Safety profile of aztreonam in clinical trials.

The clinical safety of aztreonam in the treatment of suspected aerobic gram-negative infections was assessed in 346 patients who received single doses and in 2,388 patients who received multiple doses. Of those administered multiple doses, 163 (6.8%) experienced 172 adverse clinical effects. The most common were local reactions at the injection site, rash, diarrhea, and nausea and/or vomiting. Among aztreonam and control groups, three-fold increases in serum aspartate aminotransferase (SGOT) and serum alanine aminotransferase (SGPT) values occurred at comparably low frequencies; the mean values of SGOT and SGPT were slightly higher in patients administered aztreonam than in those given cefamandole. Treatment with aztreonam was discontinued in 51 (2.1%) of 2,388 patients because of adverse clinical effects or abnormal laboratory test values. Suprainfections (infections due to new pathogens occurring at the original site of infection during treatment with the study drug that were treated with another antibiotic) were reported in 2%-6% of aztreonam-treated patients, a frequency similar to that observed in control groups. Aztreonam is well tolerated and has a safety profile similar to that of other beta-lactam antibiotics.

Captopril in the treatment of the elderly hypertensive patient.

As part of a large multicenter surveillance study of captopril, 975 hypertensive patients aged 65 years or older were treated, 418 of whom received the drug for at least 12 months. Blood pressure was lowered from an entry level of 193/105 +/- 30/16 (mean +/- SD) to 159/88 +/- 25/12 mm Hg, and side effects were infrequent. During treatment, renal function was undisturbed in the majority of patients. The frequency of clinically evident hypotensive episodes did not differ from that found in the total study population, suggesting that in this age group, despite the reduction in blood pressure, cerebral perfusion was maintained. This experience suggests that captopril can be used for the treatment of the elderly hypertensive patient.

Captopril in hypertension; seven years later.

Captopril was first administered to hypertensive patients 7 years ago. The relatively high dosage employed and the severity of diseases in the patient population initially led to a high frequency of side effects. Subsequently, an increase in the time intervals for dose titration and the earlier addition of a diuretic have made it possible to reduce the daily dose, thus significantly improving the drug's safety profile without compromising its antihypertensive effect. In a worldwide postmarketing surveillance study of captopril, 6,737 hypertensive patients were enrolled, of whom 3,219 were treated for at least 1 year. Patients had a mean entry blood pressure of 183 (+/- 31)/111 (+/- 16) mm Hg while still receiving an average of 2.3 antihypertensive drugs. However, 10.3% were not receiving therapy before entering the study. 1,811 patients (29% of those for whom relevant data were available) had impaired renal function on entry (serum creatinine concentration greater than or equal to 1.6 mg/dl). The hypertension of 881 of the patients (13.1%) was classified as mild to moderate. By design, the types of patients, dosage schedules, and patient monitoring requirements were consistent with the recommendations of the manufacturer at the time the study was initiated. The results of the study showed that long-term antihypertensive efficacy was maintained with a mean captopril dose of approximately 150 mg/day, when used either as monotherapy or more frequently with a diuretic. This dosage was associated with satisfactory control of blood pressure and a considerable reduction in the 12 months' cumulative frequency of drug discontinuation because of adverse reactions (5.8%).(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired systemic arterial compliance in borderline hypertension.

Arterial compliance was evaluated by pulse wave velocity, pulse pressure/stroke volume, and by an exponential analysis of the diastolic blood pressure decay curve in three groups of normotensive, borderline hypertensive, and established essential hypertensive patients. Two of the above three indices reflected significantly impaired arterial compliance in borderline hypertension, and all three indices were distinctly abnormal in patients with established hypertension. A close correlation among the three indices was observed in the entire study population. Multiple regression analysis indicated that age (p less than 0.005), systolic (p less than 0.005) and diastolic (p less than 0.025) pressure were independent determinants of pulse wave velocity; other factors such as total peripheral resistance, pulse pressure, and stroke volume were not. We conclude that arterial compliance becomes impaired early in hypertensive cardiovascular disease at the time when arterial pressure may be only slightly elevated. Thus structural alteration of the arterial wall can be demonstrated in borderline hypertension. Age, systolic and, to a lesser degree, diastolic pressures are the best determinants of arterial compliance in large vessels and are therefore important risk factors for evolving systemic arterial disease in essential hypertension.

