L. O. Hughes

Fibrinogen, factor VII clotting activity and coronary artery disease severity

To asses the relationship between fibrinogen, factor VII coagulant (VIIc) activity and extent of coronary artery disease, we studied 43 white males shown to have greater than 50% stenosis of at least one major coronary artery. Thirty six had a definite history of myocardial infarction at least 3 months earlier and were classified as having 1, 2 or 3 vessel disease while 7 had 2 or 3 vessel disease, but no prior infarction. Groups were similar with regard to age, body mass index and blood pressure. In those with documented prior infarction, there was a significant relationship between the extent of atheroma and coagulation variables factor VIIc and fibrinogen. However, given a similar degree of atheroma, patients with prior infarction had significantly higher levels of factor VIIc activity compared with patients without such a history. These results corroborate those from prospective studies confirming a significant role for the coagulation system in the clinical manifestation of coronary artery disease.

Ranolazine (RS-43285): A preliminary study of a new anti-anginal agent with selective effect on ischaemic myocardium

SummaryRanolazine (RS-43285) has been shown to possess significant anti-ischaemic properties in a canine model of reversible myocardial ischaemia. The clinical efficacy of this new agent was assessed by a single blind, placebo controlled study of 14 patients with chronic stable angina. A 2 week placebo phase was followed by therapy with 30 mg and 60 mg of ranolazine tid for 2 weeks each. Graded, symptom limited treadmill exercise tests were performed at the end of each phase, 1.5 h (AM) and 7 h (PM) after the morning dose. An additional exercise test 1.5 h after the first dose of 30 mg was included to assess the acute dose response.In the AM study, the mean exercise time increased from 6.9 min (placebo) to 7.8 min after the first dose of 30 mg and to 8.2 min and 8.5 min respectively at the end of 30 mg and 60 mg phases. In the PM study, exercise time improved from 6.5 min (placebo) to 8.2 min and 7.8 min respectively at the end of 30 mg and 60 mg phases. The time to onset of angina showed a similar improvement.No significant changes were observed in the resting and peak exercise heart rates and blood pressure.This preliminary study suggests that ranolazine may significantly prolong exercise time in patients with stable coronary artery disease without altering heart rates and blood pressure.

Comparison of nicorandil and atenolol in stable angina pectoris

The efficacy of nicorandil was compared with atenolol in 37 patients with chronic stable angina using a randomized, placebo-controlled, parallel study design. After a single-blind placebo phase, patients were randomized to receive nicorandil or atenolol using a double-dummy technique. Patients took nicorandil 10 mg twice daily or atenolol 50 mg once daily for the first 3 weeks, and if no adverse effects were encountered they took nicorandil 20 mg twice daily or atenolol 100 mg once daily, for the final 3-week phase. Treadmill exercise tests were performed at the end of each treatment phase immediately before and 2 hours after the morning dose of medication. Groups were demographically similar. Placebo exercise times were 7.06 (0.60) minutes (mean +/- standard error of the mean) in the nicorandil group and 6.81 (0.47) minutes in the atenolol group. After 6 weeks, improvements in exercise time were before dosing: +1.47 (0.40) minutes with nicorandil (p less than 0.005) and +1.33 (0.29) minutes with atenolol (p less than 0.001). Improvements after therapy was administered were +2.45 (0.41) minutes with nicorandil (p less than 0.001) and +2.37 (0.43) minutes with atenolol (p less than 0.0001). Whereas, the predose peak exercise double product (heart rate X systolic blood pressure mm Hg/100) was reduced with atenolol (-43.6 units; p less than 0.001), an increase (+7.56 units; difference not significant) was noted with nicorandil. One patient taking atenolol and 5 taking nicorandil developed persistent headaches. One subject with severe 3-vessel coronary artery disease had fatal myocardial infarction within 3 days of starting nicorandil, 10 mg twice daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between plasma cholesterol and coronary artery disease in Asians

Cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride concentrations were measured in 150 male survivors of first myocardial infarction and in 115 age and ethnic matched healthy controls. The total cholesterol concentration was higher in whites than in respective Asian groups and higher in patients than in controls (P less than 0.001). The ratio of cholesterol to HDL cholesterol was significantly higher in patients (P less than 0.001) and in both ethnic groups was a powerful independent predictor of cases. In Asians, the extent of coronary atheroma assessed by arteriography 2-12 weeks after infarction correlated independently with the total cholesterol concentration (P = 0.03). Thus, in Asian men, the lower level of total cholesterol compared to whites may be misleading. In Asian men the extent of atheroma correlated with the total cholesterol concentration and the relative risk of infarction increased with the ratio of total to HDL cholesterol. At a given level of cholesterol different ethnic groups may be at differing levels of cardiac risk and the cholesterol ratio may be a more appropriate means of inter-ethnic comparison.

