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Biomedical subjects

J O Parker

Publications and source records attributed to J O Parker.

At least 19 recordsLinked to original sources
PubMed1999

ARCTIC: assessment of haemodynamic response in patients with congestive heart failure to telmisartan: a multicentre dose-ranging study in Canada.

BACKGROUND: The aim of this study was to examine the acute hemodynamic and neurohormonal effects of the angiotensin II antagonist telmisartan relative to placebo in patients with chronic symptomatic (New York Heart Association class II to III) congestive heart failure and to explore the dose-response relation for these effects. METHODS AND RESULTS: After baseline hemodynamic and neurohormonal measurements made with the use of a pulmonary artery and radial arterial catheter, 82 patients were randomly assigned to placebo or 10, 20, 40, or 80 mg of telmisartan in a double-blind fashion. Hemodynamic and neurohormonal measurements were carried out over 24 hours. Telmisartan caused significant decreases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures with evidence of a dose-response relation for each of these parameters. The drug had no significant effects on heart rate, cardiac index, or systemic vascular resistance. Telmisartan did not have consistent effects on either plasma norepinephrine or plasma atrial natriuretic peptide levels, although it did cause significant increases in both plasma renin activity and angiotensin II levels at higher doses. CONCLUSIONS: The acute administration of the angiotensin II antagonist telmisartan was associated with significant dose-dependent reductions in systemic arterial blood pressure and pulmonary pressures. Long-term follow-up studies are required to translate changes in hemodynamic parameters into a clinical benefit.

Adolescent↗
PubMed1997

Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial.

BACKGROUND: We quantified cardiovascular death and/or left ventricular (LV) dilatation in patients from the SAVE trial to determine whether dilatation continued beyond 1 year, whether ACE inhibitor therapy attenuated late LV dilatation, and whether any baseline descriptors predicted late dilatation. METHODS AND RESULTS: Two-dimensional echocardiograms were obtained in 512 patients at 11+/-3 days and 1 and 2 years postinfarction to assess LV size, percentage of the LV that was akinetic/dyskinetic (%AD), and LV shape index. LV function was assessed by radionuclide ejection fraction. Two hundred sixty-three patients (51.4%) sustained cardiovascular death and/or LV diastolic dilatation; 279 (54.5%) had cardiovascular death and/or systolic dilatation. In 373 patients with serial echocardiograms, LV end-diastolic and end-systolic sizes increased progressively from baseline to 2 years (both P<.01). More patients with LV dilatation had a decrease in ejection fraction: 24.8% versus 6.8% (P<.001) (diastole) and 25.7% versus 5.3% (P<.001) (systole). Captopril attenuated diastolic LV dilatation at 2 years (P=.048), but this effect was carried over from the first year of therapy because changes in LV size with captopril beyond 1 year were similar to those with placebo. Predictors of cardiovascular death and/or dilatation were age (P=.023), prior infarction (P<.001), lower ejection fraction (P<.001), angina (P=.007), heart failure (P=.002), LV size (P<.001), and infarct size (%AD) (P<.001). CONCLUSIONS: Cardiovascular death and/or LV dilatation occurred in >50% of patients by 2 years. LV dilatation is progressive, associated with chamber distortion and deteriorating function that is unaffected by captopril beyond 1 year.

Captopril↗
PubMed1997

The effect of hydralazine on the development of tolerance to continuous nitroglycerin.

It has been reported that nitroglycerin (GTN) tolerance can be prevented by the concurrent administration of hydralazine. Although the mechanism of this effect remains unknown, it is possible that hydralazine modifies counter-regulatory responses to nitrate administration. To address this question, we examined the impact of hydralazine therapy on the development of tolerance during sustained therapy with GTN. Twenty normal volunteers and 18 patients with chronic heart failure (mean ejection fraction 30 +/- 2%) were treated for 1 week with hydralazine or placebo in a randomized double-blind fashion. Hydralazine therapy (or placebo) was continued, and subjects then received continuous transdermal GTN for 5 to 7 days. On the first and last day of transdermal GTN therapy, standing HR, systolic blood pressure and hematocrit responses were assessed. HR and blood pressure responses to sublingual GTN (0.6 mg) were also evaluated before and during sustained transdermal GTN therapy. Significant loss of the hemodynamic effects of transdermal GTN occurred during sustained therapy in both the normal volunteer and heart failure groups. Hydralazine had no effect on the development of tolerance to the hemodynamic effect of GTN in either group. In both, transdermal GTN therapy was associated with a significant fall in hematocrit that persisted for the entire treatment period. Hydralazine had no effect on this response. These data suggest that hydralazine therapy does not prevent loss of systemic arterial effects or prevent plasma volume expansion during sustained transdermal GTN therapy.

