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1.
Am J Cardiol ; 87(9): 1058-63, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11348602

ABSTRACT

Angiotensin-converting enzyme inhibitors improve endothelial function, inhibit experimental atherogenesis, and decrease ischemic events. The Quinapril Ischemic Event Trial was designed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events (the occurrence of cardiac death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or hospitalization for angina pectoris) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction. A total of 1,750 patients were randomized to quinapril 20 mg/day or placebo and followed a mean of 27 +/- 0.3 months. The 38% incidence of ischemic events was similar for both groups (RR 1.04; 95% confidence interval 0.89 to 1.22; p = 0.6). There was also no significant difference in the incidence of patients having angiographic progression of coronary disease (p = 0.71). The rate of development of new coronary lesions was also similar in both groups (p = 0.35). However, there was a difference in the incidence of angioplasty for new (previously unintervened) vessels (p = 0.018). Quinapril was well tolerated in patients after angioplasty with normal left ventricular function. Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis. However, the absence of the demonstrable effect of quinapril may be due to several limitations in study design.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Coronary Artery Disease/drug therapy , Isoquinolines/therapeutic use , Myocardial Ischemia/prevention & control , Tetrahydroisoquinolines , Adult , Aged , Angioplasty , Coronary Angiography , Coronary Artery Disease/mortality , Coronary Artery Disease/physiopathology , Disease Progression , Female , Humans , Incidence , Male , Middle Aged , Myocardial Ischemia/mortality , Proportional Hazards Models , Quinapril , Survival Analysis , Treatment Outcome , Ventricular Function, Left/physiology
2.
J Thromb Thrombolysis ; 11(1): 19-31, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11248787

ABSTRACT

LB-30057 (CI-1028) is a novel, orally bioavailable, direct thrombin inhibitor with a Ki of 0.38 nM against human thrombin. The effects of LB-30057 on thrombus formation and hemostasis were evaluated in a veno-venous shunt model of thrombosis in rabbits, and compared with inogatran, another direct inhibitor of thrombin. Each compound was studied at 5 or 6 different doses with 5 or 6 rabbits in each group. After administration as a bolus i.v. injection followed by continuous infusion, both LB-30057 and inogatran dose-dependently inhibited thrombus formation, which was measured as an increase in time to occlusion (TTO) and a decrease in thrombus weight. Both compounds also improved vena caval blood flow and reduced the overall incidence of thrombotic occlusion. LB-30057 significantly prolonged TTO from 23 +/- 4 min (before dose) to 110 +/- 10 min at the highest dose (0.7 mg/kg + 47 microg/kg/min) (p < 0.001), and reduced thrombus weight from 57 +/- 2 mg to 15 +/- 5 mg (p < 0.001). Occlusive thrombus formed in only one of six rabbits that received the highest dose of LB-30057 (vs. 13/13 in the control group, p < 0.01). At the dose that produced the maximum antithrombotic effect (0.7 mg/kg + 47 microg/kg/min), LB-30057 increased aPTT and bleeding time approximately 2-and 2.5-fold above baseline, respectively. On a gravimetric basis, LB-30057 and inogatran displayed comparable in vivo antithrombotic efficacy. When compared to equally effective anti thrombotic doses of inogatran, LB-30057 caused less prolongation in aPTT, had no effect on PT, and tended to have less of effect on bleeding time. These results indicate that LB-30057 is an effective antithrombotic compound and it appears to have a better benefit/risk profile than inogatran in this experimental model.