Antianginal efficacy of carvedilol, a beta-blocking drug with vasodilating activity

The efficacy of carvedilol, a new vasodilating beta-blocking drug, was evaluated in 20 patients with chronic angina using a single-blind, placebo-controlled protocol. A 2-week placebo phase was followed by therapy with carvedilol, 25 mg twice daily for 2 weeks, after which the dose was doubled. There was then a second placebo phase lasting 2 weeks. Treadmill exercise testing, 24-hour ambulatory electrocardiographic monitoring and drug blood level assays were performed at the end of each phase. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 minutes during placebo to 9.0 +/- 0.5 minutes carvedilol, 25 mg twice daily (p less than 0.001), and to 9.2 +/- 0.4 minutes with 50 mg twice daily (p less than 0.001). Mean time to 1 mm of ST depression in both bipolar leads CM5 and CC5 increased significantly, but peak ST depression did not change. Heart rate at rest was reduced at both dose levels, from 86 +/- 4 beats/min during placebo to 70 +/- 2 beats/min with 25 mg twice daily (p less than 0.001) and to 67 +/- 3 beats/min with 50 mg twice daily (p less than 0.001). Systolic blood pressure at rest was significantly reduced at both doses (p less than 0.05; p less than 0.01), but blood pressure during exercise was decreased only with the larger dose (p less than 0.001). The exercise rate-pressure product was 182 +/- 9 with placebo and decreased to 153 +/- 5 with 25 mg twice daily (p less than 0.001) and to 138 +/- 6 with 50 mg twice daily (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Hageman factor and risk of myocardial infarction in middle-aged men

In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.

Sustained release verapamil, a once daily preparation: Objective evaluation using exercise testing, ambulatory monitoring and blood levels in patients with stable angina

The efficacy of a once daily, sustained release formulation of verapamil (Verapamil SR, 360 mg) was evaluated in 19 patients with chronic angina pectoris using a double-blind placebo-controlled crossover protocol. Evaluation by exercise testing, 24 hour electrocardiographic ambulatory monitoring and blood drug level assays was performed at the end of each 2 week phase, 21 to 23 hours after the last dose. After the crossover protocol, all patients were given sustained release verapamil for 4 weeks and the evaluation was repeated. Exercise time (mean +/- SEM) increased from 7.4 +/- 0.6 minutes with placebo to 9.6 +/- 0.8 minutes with verapamil (p less than 0.001) and to 9.5 +/- 0.7 minutes (p less than 0.001) after 4 weeks of therapy. The mean time to 1 mm ST depression also increased significantly, from 4.5 +/- 0.4 and 4.8 +/- 0.5 minutes in bipolar leads CM5 and CC5, respectively, with placebo, to 5.5 +/- 0.6 (p less than 0.05) and 6.2 +/- 0.5 minutes (p less than 0.01) with verapamil. Maximal ST depression and rest and peak heart rates were not altered significantly. The mean rate-pressure product was 208 +/- 9.9 with placebo and decreased to 189 +/- 7.7 (p less than 0.05) with verapamil but rose to 200.6 +/- 10.4 (p = NS) after 4 weeks of therapy. The mean hourly heart rates were lower with the drug than with placebo throughout the 24 hour period but there was no significant bradycardia, arrhythmia or heart block.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive ambulatory blood pressure monitors : a cautionary note

Physicians are encouraged to use ambulatory recorders as part of their evaluation of the midly hypertensive patient. But is the information that these machines provide accurate, and is the time and expense of the procedure justified? In short, should ambulatory monitoring be performed on the larger number of mildly hypertensive patients in order to identify the significant minority who are «white coat» responders?

Acute bacterial endocarditis on a normal aortic valve following vaginal delivery

We present a case of post-partum bacterial endocarditis on a normal aortic valve. Infection occurred following vaginal delivery. This complication, due to group D Streptococcus faecalis, has not been previously described in this context.

Lack of effect of asymmetrical dosage timing of isosorbide-5-mononitrate on nitrate tolerance during long-term administration.

SummaryIsosorbide 5-mononitrate is an active metabolite of isosorbide dinitrate and possesses many theoretical advantages over its parent drug. However, the development of partial tolerance has been demonstrated when the drug is given 12 hourly or 8 hourly. We have therefore evaluated the acute and sustained (2 weeks) effects of isosorbide-5-mononitrate 40 mg given twice daily (08.00 h and 14.00 h, allowing an 18-h dose-free period) in 19 patients with stable chronic angina, using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol.There were two phases of 2 weeks each in which patients received placebo or active isosorbide-5-mononitrate. Acute testing was performed 2 h after the first dose and chronic testing 2 h after the morning dose on Day 14.Acute testing showed an increase in exercise time from a mean (SD) of 6.7 (2.2) min to 10.1 (2.95) min (P<0.01) after a single dose of isosorbide-5-mononitrate 40 mg. The time to 1 mm of ST depression, and rest and peak exercise heart rates increased significantly during acute testing with isosorbide-5-mononitrate; resting and peak exercise systolic blood pressures fell significantly.Due to drop outs cross-over analysis was performed on 11 patients who completed both chronic phases and 13 patients were assessed for the comparison of acute isosorbide-5-mononitrate with chronic isosorbide-5-mononitrate. After 2 weeks of therapy exercise time did not show a sustained increase 8.01 (2.14) min chronic placebo to 8.58 (1.93) min chronic isosorbide-5-mononitrate. The improvement in ST segment variables seen acutely was not sustained.These data suggest that the attenuation of the effect of isosorbide-5-mononitrate due to partial tolerance is not mitigated by using an asymmetrical dose regimen.