Administration, Cutaneous↗
PubMed1996

Effects of diuretic therapy on the development of tolerance to nitroglycerin and exercise capacity in patients with chronic stable angina.

BACKGROUND: Therapy with diuretics has been reported to prevent the development of nitrate tolerance. Importantly, diuretics may have independent antianginal effects through their effects on intravascular volume. The present investigation was designed to determine whether diuretic therapy could prevent the development of tolerance to continuous transdermal nitroglycerin. The study was also designed to examine whether diuretic therapy has an independent antianginal effect. METHODS AND RESULTS: Twelve patients with chronic stable angina were studied in a randomized, double-blind, crossover trial. Patients received diuretic (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each double-blind treatment period, patients underwent treadmill exercise testing on three separate occasions. The first exercise testing was performed after 7 to 10 days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently, exercise testing was repeated on the first day of active transdermal nitroglycerin therapy and following 7 to 10 days of continuous transdermal nitroglycerin application. Therapy with a diuretic was associated with an increase in exercise capacity but had no effect on nitroglycerin tolerance. During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an increase in treadmill walking time to the development of moderate angina compared with placebo (371 +/- 26 versus 288 +/- 16 seconds, diuretic versus placebo, P < .01). Similar results were obtained during both acute and sustained nitroglycerin therapy. CONCLUSIONS: The results of this study demonstrate that therapy with a diuretic has no effect on the development of tolerance to continuous transdermal nitroglycerin. Interestingly, diuretic therapy itself has important antianginal effects and improves exercise capacity in patients with stable angina.

Administration, Cutaneous↗
PubMed1996

Nitrate tolerance--problems both new and old.

Nitrate tolerance has been recognized for many years but only recently has it been shown to be an important clinical problem. Tolerance develops very rapidly during oral, transdermal or intravenous nitrate administration and treatment strategies designed to provide therapeutic effects throughout 24 h each day are associated with marked attenuation of nitrate effects. The mechanisms responsible for tolerance are not clearly understood. The hypotheses put forward to explain this phenomenon include reduction of sulfhydryl groups in vascular smooth muscle with resultant diminished nitric oxide production, neurohormonal activation, plasma volume expansion, and superoxide anion production. Attempts to prevent or reverse tolerance with sulfhydryl group donors, angiotensin-converting enzyme inhibitors, and hydralazine have not been uniformly successful and such approaches are impractical. The beneficial nitrate effect can be preserved by appropriate dosing which provides a period of many hours of nitrate washout during each 24 h period.

Administration, Cutaneous↗
PubMed1995

Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group.

BACKGROUND: The objectives of this study were to assess the antianginal and anti-ischemic effects of three dose levels of transdermal nitroglycerin patches applied for 12 hours daily for 30 days. The study also assessed the development of tolerance and rebound. Intermittent transdermal nitroglycerin therapy with a patch-free period of 10 to 12 hours each day has documented clinical benefits during the period of patch application, but studies have failed to clearly document prolonged exercise duration for the entire period of patch application. This study was designed to evaluate the efficacy and duration of action of a range of doses of nitroglycerin. The study also permitted the assessment of the maintenance of initial effects, the development of tolerance, and the presence of rebound. METHODS AND RESULTS: This study was a multicenter, randomized, double-blind, placebo-controlled parallel design trial with treadmill exercise tests at days 0, 1, 7, 15, and 30. Tests were carried out up to 12 hours after patch application. There was a statistically significant treatment effect with increases in treadmill walking time to moderate angina in each nitroglycerin patch group compared with placebo at various time points up to 12 hours throughout the 30-day study period. Secondary efficacy parameters, including the consistent increase in time to 1-mm ST-segment depression, supported the primary efficacy results. There was no evidence of tolerance or rebound. CONCLUSIONS: Intermittent transdermal nitroglycerin therapy increases exercise duration and maintains anti-ischemic effects for 12 hours after patch application, throughout 30 days of therapy, without significant evidence of nitrate tolerance or rebound phenomena.