Subject(s)
Benzamides/pharmacology , Thrombin/antagonists & inhibitors , Thrombosis/drug therapy , Animals , Benzamides/blood , Benzamides/pharmacokinetics , Bleeding Time , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Fibrinolytic Agents/blood , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Hemostasis/drug effects , Implants, Experimental , Injections , Piperidines/pharmacology , Rabbits , Regional Blood Flow/drug effects , Thrombosis/prevention & control , Vena Cava, Superior
3.
J Pharmacol Toxicol Methods ; 39(4): 193-202, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9845298

ABSTRACT

The objective of this study was to develop and validate a new experimental model of venous thrombosis in the rabbit. A 3-cm length of siliconized PE tubing was used as a veno-venous shunt inserted into the abdominal vena cava of anesthetized rabbits. The PE tubing contained six cotton threads which helped to restrict blood flow through the tubing and served as a foreign, thrombogenic surface upon which a thrombus could develop. By continuously measuring blood flow through the vena cava, the rate of thrombus development can be monitored until zero flow is achieved indicating that a completely occlusive thrombus is present. The shunt can be removed making it possible to weigh the thrombus and/or determine its composition. A second shunt can be placed in the vena cava to make a second determination of time to occlusion and thrombus weight, using the data from the first shunt as an internal control standard for comparison. Reproducibility of the technique was demonstrated in a control group (n = 7) in which two successive shunts were used without an antithrombotic intervention. In studies with the first and second shunts, time to occlusion averaged 20.6+/-5.2 min and 20.2+/-5.7 min (pNS), respectively. The net thrombus weights (less the wet weight of the cotton threads) were 49.0+/-3.5 mg and 47.0+/-3.3 mg (pNS). Histologic examination of the thrombi indicated that they were largely composed of fibrin and red blood cells, consistent with the characteristics of venous thrombi. The low molecular weight heparin (LMWH) enoxaparin was used as an antithrombotic intervention to validate the model. Dose-dependent changes in time to occlusion and thrombus weight were achieved which paralleled alterations in coagulation parameters (thrombin time and activated partial thromboplastin time) and bleeding time determined with an ear bleeding technique. The veno-venous shunt model is easy to use, reproducible, and responds appropriately to an antithrombotic intervention, indicating that it should be useful for experimental evaluation of antithrombotic agents designed for venous thromboembolic disorders.


Subject(s)
Vena Cava, Superior/physiopathology , Venous Thrombosis/physiopathology , Animals , Bleeding Time , Blood Coagulation , Disease Models, Animal , Enoxaparin/administration & dosage , Enoxaparin/pharmacology , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/pharmacology , Image Processing, Computer-Assisted , Laparotomy , Male , Microscopy, Electron , Rabbits , Vena Cava, Superior/pathology , Venous Thrombosis/pathology
4.
Pharm Biotechnol ; 11: 81-112, 1998.
Article in English | MEDLINE | ID: mdl-9760677

ABSTRACT

PD 156707 is a highly potent, selective antagonist of the ETA receptor that has demonstrated efficacy in a number of different disease models. The next few years will be exciting in the field of ET research as several compounds progress through clinical development. It is our hope that the efficacy that data demonstrated to date with PD 156707 will some day be translated into real hope for the patients who are waiting beyond the confines of our research laboratories.


Subject(s)
Dioxoles/pharmacology , Endothelin Receptor Antagonists , Animals , Cerebrovascular Disorders/drug therapy , Dioxoles/chemical synthesis , Dioxoles/therapeutic use , Heart Failure/drug therapy , Humans , Hypertension/drug therapy , Hypertension, Pulmonary/drug therapy , Receptor, Endothelin A , Structure-Activity Relationship
5.
J Cardiovasc Pharmacol ; 31 Suppl 1: S331-5, 1998.
Article in English | MEDLINE | ID: mdl-9595473

