary diastolic pressure. It also redistributes coronary flow so as to preserve endocardial flow. Myocardial oxygen consumption was reduced and lactate uptake enhanced by the drug. It had no effect upon the threshold for ischemic-induced left ventricular failure.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Lung; Myocardium; Oxygen Consumption; Perhexiline; Piperidines

Topics: Angina Pectoris; Cardiac Complexes, Premature; Congresses as Topic; Coronary Disease; Germany, West; Humans; Maleates; Perhexiline; Piperidines

In a preliminary study which lasted 14 weeks, an anti-anginal preparation, perhexiline maleate (Pexid), was prescribed in a dosage of 200 mg twice a day to 7 patients who were suffering from cardiac arrhythmias associated with ischaemic heart disease. There was a significant reduction in ventricular extrasystoles during the 4th and 8th weeks of the study in 6 of the patients who had multiple ventricular ectopic beats. In 4 of these patients, an effective anti-arrhythmic response was maintained until the end of the study. These findings confirm other studies regarding the efficacy of the preparation in reducing ventricular extrasystoles in patients with cardiac ischaemia.

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Cardiac Complexes, Premature; Coronary Disease; Female; Heart Ventricles; Humans; Male; Middle Aged; Perhexiline; Piperidines

Topics: Age Factors; Coronary Disease; Female; Humans; Male; Maleates; Perhexiline; Piperidines; Sex Factors; Vertigo; Vestibular Nuclei

Topics: Aged; Basal Ganglia Diseases; Coronary Disease; Humans; Male; Maleates; Myocardial Infarction; Perhexiline; Piperidines

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Cyclohexanes; Drug Evaluation; Female; Humans; Male; Middle Aged; Piperidines; Prenylamine

Topics: Adult; Aged; Coronary Disease; Drug Evaluation; Female; Heart Rate; Humans; Male; Middle Aged; Perhexiline; Piperidines; Time Factors

Topics: Administration, Oral; Adult; Aged; Angina Pectoris; Coronary Disease; Electrocardiography; Female; Humans; Male; Maleates; Middle Aged; Perhexiline; Piperidines

Topics: Body Weight; Coronary Disease; Diuresis; Feeding and Eating Disorders; Humans; Maleates; Perhexiline; Piperidines; Vasodilator Agents

Topics: Chemical and Drug Induced Liver Injury; Coronary Disease; Female; Humans; Middle Aged; Perhexiline; Piperidines; Vasodilator Agents

Topics: Adolescent; Adult; Aged; Arteriosclerosis; Coronary Disease; Diuretics; Ethacrynic Acid; Female; Furosemide; Heart Failure; Humans; Liver Cirrhosis; Male; Middle Aged; Piperidines; Pulmonary Heart Disease; Rheumatic Heart Disease; Triamterene

Topics: Adrenal Cortex Hormones; Adult; Amides; Body Weight; Clopamide; Coronary Disease; Diabetes Insipidus; Diuretics; Edema; Female; Heart Valve Diseases; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pulmonary Heart Disease

Topics: Angina Pectoris; Benzophenones; Coronary Disease; Humans; Myocardial Infarction; Piperidines; Pyrazoles; Quaternary Ammonium Compounds; Sulfonic Acids

Topics: Analgesics; Animals; Coronary Disease; Coronary Vessels; Dihydroxyphenylalanine; Heart Conduction System; Monoamine Oxidase Inhibitors; Morphine; Nialamide; Piperidines; Reflex; Reserpine; Tranquilizing Agents; Vasodilator Agents