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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
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↗
PubMed1992

Absence of pre-dose rebound phenomena with once daily 5-ISMN in a controlled-release formulation.

To avoid the development of nitrate tolerance secondary to relatively constant elevated plasma nitrate concentrations, intermittent nitrate dosing has been advocated. However, a nitrate-free interval may induce a rebound increase in myocardial ischaemia, and thus increase anginal symptoms during the latter portion of the dosing interval. This was suggested by the results of recent studies in which nitroglycerin patches were administered intermittently with a 12 h nitrate-free interval. The present investigation was carried out to determine whether a controlled-release formulation of 60 mg isosorbide-5-mononitrate (5-ISMN) would produce such a rebound phenomenon. Seventy-nine patients, who had participated in four crossover, placebo-controlled studies in which the treatment arms lasted for between 1 and 2 weeks, were reviewed. These studies had assessed the efficacy of this nitrate preparation by exercise testing and each had included exercise testing at the end of each treatment phase, 24 h after the last medication had been administered. There were no differences noted in the time to onset of angina, the time to onset of 1 mm ST segment depression or the total exercise duration between the two treatment phases, indicating an absence of rebound phenomena at the end of the dosing interval. The reason for the absence of a detectable pre-dose rebound is unclear, but the plasma concentration profile of 5-ISMN produced by the presently used preparation, resulting in a nitrate-low instead of nitrate-free interval, may have contributed.

Adult↗
PubMed1992

Update on nitrate tolerance.

1. It is now recognised that nitrate therapy designed to provide effects throughout 24 h each day induces tolerance. Such tolerance may be partial or complete and is associated with diminished haemodynamic and clinical effects. 2. The mechanism of tolerance is not completely understood but it seems to be related to the depletion of reduced sulphydryl groups in vascular smooth muscle and to the activation of counter-regulatory forces. These include elevated plasma catecholamines, arginine vasopressin and plasma renin activity. Activity of the renin-angiotensin system is associated with sodium and water retention and plasma volume expansion. The increase in vasoconstrictor influences and augmented plasma volume could modulate the effect of nitrate-induced vasodilatation.

Animals↗
PubMed1991

Doxazosin for the treatment of chronic congestive heart failure: results of a randomized double-blind and placebo-controlled study.

In this study we evaluated the effects of once-daily administration of oral doxazosin in patients with chronic congestive heart failure (CHF). After a stabilization period of at least 2 weeks with digitalis and diuretics, 73 patients with chronic CHF were randomized to receive additionally either doxazosin or placebo in double-blind fashion. Patients underwent weekly dose adjustments with increasing doses of doxazosin (1, 2, 4, 8, and 16 mg daily) or placebo for 5 weeks, and 67 were evaluated for 12 additional weeks on maximally tolerated doses of blinded study drugs. Treatment groups were evaluated with respect to symptoms of heart failure, indexes of quality of life and left ventricular function, frequency and type of arrhythmia, adverse events, and mortality rates. Doxazosin (11.9 +/- 0.9 mg) given once daily produced a favorable trend in the investigators' and patients' assessments of symptomatic change. Doxazosin was associated with a significantly higher level of voluntary submaximal exercise and a favorable trend on left ventricular ejection fraction (increase of 9.8% of the baseline value vs 2.7% with placebo; p = NS). During the 3-month steady-dosing period, patients treated with doxazosin had a significant (p less than 0.004) reduction in ventricular arrhythmias and significantly fewer morbid and mortal cardiac events (including episodes of worsening heart failure severe enough to prompt discontinuation of the study, myocardial infarction, and death). Doxazosin was well tolerated, producing no major side effects and only a slightly higher frequency of minor treatment-related side effects compared with placebo (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1991

Enalapril versus digoxin in patients with congestive heart failure: a multicenter study. Canadian Enalapril Versus Digoxin Study Group.

Patients with New York Heart Association functional class II or III heart failure stabilized on furosemide therapy were entered into a randomized controlled trial comparing enalapril (n = 72) and digoxin (n = 73). End points were clinical outcome, treadmill exercise capacity and echocardiographic left ventricular dimensions. Improvement in clinical outcome was defined as a reduction of at least one functional class or withdrawal because of an adverse clinical event. After 4 weeks, 13 patients receiving enalapril showed improvement, 55 had no change and 9 manifested deterioration compared with 7, 49 and 17, respectively, in the digoxin group (p less than 0.01). After 14 weeks, 13 patients receiving enalapril showed improvement, 50 had no change and 9 manifested deterioration, compared with 14, 37 and 22, respectively, in the digoxin group (p less than 0.025). More patients in the digoxin group were withdrawn because of an adverse clinical event (p less than 0.05). Exercise time and percent fractional shortening improved in both groups (p less than 0.001 and less than 0.05, respectively), with no significant difference between groups (p greater than 0.50). Both rate-pressure product and subjectively evaluated exertion during submaximal exercise were reduced only in the enalapril group. Although the majority of patients in both groups did well, those receiving enalapril experienced fewer adverse clinical events and had less fatigue during submaximal exercise.