ABSTRACT

We previously showed that CI-1020, an endothelin (ET)-A-selective receptor antagonist, dose-dependently blocked acute hypoxic pulmonary hypertension (PH) in rats. In this study we show that CI-1020 can reverse existing PH and prevent progression of right ventricular hypertrophy (RVH) in rats exposed to chronic hypoxia. Male Sprague-Dawley rats were exposed to 20 days of hypoxia (10% O2) with CI-1020 treatment (20 or 40 mg/kg/day) starting on day 10. On day 20 of hypoxia, the rats were instrumented under anesthesia with a pulmonary artery cannula and allowed to recover to consciousness before measurement of mean pulmonary arterial pressure (MPAP). Blood samples were then collected for plasma ET-1 measurements, the rats killed, and their hearts dissected, dried, and weighed. RV/LV + septum ratio (g/g) was used as an index of RVH (RVHi). Normoxic rats and rats exposed to hypoxia for only 10 days were also evaluated as controls. Normoxic rats had MPAPs of 13 +/- 1 mm Hg, plasma ET-1 levels of 2.1 +/- 0.1 pg/ml, and an average RVHi of 0.29 +/- 0.03. Rats exposed to 10 or 20 days of hypoxia had MPAPs of 33 +/- 2 and 44 +/- 0 mm Hg, plasma ET-1 levels of 4.2 +/- 0.8 and 4.6 +/- 0.8 pg/ml, and average RVHis of 0.47 +/- 0.05 and 0.52 +/- 0.03, respectively. In comparison, rats treated with CI-1020 had MPAPs that were 37% (20 mg/kg/day) and 44% (40 mg/kg/day) lower than untreated 20-day hypoxic rats. Furthermore, rats dosed with 40 mg/kg/day of CI-1020 had MPAPs that were significantly lower (24%) than control 10-day hypoxic rats, indicating a significant reversal of PH. Along with this reversal in PH, their average RVHi was 23% lower (p < 0.05) relative to untreated 20-day hypoxic rats.


Subject(s)
Dioxoles/pharmacology , Endothelin Receptor Antagonists , Hypertension, Pulmonary/drug therapy , Hypoxia/complications , Animals , Blood Pressure/drug effects , Cardiomegaly/drug therapy , Cardiomegaly/pathology , Chronic Disease , Endothelin-1/blood , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/physiopathology , Hypoxia/physiopathology , Male , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A
6.
Adv Pharmacol ; 39: 313-51, 1997.
Article in English | MEDLINE | ID: mdl-9160119

ABSTRACT

One of the most frustrating aspects of restenosis is that it is the result of advances in medical care (there was no restenosis before the days of balloon angioplasty), yet it seems to be resistant to all that science has to offer. Still we believe there is reason to be optimistic. We are at last beginning to see some promise from clinical trials, and data being generated confirm some of the hypotheses previously generated from animal experiments. Thus the effects seen with the GP IIb/IIIa antibody 7E3 suggest that thrombosis may be as important in its long-term sequelae as it is for acute reocclusion. The jury is still out on whether antiproliferative approaches will be a therapeutic option, but local delivery paradigms using novel formulations delivered by catheter or impregnated in stents may allow the concept to be tested without the risk of systemic toxicity. Plans are also underway for gene therapy trials, although we may have to wait for better vector technology before taking these into the coronary bed. Perhaps we should move away from the "single pill" approach and accept that, like many infections, malignancies, or even heart failure, a multifaceted approach with combination therapy will provide the first glimmer of that brighter tomorrow.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Coronary Disease/therapy , Coronary Vessels/pathology , Fibrinolytic Agents/therapeutic use , Immunoglobulin Fab Fragments/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Abciximab , Angioplasty, Balloon, Coronary , Animals , Coronary Disease/physiopathology , Genetic Therapy , Growth Inhibitors/therapeutic use , Heparin/therapeutic use , Humans , Phototherapy , Platelet Glycoprotein GPIIb-IIIa Complex/immunology , Recurrence
7.
Expert Opin Investig Drugs ; 6(11): 1591-605, 1997 Nov.
Article in English | MEDLINE | ID: mdl-15989566