Administration, Cutaneous↗
PubMed1995

Intermittent transdermal nitroglycerin therapy. Decreased anginal threshold during the nitrate-free interval.

BACKGROUND: Intermittent transdermal nitroglycerin therapy is effective in the treatment of stable angina and prevents the development of tolerance. Previous investigations have suggested that removal of nitroglycerin patches may be associated with a decrease in anginal threshold. This study examines the effect of nitroglycerin patch removal on anginal threshold in a group of patients with stable angina. METHODS AND RESULTS: Twelve patients with stable angina were enrolled in a randomized, double-blind, placebo-controlled, crossover study. These patients had reproducible treadmill walking times and were taking no other long-acting antianginal medications or vasodilators. They received 0.8 mg/h transdermal nitroglycerin or wore a matching placebo patch for 5 to 7 days and then crossed over to the other treatment arm of the study. Transdermal nitroglycerin was applied at 8:00 PM and removed at 8:00 AM each day. On the last day of each treatment period, patients underwent treadmill exercise testing at 8:00 AM (before patch removal) and at 2, 4, and 6 hours after patch removal. The primary end point was the treadmill walking time until moderate angina (P2). Other end points included the treadmill walking time until onset of angina (P1), the amount of ST segment depression at P1 and P2, and treadmill walking time until the development of 1 mm ST depression. Heart rate, systolic blood pressure, and the rate-pressure product were determined at rest before exercise and at P1 and P2. At 8:00 AM P1 and P2 were not significantly affected by active nitroglycerin compared with placebo, indicating the development of tolerance. Removal of the active transdermal nitroglycerin patch was associated with a significant decrease in the time to P1 at 2, 4, and 6 hours after patch removal compared with placebo. There was also a decrease in the time to P2 after active patch removal that was statistically significant compared with placebo at 2 and 4 hours and was of borderline significance at 6 hours. There were no differences in heart rate, blood pressure, or amount of ST segment depression at either P1 or P2 after active compared with placebo patch removal. CONCLUSIONS: In patients with stable angina pectoris, intermittent transdermal nitroglycerin therapy is associated with a decrease in anginal threshold for 4 to 6 hours after patch removal. Although the cause of this phenomenon remains uncertain, it may be due to counterregulatory responses that develop during nitroglycerin patch application.

Administration, Cutaneous↗
PubMed1994

Limited usefulness of exercise testing and thallium scintigraphy in evaluation of ambulatory patients several months after recovery from an acute coronary event: implications for management of stable coronary heart disease. Multicenter Myocardial Ischemia Research Group.

OBJECTIVES: This study evaluated the value of noninvasive testing to predict cardiac events in patients with stable coronary disease after hospital admission (and risk stratification) for an acute coronary event. BACKGROUND: Exercise testing with thallium perfusion imaging identifies patients with obstructive coronary artery disease and has been used to stratify patients after myocardial infarction. Its usefulness for predicting cardiac events in patients with stable coronary disease after recovery from an acute coronary event was explored. METHODS: Nine hundred thirty-six patients were enrolled 1 to 6 months after hospital admission for a coronary event. Patients underwent exercise treadmill testing with planar thallium-201 scintigraphy and were followed up for an average of 23 months (range 6 to 43). End points were 1) unstable angina requiring hospital admission, nonfatal myocardial infarction or cardiac death; 2) nonfatal infarction or cardiac death; or 3) cardiac death alone. RESULTS: Twelve patients died of cardiac causes (1.2%); 32 had a nonfatal myocardial infarction (3.4%); and 79 patients (8.4%) developed unstable angina in the first year. Exercise testing improved proportional hazards models constructed from clinical variables for all three end points (p < 0.05). The perfusion scan further improved models for the end points (nonfatal infarction or cardiac death and cardiac death alone, p < 0.05). However, the exercise test with or without thallium added little to the overall prediction of primary events (area under the receiver operating curve increased from 0.649 to 0.663), and only 2% to 13% of patients with abnormal results either had a nonfatal infarction or died. CONCLUSIONS: Thallium-201 scintigraphy and exercise testing variables identify patients at risk for subsequent cardiac events. However, the poor predictive performance of these tests in this group of patients with stable coronary disease severely limits their usefulness. These results suggest a limited role for exercise and thallium testing in predicting cardiac events in patients with known coronary disease.