Adult↗
PubMed1991

Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

BACKGROUND: Vasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN). METHODS AND RESULTS: Standing systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval. CONCLUSIONS: Continuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.

Administration, Cutaneous↗
PubMed1991

Nitrate tolerance--can it be prevented?

Tolerance develops during therapy with all organic nitrates, particularly when dosing strategies are designed to provide therapeutic effects throughout 24 h. Such tolerance can be demonstrated by assessing haemodynamic, anti-anginal and anti-ischaemic effects during therapy. The mechanism of nitrate tolerance is not completely understood. Tolerance may be related to depletion of reduced sulfhydryl groups in vascular smooth muscle with resultant reduction in nitric oxide production, adenylate cyclase activation and cyclic guanosine monophosphate (GMP) production. Nitrate exposure also activates counter-regulating influences which lead to fluid retention and augmented vasoconstrictor effects. Intermittent nitrate therapy avoids the problem of tolerance by providing a period of washout. Controlled-release formulations of oral nitrates providing a period of low nitrate exposure should prevent tolerance. This has been documented by studies with a controlled-release formulation of isosorbide-5-mononitrate.

Angina Pectoris↗
PubMed1991

Controlled release isosorbide-5-mononitrate in angina pectoris: a comparison with standard formulation isosorbide dinitrate.

In a randomized, double-blind, placebo controlled, crossover study, the antianginal and anti-ischemic effects of a controlled release formulation of isosorbide-5-mononitrate 60 mg once daily and of a standard formulation of isosorbide dinitrate 30 mg qid, were assessed during the first day of treatment and after seven days of sustained therapy. In comparison to placebo, the acute administration of isosorbide-5-mononitrate increased treadmill walking time at 4 and 8 h, and isosorbide dinitrate prolonged treadmill walking time when tested at 4 h after each of the first three doses. During sustained therapy, isosorbide dinitrate produced no significant changes over placebo values. Isosorbide-5-mononitrate prolonged treadmill walking time 4, 8 and 12 h after morning dosing by 54, 41 and 52 s, but these changes were not significant compared to placebo. Treadmill walking time was, however, significantly greater at 4 and 12 h during isosorbide-5-mononitrate therapy compared with isosorbide dinitrate. There was no significant difference in treadmill walking time during acute and sustained therapy with isosorbide-5-mononitrate indicating a lack of tolerance; there was a complete loss of effect during sustained qid therapy with isosorbide dinitrate.

Angina Pectoris↗
PubMed1990

Nitrate tolerance. A problem during continuous nitrate administration.

The organic nitrates are effective agents in the management of patients with angina pectoris. They are the agents of choice in the treatment of acute episodes of angina pectoris and are useful in angina prophylaxis. While the organic nitrates are extremely effective in angina prophylaxis during acute therapy, there is increasing evidence that with many dosing regimens for oral and transdermal therapy, substantial attenuation of the antianginal effects develops. Thus, during acute therapy the organic nitrates improve exercise tolerance for many hours, but during sustained therapy designed to provide antianginal efficacy throughout the 24-h period there is significant attenuation of the beneficial effects. It has been documented that treatment regimens designed to provide a period of nitrate washout prevent or reverse nitrate tolerance, and such changes in dosing regimens have been shown to provide continued antianginal protection. It is clear that the objective of providing 24-h antianginal protection with the organic nitrates cannot be achieved. With appropriate dosing schedules, however, it is possible to improve exercise tolerance throughout the major portion of the 24-h dosing period.

Angina Pectoris↗
PubMed1989

Nitrate tolerance in angina pectoris.