ABSTRACT

Conventional anticoagulant therapy has been based on indirect inhibition of coagulation factors with heparin and warfarin. These agents display liabilities prompting the development of new anticoagulants over the last two decades. The first to be developed was a series of low molecular weight heparins(LMWHs). Their favourable pharmacokinetic profiles and risk/benefit ratios led to widespread use in Europe and, more recently, approval for their use in the USA. Paralleling the development of LMWHs has been the pursuit of a different strategy focused on direct rather than indirect inhibition of enzymes in the coagulation cascade. In contrast to heparin, LMWHs, or other glycosaminoglycans, direct inhibitors exert their effects independent of either antithrombin III (ATIII) or heparin cofactor II (HCII) and more effectively inhibit clot-bound thrombin or FXa. Highly potent, selective (versus other serine proteases)direct thrombin and FXa inhibitors have been identified and isolated from natural sources, such as leeches, ticks and hookworms. The recombinant forms and analogues of the senatural proteins have been produced using molecular biology techniques, i.e., rHirudin, Hirulogs, recombinant tick anticoagulant peptide (rTAP), recombinant antistasin (rATS) and recombinant nematode anticoagulant peptide-5 (rNAP-5). The design of novel structures or the modification of existing chemicals has led to the synthesis of many non-peptide, low molecular weight inhibitors of thrombin and FXa. Some of them are orally active and may be suitable for long-term clinical use. In addition, considerable progress has been made in developing specific TF/VIIa complex inhibitors. The anticoagulation properties of the new agents are being characterised in experimental studies. Some of them have been advanced to large scale clinical trials and their effectiveness, and sometimes relative ineffectiveness,in arterial and venous thromboembolic disorders has been demonstrated. They are being tested for their potential as new antithrombotic agents that act via direct enzyme inhibition. Thus,the clinician should in future be able to target different thrombotic conditions with proven, specific anticoagulant interventions.

8.
Circulation ; 94(3): 258-65, 1996 Aug 01.
Article in English | MEDLINE | ID: mdl-8759064

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors may exert some of their benefits in the therapy of hypertension, congestive heart failure, and acute myocardial infarction by their improvement of endothelial dysfunction. TREND (Trial on Reversing ENdothelial Dysfunction) investigated whether quinapril might improve endothelial dysfunction in normotensive patients with coronary artery disease and no heart failure, cardiomyopathy, or major lipid abnormalities so that confounding variables that affect endothelial dysfunction could be minimized. METHODS AND RESULTS: Using a double-blind, randomized, placebo-controlled design, we measured the effects of quinapril (40 mg daily) on coronary artery diameter responses to acetylcholine using quantitative coronary angiography. The primary response variable was the net change in the acetylcholine-provoked constriction of target segments between the baseline (prerandomization) and 6-month follow-up angiograms. The constrictive responses to acetylcholine were comparable in the placebo (n = 54) and quinapril (n = 51) groups at baseline. After 6 months, only the quinapril group showed significant net improvement in response to incremental concentrations of acetylcholine (4.5 +/- 3.0% [mean +/- SEM] versus -0.1 +/- 2.8% at 10(-6) mol/L and 12.1 +/- 3.0% versus -0.8 +/- 2.9% at 10(-4) mol/L, quinapril versus placebo, respectively; overall P = .002). CONCLUSIONS: TREND shows that ACE inhibition with quinapril improved endothelial dysfunction in patients who were normotensive and who did not have severe hyperlipidemia or evidence of heart failure. These benefits of ACE inhibition are likely due to attenuation of the contractile effects and superoxide-generating effects of angiotensin II and to enhancement of endothelial cell release of nitric oxide secondary to diminished breakdown of bradykinin.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Coronary Disease/drug therapy , Coronary Disease/physiopathology , Endothelium, Vascular/physiopathology , Isoquinolines/therapeutic use , Tetrahydroisoquinolines , Vasomotor System/physiopathology , Acetylcholine , Coronary Disease/diagnostic imaging , Double-Blind Method , Endothelium, Vascular/drug effects , Female , Follow-Up Studies , Humans , Male , Middle Aged , Quinapril , Radiography , Vasomotor System/drug effects
9.
J Clin Pharmacol ; 36(7): 623-33, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8844445