Coronary Disease↗
PubMed1994

Morning increase in ambulatory ischemia in patients with stable coronary artery disease. Importance of physical activity and increased cardiac demand.

BACKGROUND: The morning increase in asymptomatic ambulatory ischemia may be due to heightened coronary tone, increased physical activity, or both. If ambulatory ischemia is primarily due to physical activity, then alterations in the schedule of physical activity should be reflected in a corresponding alteration in the occurrence of ischemia. This study was designed to examine the relation between activity patterns and the frequency of ambulatory ischemic episodes and the effect of nadolol on these relations. METHODS AND RESULTS: A double-blind, randomized, placebo-controlled, crossover trial of nadolol versus placebo was performed in 20 patients with stable coronary artery disease. At the end of each 2-week treatment phase, patients were hospitalized for 48 hours. In the hospital, there was a regular activity day (awaken and assume normal activities at 8:00 AM) and a delayed activity day (awaken at 8:00 AM, arise at 10:00 AM, and begin normal activity at noon). Ambulatory ECG monitoring was performed throughout the hospitalization. On the regular activity day, there was a morning increase in heart rate and in the number of ischemic episodes during therapy with placebo that began at 8:00 AM. In contrast, on the delayed activity day, there was a 4-hour phase shift of the increases in heart rate and the increase in ischemic episodes (ie, at noon) corresponding to the onset of physical activities. Therapy with nadolol caused a 50% reduction in the total number of ischemic episodes (129 versus 65, placebo versus nadolol; P < .02). During nadolol therapy, there was no discernible circadian peak in the number of ischemic episodes on either activity day. During placebo treatment, 87% of ischemic episodes were preceded by an increase in heart rate > or = 5 beats per minute. Although nadolol caused a significant reduction in the total number of episodes preceded by a heart rate increase compared with placebo (99 versus 38 episodes, P < .04), this therapy was associated with a significant increase in the number of episodes not associated with a heart rate increase (15 versus 21 episodes, P < .002). CONCLUSIONS: The morning increase in ambulatory ischemic episodes is due to physical activity patterns. The majority of ischemic episodes are preceded by a heart rate increase, and it is these episodes that are primarily responsible for the morning increase in ischemia. Therapy with nadolol caused a reduction in the total number of ischemic episodes solely by reducing those episodes preceded by a heart rate increase. In contrast, nadolol caused a significant increase in the number of ischemic episodes not associated with a heart rate increase, perhaps in part because it potentiated coronary vasoconstriction.

Aged↗
PubMed1994

Efficacy of eccentric dosing with sustained-release isosorbide dinitrate in patients with angina pectoris.

OBJECTIVE: To assess the anti-anginal efficacy of eccentric dosing with a sustained-release formulation of isosorbide dinitrate (ISDN) administered twice daily in an eccentric fashion (08:00 and 14:00). DESIGN: A placebo controlled crossover study of 16 patients with chronic stable angina who received, in random order, either placebo or sustained-release ISDN 40 mg twice daily for a period of seven to 10 days. Patients were entered who had reproducible exercise test to the development of moderate angina. All anti-anginal drugs with the exception of beta-blockers were withheld during the study period. The primary end-point was the treadmill walking time to the development of moderate angina. RESULTS: Patients receiving active therapy showed a significant increase in treadmill walking time to moderate angina over that seen with placebo at 3 and 6 h after the morning dose and 3 and 8 h after the afternoon dose. Similar trends occurred for the time to onset of angina and the time to development of 1 mm of ST segment depression on the electrocardiogram. CONCLUSIONS: Eccentric dosing with sustained-release ISDN, 40 mg given 6 h apart, provided significant improvement in exercise performance for up to 14 h during sustained therapy.