Dimorphic cardiac adaptation to obesity and arterial hypertension.

Cardiovascular function and structure were evaluated by M-mode echocardiography and systemic hemodynamics in paired lean and obese patients, either hypertensive or normotensive. Compared to lean patients, obese patients had greater left atrial (p less than 0.0001), ventricular (p less than 0.001), and aortic root (p less than 0.002) diameters; posterior and septal wall thickness (p less than 0.001); and ventricular mass, cardiac output, stroke volume, and stroke work (all p less than 0.0001). Hypertensive patients had increased posterior wall thickness, end diastolic wall stress, stroke work (p less than 0.01), and a lower radius to posterior wall thickness ratio indicating concentric hypertrophy (p less than 0.001) when compared to normotensive patients. Cardiac adaptation to obesity consists of left ventricular dilatation and hypertrophy (eccentric hypertrophy) irrespective of arterial pressure levels. In contrast, essential hypertension solely produces concentric hypertrophy. Both obesity and hypertension increase left ventricular stroke work by disparate hemodynamic mechanisms; their presence in the same patient will tax the heart and increase the long-term risk of congestive failure.

Long-term antihypertensive therapy with captopril.

Most forms of hypertension require life-long treatment; thus, it is important to determine the continuing effectiveness and safety of any new therapeutic agent. While participating in various investigational studies, 7103 hypertensive patients received captopril, of whom 4397 were treated for 3 months to 4 years. The 4-year patients included 2498 with mild or moderate essential hypertension (diastolic pressure less than 120 mm Hg), 893 with severe essential hypertension, and 517 with renovascular hypertension. Repeated examinations of these long-term therapy patients, the majority of whom also were receiving a diuretic, indicated no drug tolerance to the combination, i.e., there was continuing control of the blood pressure without significant increases in dosage or addition of other drugs. Side-effects occurring during the first few months of captopril administration (rash, taste disturbances, and, rarely, neutropenia) were not a problem during prolonged therapy. A few patients (70/7,103, or 1.0%) developed proteinuria, usually reversible and seldom associated with any deterioration of renal function. The proteinuria occurred most often in patients who had preexisting renal disease and were receiving high doses of the drug. There were no significant changes in key biochemical parameters. A total of 230 patients discontinued treatment for failure to maintain adequate blood pressure reduction, and 397 for side-effects. The estimated 4-year cumulative frequency of drug discontinuance for side-effects was 11.6% (life table method), which compares favorably with other classes of antihypertensive drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of left ventricular hypertrophy: chest roentgenography, echocardiography, and electrocardiography.

The assessment of cardiac anatomy and function in the hypertensive population is an important aspect of the total evaluation of this patient group. The finding of cardiomegaly requires elucidation of its etiology. The finding of left ventricular hypertrophy on electrocardiogram is a harbinger for potential catastrophe, but other studies have indicated that the electrocardiogram may miss a substantial portion of the left ventricular hypertrophy which can be shown by echocardiogram: a normal electrocardiogram does not mean left ventricular hypertrophy is absent. Subtle changes on the electrocardiogram suggestive of left atrial abnormality must be pursued with echocardiography to eliminate the possibility of changes in left ventricular compliance or left ventricular hypertrophy. The prevention of left ventricular hypertrophy (or regression thereof) should be of major consideration to the clinician as he initiates antihypertensive therapy. The finding of left ventricular hypertrophy at the time of diagnosis tells the physician to implement aggressive and effective antihypertensive therapy. The absence of these findings should never imply, however, that therapy be withheld until indices of early or frank left ventricular hypertrophy are apparent.

Disparate cardiovascular effects of obesity and arterial hypertension.