ABSTRACT

A study was conducted to evaluate the pharmacokinetics of procainamide and its active metabolite, N-acetylprocainamide (NAPA), as a function of dose and formulation and to characterize the relationship between ventricular premature depolarization (VPD) rate and plasma concentrations of procainamide and NAPA. A subset of patients (n = 43) with frequent VPD who were enrolled in a double-blind, multicenter, activity trial were assigned in randomized fashion to receive 1 of 4 dose levels (placebo or 1,000, 2,000, or 4,000 mg/day procainamide) and to receive Procanbid (Parke-Davis) tablets every 12 hours or Procan SR (Parke-Davis) tablets every 6 hours during the first week of a blinded crossover phase. Patients crossed over to the alternative formulation after one week. Maximum and steady-state average concentrations of procainamide and NAPA after administration of Procanbid tablets were equivalent to those after administration of an equivalent daily dose of Procan SR tablets. Corresponding trough concentrations of procainamide were lower after administration of Procanbid tablets than after administration of Procan SR tablets. Both formulations produced disproportionate increases in procainamide concentrations with increasing dose; concentrations of NAPA increased in proportion to dose. Assessment of the relationship between VPD rate and drug concentration in plasma indicated no substantive difference between the two formulations. It was concluded that administration of Procanbid tablets every 12 hours is essentially equivalent to administration of procainamide extended-release tablets (Procan SR) every 6 hours with respect to pharmacokinetics of procainamide and NAPA and to VPD suppression.


Subject(s)
Acecainide/pharmacokinetics , Anti-Arrhythmia Agents/pharmacokinetics , Procainamide/pharmacokinetics , Acecainide/administration & dosage , Acecainide/blood , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/blood , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/metabolism , Chemistry, Pharmaceutical , Cross-Over Studies , Delayed-Action Preparations , Double-Blind Method , Female , Humans , Male , Procainamide/administration & dosage , Procainamide/blood , Tablets , Ventricular Premature Complexes
12.
Am J Cardiol ; 72(16): 25F-44F, 1993 Nov 26.
Article in English | MEDLINE | ID: mdl-8237827

ABSTRACT

Pathophysiology of the coronary circulation is a major contributor to altering the myocardial substrate, rendering the heart susceptible to the onset of arrhythmias associated with sudden cardiac death. Antiarrhythmic drug therapy for the prevention of sudden cardiac death has been provided primarily on the basis of trial and error and in some instances based on ill-suited preclinical evaluations. The findings of the Cardiac Arrhythmia Suppression Trial (CAST) requires a reexamination of the manner in which antiarrhythmic drugs are developed before entering into clinical testing. The major deficiency in this area of experimental investigation has been the lack of animal models that would permit preclinical studies to identify potentially useful or deleterious therapeutic agents. Further, CAST has emphasized the need to distinguish between pharmacologic interventions that suppresses nonlethal disturbances of cardiac rhythm as opposed to those agents capable of preventing lethal ventricular tachycardia or ventricular fibrillation. Preclinical models for the testing of antifibrillatory agents must consider the fact that the superimposition of transient ischemic events on an underlying pathophysiologic substrate makes the heart susceptible to lethal arrhythmias. Proarrhythmic events, not observed in the normal heart, may become manifest only when the myocardial substrate has been altered. We describe a model of sudden cardiac death that may more closely simulate the clinical state in humans who are at risk. The experimental results show a good correlation with clinical data regarding agents known to reduce the incidence of lethal arrhythmias as well as those showing proarrhythmic actions.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Death, Sudden, Cardiac/prevention & control , Heart Conduction System/drug effects , Ventricular Fibrillation/prevention & control , Animals , Anti-Arrhythmia Agents/therapeutic use , Death, Sudden, Cardiac/etiology , Disease Models, Animal , Humans , Myocardial Ischemia/complications , Myocardial Ischemia/metabolism , Tachycardia, Ventricular/drug therapy , Ventricular Fibrillation/etiology , Ventricular Fibrillation/physiopathology
13.
Pharmacology ; 47(5): 277-85, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8265718