Tolerance to the hemodynamic and antianginal effects of the organic nitrates develops rapidly during therapy. This has been documented with a variety of nitrate preparations and with different routes of administration. Dosing strategies designed to provide therapeutic plasma nitrate concentrations throughout the 24 hours of the day are regularly associated with the development of tolerance. Recent information indicates that dosing schedules providing a nitrate-free period will permit continued efficacy of the organic nitrates without tolerance development. This can be accomplished in several ways. With oral preparations of isosorbide dinitrate, medication can be given 3 times daily, omitting the evening dose. Buccal nitroglycerin is usually given 3 times daily after meals, and this has been shown not to be associated with tolerance. Likewise, preliminary studies suggest that removal of the nitroglycerin patches for a period of several hours each day will prevent the development of tolerance. Much needs to be learned about the nitrate-free period. With oral isosorbide dinitrate, it appears that 12 hours is required, but this could be substantially less with nitroglycerin preparations. It is also possible that several short periods with low nitrate levels each day would suffice. Thus, simply increasing the interval between dosing of oral preparations may provide an adequate, low, nitrate-free period.

Angina Pectoris↗
PubMed1989

Antianginal efficacy of a new nitroglycerin patch.

Sixteen patients with chronic, stable exercise-induced angina pectoris were studied during acute and sustained therapy with a new nitroglycerin (GTN) patch*. This patch provides a biphasic GTN release profile with therapeutic GTN plasma concentrations developing soon after application and persisting for 12h, but with low plasma concentrations during the remainder of the 24h period. This profile of GTN release was designed to avoid nitrate tolerance by providing a low nitrate period for substantial periods during each 24-h application period. In a placebo-controlled double-blind study, two GTN patches each releasing 7.5 mg GTN were applied. The active patches induced a significant decrease in systolic blood pressure and an increase in heart rate during initial application. Exercise duration to the end-point of moderate angina (P2) was increased at 4 and 8h during acute therapy and the changes during sustained therapy were similar. Thus, the Biophase GTN patch has been shown to improve exercise performance during acute therapy and, more importantly, to maintain this effect during sustained once-daily therapy.

Administration, Cutaneous↗
PubMed1988

Efficacy of the calcium antagonist isradipine in angina pectoris.

Thirty-six patients with chronic, stable angina pectoris were studied during 2-week treatment periods in which they received, in a randomized double-blind, crossover study, a new calcium entry blocking agent, isradipine, 7.5 mg three times daily or placebo. Antianginal efficacy was determined by treadmill exercise testing carried out 3 and 9 hours after drug administration on the final day of each treatment period. During placebo therapy, treadmill exercise time to the onset of angina (P1) and to the development of moderate angina (P2) was similar at 3 and 9 hours and similar to the placebo run-in period. During isradipine therapy, treadmill exercise time 3 hours after dosing was greater than with placebo therapy (P1 312 +/- 23.0 vs. 267 +/- 19.5 seconds, p less than 0.001; P2 410 +/- 20.2 vs. 355 +/- 18.8 seconds, p less than 0.002). Nine hours after drug administration, the results of exercise testing were similar to placebo.

Aged↗
PubMed1988

Adult cardiology and the expanding supply of physicians.

The number of cardiologists can be projected with considerable accuracy into the next century. The total cardiology pool of physicians will increase until the year 2015 at which time those entering and leaving the pool will come into equilibrium. At that time the ratio of active cardiologists to the population will have greatly increased. This nation's future need for cardiologists is difficult to assess with any degree of precision. Therefore, this is the time for updating practice profile studies. Such studies today could be formulated in a manner to provide more detailed information on the cardiologist's daily activities. In addition, a data base developed through methodology such as the consensus formation approach must be developed and updated on a periodic basis. Through such analyses it will be possible to quantitate the future needs of cardiovascular manpower.

Adult↗
PubMed1987

Nitrate tolerance.

The organic nitrates are the most widely used agents in the management of patients with angina pectoris. When initially administered by the oral route, the nitrates produce profound changes in systemic hemodynamics and significant and prolonged improvement in exercise duration. It has been shown that during short periods of regular oral nitrate administration, the hemodynamic, antiischemic and antianginal effects of the nitrates are greatly reduced. Thus, when initially administered, oral isosorbide dinitrate prolongs exercise duration for a period of several hours, but during sustained 4-times-daily therapy, exercise tolerance is improved for only 2 hours after administration. Studies with transdermal preparations of isosorbide dinitrate and nitroglycerin also show improvement during short-term administration for up to 8 hours, but after several days of once-daily therapy, the effects of these agents are similar to placebo. It is apparent that nitrate tolerance is a clinically relevant problem. Although tolerance develops rapidly during nitrate therapy, it is reversed promptly during nitrate-free periods. Oral nitrates maintain their antianginal effects when given 2 or 3 times daily with provision of a nitrate-free period. Studies are currently underway to investigate the effects of intermittent administration schedules with transdermal nitrate preparations.

Dosage Forms↗