Angina Pectoris↗
PubMed1993

Eccentric dosing with isosorbide-5-mononitrate in angina pectoris.

In a placebo-controlled, parallel, double-blind study, 214 patients with stable angina were studied. Doses of 5, 10 and 20 mg of immediate-release isosorbide-5-mononitrate (IS-5-MN) or placebo were administered at 0800 and 1500 hours for a period of 3 weeks. On days 1 and 14, patients underwent exercise testing before, and 2 and 7 hours after both doses; on days 7 and 21, testing was performed 2 hours after morning dosing. Study variables included total exercise duration and time to moderate angina. On day 1, the active treatment groups showed improvement over the placebo group 2 and 7 hours after dose 1, and 2 hours after dose 2. Throughout the subsequent study period, each active treatment group was superior to placebo 2 hours after the first and second doses. Only the 20 mg dose increased exercise duration 7 hours after dosing, and this was observed after both doses 1 and 2 on day 14. There were fewer episodes of angina in patients receiving the 20 mg dose. There was no increase in nocturnal angina during eccentric dosing with IS-5-MN. In comparing exercise times throughout the study, tolerance did not develop during eccentric dosing. The morning exercise tests before tablet administration showed a progressive increase during the study period, with slightly greater improvement in patients receiving active therapy. This absence of a zero hour effect suggests that rebound does not occur during eccentric dosing with immediate-release IS-5-MN.

Adult↗
PubMed1993

Nitrates and angina pectoris.

This review discusses the mechanisms of action of the organic nitrates, nitrate tolerance, and the effects of nitrates in patients with stable angina pectoris. The nitrates are prodrugs that enter the vascular smooth muscle, where they are denitrated to form the active agent nitric oxide (NO). NO activates guanylate cyclase, which results in cyclic guanosine monophosphate (cGMP) production and vasodilation as a result of reuptake of calcium by the sarcoplasmic reticulum. NO is identical to endothelium-derived relaxing factor (EDRF), which induces vasodilation, inhibits platelet aggregation, reduces endothelium adhesion, and has anticoagulant and fibrinolytic effects. Thus, the nitrates may be more than vasodilators and, in addition to reducing ischemia, may affect the process of atherosclerosis. The vascular effects of nitrates are attenuated during sustained therapy. Although the basis for the phenomenon of nitrate tolerance is not completely understood, sulfhydryl depletion as well as neurohormonal activation and increased plasma volume may be involved. The administration of N-acetylcysteine, angiotensin-converting enzyme (ACE) inhibitors, or diuretics do not consistently prevent nitrate tolerance. At present, intermittent nitrate therapy is the only way to avoid nitrate tolerance. The intermittent administration of nitrates, however, cannot provide continuous therapeutic benefits, and thus monotherapy with nitrates is not suitable for many patients with stable angina pectoris.

Angina Pectoris↗
PubMed1993

The effects of oral ibopamine in patients with mild heart failure--a double blind placebo controlled comparison to furosemide. The Ibopamine Study Group.

The effect of ibopamine and furosemide in 130 patients with NYHA Class I and II heart failure were studied in a parallel, double-blind, randomized placebo-controlled multi-centre trial. Ibopamine 200 mg b.i.d. was compared to furosemide 40 mg q.d. and placebo. A 1- to 2-week single-blind run-in period was followed by an 8-week double-blind treatment period. Reproducible treadmill exercise test times with the modified Naughton-Balke protocol were required for randomization. Exercise times increased significantly in comparison to the placebo group after 8 weeks of therapy for both the furosemide group (1.2 min, P < 0.035) and the ibopamine group (1.3 min, P < 0.025). Neither furosemide nor ibopamine affected quality of life assessments. Adverse clinical experiences were generally mild and similar in frequency amongst the three treatment groups. The results of this study show the usefulness of both ibopamine and furosemide as monotherapy in patients with mild congestive heart failure.

Administration, Oral↗
PubMed1993

Effect of therapy with an angiotensin-converting enzyme inhibitor on hemodynamic and counterregulatory responses during continuous therapy with nitroglycerin.