ABSTRACT

The role of neutrophils in the conversion of big endothelin (Big-ET) to endothelin-1 (ET-1) was assessed in two models. In rabbit isolated hearts, ET-1 demonstrated significant increases in coronary perfusion pressure (PP) at doses greater than 100 pmol. With Big-ET, significant increases were obtained only at doses greater than 3 nmol. Similarly, this dose of Big-ET did not increase PP in isolated, perfused hearts from rabbits previously subjected to 60 min of coronary artery occlusion and 4 h of reperfusion (n = 7). However, when isolated rabbit neutrophils were incubated with Big-ET (n = 5) or vehicle (n = 4) and 3 nmol aliquots assayed in isolated hearts, results demonstrated a time-dependent conversion to a vasoactive product. These findings suggest that isolated neutrophils are capable of converting Big-ET to an ET-1-like vasoactive substance. The model may be useful in assessing antagonists of endothelin-converting enzyme activity and/or the endothelin receptor.


Subject(s)
Endothelins/metabolism , Myocardial Infarction/metabolism , Neutrophils/metabolism , Animals , Blood Pressure , Coronary Vessels/physiology , Dose-Response Relationship, Drug , In Vitro Techniques , Male , Myocardium/metabolism , Rabbits , Time Factors
14.
Cardiovasc Drugs Ther ; 7(2): 273-82, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8357782

ABSTRACT

The rationale, trial design, and statistical aspects of QUIET, the QUinapril Ischemic Event Trial, are described. QUIET is a prospective, double-blind placebo-controlled study that will assess the ability of the angiotensin-converting enzyme (ACE) inhibitor quinapril to reduce the rate of cardiac ischemic events and to slow or prevent the development of coronary artery atherosclerosis as assessed by serial angiography in a normolipidemic population without left ventricular dysfunction. The study began in September 1991 and has completed recruitment with 1740 patients across 38 centers (28 U.S., 4 Canada, 6 Europe) by the end of 1992. Patients are randomized to 20 mg of quinapril or placebo once daily and continue in the study for 3 years. Study completion is projected for 1995.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Coronary Artery Disease/drug therapy , Isoquinolines/therapeutic use , Tetrahydroisoquinolines , Adult , Aged , Angioplasty , Atherectomy , Coronary Artery Disease/prevention & control , Coronary Artery Disease/surgery , Double-Blind Method , Evaluation Studies as Topic , Female , Humans , Incidence , Male , Middle Aged , Placebos , Prospective Studies , Quinapril
16.
Methods Find Exp Clin Pharmacol ; 14(3): 165-73, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1625500

ABSTRACT

The natural history of inducible ventricular tachycardia in post-infarction dogs was followed with serial programmed electrical stimulation (PES: 1-3 extrastimuli, 4 msec duration, 2 x diastolic threshold). Arrhythmia inducibility was defined as a minimum of four unstimulated ventricular ectopic beats. Of 119 dogs prepared for chronic electrophysiological study, 87 (73.1%) were ambulant 24 hours after surgery. Mean infarct size was 11.1 +/- 1.5% of left ventricular (LV) mass for animals dying in the first week, before stimulation. 92.4% of 66 animals were inducible when stimulated at one week, 66.7% at two weeks and 64.3% and 55.6% at the third and fourth weeks respectively (p less than 0.01, Chi-square analysis). Infarct sizes fell from 7.0 +/- 0.5% LV mass at first stimulation to 4.6 +/- 0.8% at third stimulation and could not be visualized thereafter (p less than 0.01,ANOVA). There was no statistical difference between infarct sizes for inducible and non-inducible animals, but in both cases infarcts were smaller (p less than 0.01) than for those animals which died suddenly during the first week. This time-dependent decrease in arrhythmia inducibility, which may be related to infarct size, should be considered when similar models are employed for chronic electrophysiological studies.