Since obesity and essential hypertension frequently coexist, a study was designed to analyze some of their cardiovascular effects. Twenty-eight obese patients, half of whom were normotensive and half with established hypertension, were matched for mean arterial pressure with 28 corresponding lean subjects. Systemic and renal hemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels were measured. Obese patients had increased cardiac output (p less than 0.001), stroke volume (p less than 0.001), central blood volume (p less than 0.02), plasma and total blood volume (p less than 0.01), and decreased total peripheral resistance (p less than 0.001). In contrast, cardiac output, central blood volume, and stroke volume of hypertensive patients were normal, but they had increased total peripheral (p less than 0.001) and renal vascular resistance (p less than 0.001) and a contracted intravascular volume. Left ventricular stroke work was elevated to a similar level in obesity (p less than 0.001) and hypertension (p less than 0.02), but the increase was caused by an expanded stroke volume in the former and by an increase in systolic pressure in the latter. It is concluded that the disparate effects of obesity and hypertension on total peripheral resistance and intravascular volume counteract and may even offset each other. Thus, obesity may mitigate the effects of chronically elevated total peripheral resistance (and therefore end-organ damage) in essential hypertension. Since both entities affect the heart through different mechanisms, their presence in the same patient results in a double burden to the left ventricle, thereby gently enhancing the long-term risk of congestive failure.

Cardiovascular changes after weight reduction in obesity hypertension.

Intravascular volumes and systemic and regional hemodynamic variables were measured before and after weight reduction in 12 patients with obesity and essential hypertension. These findings were compared with those in nine patients who did not have any weight loss. Reduction of mean arterial pressure significantly correlated with the fall in total body weight (r = 0.46, p less than 0.05). Total circulating and cardiopulmonary blood volumes were significantly reduced (p less than 0.05 and p less than 0.01, respectively), and these changes permitted a decreased venous return and cardiac output (p less than 0.01). This fall in cardiac output was directly related to a contracted total blood volume (r = 0.49, p less than 0.05) and decreased cardiopulmonary blood volume (r = 0.52, p less than 0.05). Patients who did not lose weight showed no changes in any of these hemodynamic measurements. In addition, weight loss was associated with reduced resting circulating levels of plasma norepinephrine (p less than 0.01), suggesting that diminished adrenergic function may also be related to weight reduction and its associated fall in arterial pressure.

Hemodynamic effects of intravenous labetalol in essential hypertension.

Labetalol inhibits alpha- and beta-adrenergic receptors. Systemic and regional hemodynamic alterations after intravenous labetalol and its cardiovascular reflexive and metabolic effects were evaluated in 12 subjects with mild to moderately severe essential hypertension. Supine systolic, diastolic, and mean pressures were reduced (from 180/101 and 125 to 149/86 and 109 mm Hg; P less than 0.001). The fall was accentuated during head-up tilt and was accompanied by decreased cardiac output and central blood volume in subjects in both the supine and tilted positions. Neither heart rate nor total peripheral resistance was changed by labetalol, suggesting that venodilation resulting from alpha-adrenergic-receptor inhibition played an important role in arterial pressure reduction.

Borderline hypertension and obesity: two prehypertensive states with elevated cardiac output.

Systemic, renal and splanchnic hemodynamics, intravascular volume, circulating catecholamine levels and plasma renin activity were compared in 39 patients with borderline hypertension and 28 normotensive subjects, who were less than 5% (n = 42, lean patients) or more than 40% overweight (n = 25, obese patients). Lean borderline hypertensive patients had greater cardiac output (p less than 0.05), heart rate (p less than 0.01) and renal blood flow (p less than 0.05); cardiopulmonary redistribution of intravascular volume (p less than 0.05); and higher circulating norepinephrine levels (p less than 0.05). Obese normotensive subjects also showed an increased cardiac output (p less than 0.005), stroke volume (p less than 0.01), left ventricular stroke work (p less than 0.05), and renal blood flow (p less than 0.05) (but not respective indexes), but intravascular volume was expanded (p less than 0.05) without redistribution and circulating catecholamine levels were normal. Obese borderline hypertensive patients had hemodynamic characteristics similar to those of obese normotensive subjects except for an increased peripheral resistance (p less than 0.05). The data indicate that although both populations have an increased cardiac output, the lean borderline hypertensive patients have signs of enhanced adrenergic activity as evidenced by higher circulating catecholamine levels and heart rate with blood volume translocation to the cardiopulmonary circulation. In contrast, the obese subjects (whether normotensive or borderline hypertensive), who also have increased cardiac output, seem to have normal adrenergic activity and an expanded intravascular volume without cardiopulmonary redistribution.