OBJECTIVES: We sought to characterize the reflex counterregulatory responses throughout a 6-day period of continuous nitroglycerin therapy and to examine the effect of concurrent administration of a non-thiol angiotensin-converting enzyme inhibitor (benazepril) on the nature of those responses. BACKGROUND: Therapy with nitroglycerin has been shown to be associated with reflex counterregulatory responses. METHODS: Standing systolic blood pressure, hormonal responses, urinary sodium and hematocrit levels were monitored during 6 days of continuous transdermal nitroglycerin therapy in normal volunteers. Using a double-blind randomized parallel design, 11 subjects received placebo and 9 received benazepril. Hemodynamic responses to sublingual nitroglycerin administration were evaluated before and after sustained therapy with transdermal nitroglycerin. RESULTS: Attenuation of the hypotensive response to transdermal nitroglycerin was rapid in the group receiving placebo and the group receiving benazepril. There were no significant hormonal responses to transdermal nitroglycerin in either group, and sodium retention was modest and transient. Hematocrit levels decreased after transdermal nitroglycerin therapy and remained depressed for the duration of nitroglycerin therapy, a finding that suggests plasma volume expansion. Blood pressure responses to sublingual nitroglycerin in both groups were similar before and after continuous transdermal nitroglycerin therapy. CONCLUSIONS: These data suggest that plasma volume expansion plays a more important role than neurohormonal responses in the loss of nitrate effects during sustained therapy. That therapy with an angiotensin-converting enzyme inhibitor did not modify the hemodynamic responses to continuous nitroglycerin therapy supports this conclusion. Further investigation will be necessary to confirm whether therapy with an angiotensin-converting enzyme inhibitor has any role in the prevention of nitrate tolerance.

Administration, Cutaneous↗
PubMed1992

Neurohormonal activation during nitrate therapy: a possible mechanism for tolerance.

The hemodynamic and antianginal effects of the organic nitrates are greatly reduced during therapy designed to provide 24-hour protection throughout each day. Although the mechanisms of tolerance are not clearly understood, it is likely that tolerance is related to a combination of reduced sulfhydryl groups in vascular smooth muscle and neurohormonal activation. These changes would reduce nitrate-induced vasodilation and induce sodium and water retention with an increase in plasma volume. These reflex neurohormonal changes would reduce the hemodynamic effect of any given degree of nitrate-induced vasodilation. Although preliminary studies suggest that diuretic therapy or the use of converting enzyme inhibitors may reduce or abolish tolerance, further clinical studies are required to confirm these findings.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Effects of diuretic therapy on the development of tolerance during continuous therapy with nitroglycerin.

OBJECTIVES: This study examined the effects of concurrent diuretic therapy on the hemodynamic responses to short-term and sustained therapy with transdermal nitroglycerin. BACKGROUND: Sodium retention and plasma volume expansion occur during therapy with nitroglycerin and may play a role in the loss of nitroglycerin effects during sustained therapy. METHODS: Twenty-two normal male volunteers were treated for 1 week with either hydrochlorothiazide and amiloride (50 + 5 mg) (n = 11) or placebo (n = 11) in a randomized, double-blind fashion. All 22 subjects then received continuous transdermal nitroglycerin (19 +/- 1 mg/24 h) for 5 to 7 days. RESULTS: On the first and last day of transdermal nitroglycerin therapy, standing heart rate, systolic blood pressure and hematocrit values were assessed at 8, 9 and 10 AM and 12 noon. Heart rate and blood pressure responses to sublingual nitroglycerin (0.6 mg) were also evaluated before and after sustained transdermal nitroglycerin therapy. A significant loss of the hemodynamic effects of transdermal and sublingual nitroglycerin occurred during sustained therapy in both the diuretic and placebo therapy groups. In both groups, transdermal nitroglycerin therapy was associated with a significant decrease in hematocrit that persisted for the entire treatment period. CONCLUSIONS: These results suggest that diuretic therapy does not prevent plasma volume expansion or the loss of hemodynamic effects during sustained transdermal nitroglycerin therapy. The persistent decrease in hematocrit suggests that plasma volume expansion plays a role in the attenuation of nitrate effects. It also provides evidence of continued vascular activity of nitroglycerin despite loss of systemic hemodynamic effects.

Administration, Cutaneous↗