Subject(s)
Tachycardia/physiopathology , Animals , Disease Models, Animal , Dogs , Electric Stimulation , Electrocardiography , Female , Male , Myocardial Infarction/physiopathology , Survival Rate , Time Factors
17.
J Cardiovasc Pharmacol ; 18(5): 703-10, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1723767

ABSTRACT

The protective effect of hypothyroidism against lethal ventricular tachyarrhythmias (VT) in the subacute phase of experimental myocardial infarction (MI) was investigated in 10 thyroidectomized dogs using a conscious model of sudden coronary death. Four weeks after surgical ablation of the thyroid, and having established biochemical hypothyroidism, anterior MI was produced by 120 min of occlusion-reperfusion of the left anterior descending coronary artery. In the subacute phase of MI, the inducibility of VT was investigated using programmed ventricular stimulation (PVS), and the effects on spontaneous development of ventricular fibrillation (VF) were studied by production of posterolateral ischemia at a site remote from the area of the previous infarction. Ischemia was produced by the passage of anodal direct current through a silver wire electrode implanted in the left circumflex coronary (LCX) artery. The results were compared to those from a cohort of 20 existing euthyroid controls that had undergone an identical experimental protocol. No differences were found in heart rate and other electrocardiographic parameters such as the PR, QRS, and QT (paced at 2.5 Hz) and the QTc interval between the hypo- and euthyroid groups. During PVS in the subacute phase of anterior MI, the measured threshold voltage and ventricular refractory periods were similar in both groups. The incidence of inducibility of VT was 100% in the euthyroid animals compared to 60% in the hypothyroid dogs, suggesting an antiarrhythmic effect of hypothyroidism. The incidence of sustained vs. nonsustained VT was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Arrhythmias, Cardiac/prevention & control , Death, Sudden, Cardiac/etiology , Hypothyroidism/physiopathology , Animals , Arrhythmias, Cardiac/physiopathology , Dogs , Electroencephalography , Electrophysiology , Heart Rate/drug effects , Heart Ventricles/physiopathology , Isoproterenol/pharmacology , Myocardial Infarction/physiopathology , Tachycardia/physiopathology , Thyroid Gland/physiology , Thyroidectomy , Thyroxine/blood , Triiodothyronine/blood , Ventricular Fibrillation/physiopathology
18.
J Pharm Pharmacol ; 43(9): 630-5, 1991 Sep.
Article in English | MEDLINE | ID: mdl-1685521

ABSTRACT

Resolution of mexiletine enantiomers from the racemic mixture has been achieved by fractional crystallization through the formation of diastereoisomeric p-toluoyl tartrate salts. Following three crystallization steps in methanol, R-(-)- and S-(+)-mexiletine were resolved with an optical purity greater than 98% (yield approximately 30%) and their hydrochloride salts formed. Incremental doses of mexiletine enantiomers were administered to dogs with experimentally-induced arrhythmias to investigate the stereoselective antiarrhythmic and electrophysiological effects of these compounds. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious animals 7-30 days after coronary ligation. R-(-)-Mexiletine prevented ventricular tachycardia in 3/6 dogs (2 after 0.5 mg kg-1, 1 after 8 mg kg-1); two animals died after 1 and 8 mg kg-1, respectively; one remained unchanged even at the highest dosage (16 mg kg-1). S-(+)-Mexiletine prevented ventricular tachycardia in only one dog (after 1 mg kg-1); two died after 4 and 8 mg kg-1, respectively; 2/5 remained unchanged even after the administration of 16 mg kg-1. No significant changes in any electrocardiographic intervals (PR, QRS, QTc) or refractory periods were induced by mexiletine enantiomers at any doses used (0.5-16.0 mg kg-1). These results suggest that R-(-)-mexiletine possesses greater antiarrhythmic properties than the opposite enantiomer.


Subject(s)
Mexiletine/therapeutic use , Tachycardia/drug therapy , Animals , Dogs , Electric Stimulation , Electrocardiography/drug effects , Electrophysiology , Heart/physiology , Mexiletine/chemistry , Mexiletine/isolation & purification , Stereoisomerism
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