Diurnal variations of cardiac rhythm, arterial pressure, and urinary catecholamines in borderline and established essential hypertension.

Ambulatory continuous ECG and arterial pressure (BP) were recorded simultaneously (Delmar Avionics Pressurometer II) for 24 hours in 13 age-matched normotensive subjects, 11 patients with borderline hypertension (HBP), and in 10 patients with uncomplicated established essential HBP. Urinary concentrations of epinephrine, norepinephrine, and dopamine were simultaneously collected over four successive 4-hour periods and one 8-hour period. Prevalence and total number of ventricular and supraventricular ectopic beats was low and not affected by arterial BP. Twenty-four-hour rate (HR) and 4-hourly excretion of epinephrine, norepinephrine, and dopamine were comparable between normotensive and HBP persons and no correlation between urinary catecholamines and arterial BP (systolic, diastolic, or mean), HR, or prevalence of ectopic beats was found in any of the three groups or in the total study population. We conclude that HBP patients without ECG evidence of left ventricular hypertrophy do not have a higher prevalence of supraventricular or ventricular ectopic beats. Urinary catecholamines are not related to circadian fluctuations or variability in arterial BP, HR, or prevalence of ectopic beats.

Early hypertension and cardiac work.

Myocardial function and ventricular work in early essential hypertension were assessed by comparing systemic hemodynamics and echocardiographic data in 33 normotensive subjects and 38 hypertensive patients, all without left ventricular hypertrophy. External work (tension-time index and cardiac work) and internal work (fiber shortening velocity) were significantly increased in the patients with mild hypertension. Because factors other than blood pressure contribute to cardiac work, antihypertensive therapy must favorably affect both blood pressure and cardiac work.

Hemodynamics, biochemical and reflexive changes produced by atenolol in hypertension.

Hemodynamic (systemic and regional), metabolic and cardiovascular reflexive variables were measured before and after 4 weeks of beta blockade with atenolol in 10 patients with mild essential hypertension. Atenolol reduced mean arterial pressure, heart rate, cardiac index (all p less than 0.005) and renal vascular resistance (p less than 0.01) and increased total peripheral resistance (p less than 0.005). Glomerular filtration rate and renal blood flow were unchanged; plasma renin activity fell 43%. Reflexive cardioacceleration during the Valsalva maneuver and upright passive tilt was blunted. No changes were observed in circulating fluid volumes. In six patients followed for 1 year, blood pressure and heart rate were maintained at levels similar to those during the first 4 weeks. Atenolol was shown to be an effective oral antihypertensive that has no apparent deleterious hemodynamic effects on the renal and splanchnic circulations.

Baroreceptor stimulation and isometric exercise in normotensive and borderline hypertensive subjects.

1. The effects of carotid baroreceptor stimulation (neck chamber) on systemic haemodynamics were determined for normotensive and borderline hypertensive subjects during periods of resting and isometric exercise. 2. Both groups reacted to baroreceptor stimulation with a similar decrease in mean arterial pressure and cardiac index at rest and during isometric exercise, but baseline heart rate decreased more in borderline hypertensive patients. 3. Baroreceptor stimulation elicited the same haemodynamic response at rest and during exercise-induced arterial pressure increase. Since the magnitude of arterial pressure had no bearing on the subsequent response, these data suggest resetting of baroreceptors during this short-term blood pressure increase.

Arterial compliance in systolic hypertension.

Arterial compliance as estimated by pulse wave velocity and the pulse pressure/stroke volume index was evaluated in 27 normotensive subjects, 21 patients with established, and 18 patients with systolic essential hypertension. Pulse wave velocity was elevated to the same degree in both hypertensive groups when compared to the normotensive controls. The pulse pressure/stroke volume index was higher in essential hypertension than in normotensive subjects and even higher in patients with systolic hypertension. It is concluded that both indices are useful clinical tools to determine arterial compliance. Systolic hypertension does not always indicate stiffening of the arterial tree, but may result from a high stroke volume in the presence of a normal arterial compliance.