BP as a determinant of cardiac left ventricular muscle mass.

The relationship between casual BPs and measures of cardiac hypertrophy, derived from the ECG, has been described as fairly weak. In this study, ECG and echocardiographic measurements of left ventricular muscle mass were related to various measures of BP obtained during circadian ambulatory BP monitoring in 12 patients with hypertension. Casual BP did not correlate substantially with ECG voltages or with echocardiographic measurements of muscle mass. The correlations between whole-day, daytime, or nighttime BP averages and ECG voltages were not significant. However, echocardiographic left ventricular muscle mass correlated significantly with the averages of whole-day, daytime, and nighttime, and two-hour morning systolic pressures. The correlations between diastolic BP and left ventricular muscle mass were not significant. Therefore, serial BP measurements are required to evaluate the relationship between BP and left ventricular muscle mass as measured by the M-mode echocardiogram. The ECG is of little value in this relationship.

Long-term BP monitoring in the evaluation of antihypertensive therapy.

Noninvasive BP monitoring was performed in hypertensive patients before and during placebo therapy and before and during therapy with the long-acting peripheral alpha-adrenergic receptor antagonist, terazosin hydrochloride. Placebo therapy did not result in significant changes in casual BP or in averages of whole-day, daytime, or nighttime BPs. Short-term therapy with terazosin did not induce significant changes in casual supine or daytime BPs. However, whole-day BP monitoring disclosed that nighttime BPs were lower during shortterm therapy. Moreover, the circadian pattern of BP was shifted downward during terazosin therapy. Long-term therapy with terazosin resulted in significant changes in BP. All BP values were lowered significantly. The differences in the circadian BP pattern between placebo and long-term terazosin therapy show that in these patients BP was lowered throughout the 24 hours of the day. The results of the study emphasize the usefulness of 24-hour BP monitoring in the evaluation of the effectiveness of long-acting antihypertensive agents.

Circadian blood pressure patterns in ambulatory hypertensive patients: effects of age.

Circadian blood pressure monitoring was performed in 50 untreated ambulatory hypertensive patients to study the effects of age on the pattern and variability of blood pressure and heart rate. Casual blood pressure, measured in the morning, was greater than the average of the blood pressures measured at 7.5 minute intervals for 24 hours (148 +/- 2/95 +/- 2 and 137 +/- 2/88 +/- 2 mm Hg, p less than 0.001). The correlation between casual systolic pressure and the 24 hour average was stronger (p less than 0.05) in younger (less than 55 years of age) patients (r = 0.69, n = 24, p less than 0.001) than in older patients (r = 0.42, n = 26, p less than 0.1). Similarly, diastolic pressures correlated more strongly (p less than 0.05) in younger patients (r = 0.71, p less than 0.001) than in older patients (r = 0.43, p less than 0.05). Variability of systolic pressure, defined as the standard deviation of all readings obtained during 24 hours, was greater than that of diastolic pressure (16.7 and 13.1 mm Hg, respectively, p less than 0.001). Moreover, the variability of systolic pressure was greater in older than in younger patients (18.1 and 15.2 mm Hg, respectively, p less than 0.01). The variability of diastolic pressure was slightly but not significantly greater in older patients (13.7 and 12.5 mm Hg, not significant). The circadian pattern of blood pressure, expressed as averages of readings obtained during consecutive 2 hour intervals, was similar in the two age groups. However, the level of systolic pressure was consistently higher (p less than 0.01) and that of both diastolic pressure and heart rate consistently lower (p less than 0.01) in older patients. Thus, ambulatory circadian blood pressure monitoring reveals significant changes in blood pressure levels and its variability with age; the casual blood pressure does not accurately reflect these changes. Longer periods of blood pressure monitoring are required for accurate assessment of the characteristics of hypertension in the aged.

Whole blood viscosity as a determinant of cardiac hypertrophy in systemic hypertension.

The relationships among blood pressure (BP), blood viscosity and echocardiographic left ventricular (LV) muscle mass were evaluated in 24 patients with essential hypertension and in 13 normotensive control subjects. LV mass was greater in the hypertensive patients than in the control subjects (225 +/- 69 vs 170 +/- 31 g, p less than 0.02) as was blood viscosity at a shear rate of 104 sec-1 (4.7 +/- 0.1 vs 4.3 +/- 0.2 cp, p less than 0.005). Among the hypertensive patients, LV mass was most closely related to viscosity at 104 sec-1 (r = 0.80, p less than 0.001), whereas only weak correlations were found between LV mass and systolic or diastolic BP (r = 0.45, p less than 0.05 for both). The 14 hypertensive patients with normal LV mass had viscosity similar to that in control subjects (4.5 +/- 0.3 vs 4.3 +/- 0.2 cp), whereas viscosity was consistently increased (5.0 +/- 0.4 cp, p less than 0.02) in hypertensive patients with LV hypertrophy. Thus, increased blood viscosity may be a determinant of or a response to hypertensive cardiac hypertrophy.

Kinetics and mechanisms of degradation of the antileukemic agent 5-azacytidine in aqueous solutions.

The hydrolytic degradation of 5-azacytidine was studied spectrophotometrically as a function of pH, temperature, and buffer concentration. Loss of drug followed apparent first-order kinetics in the pH region below 3. At pH less than 1,5-azacytosine and 5-azauracil were detected; at higher pH values, drug was lost to products which were essentially nonchromophoric if examined in acidic solutions. The apparent first-order rate constants associated with formation of 5-azacytosine and 5-azauracil from 5-azacytidine are reported. Above pH 2.6, first-order plots for drug degradation are biphasic. Apparent first-order rate constants and coefficients for the biexponential equation are given as a function of pH and buffer concentration. A reaction mechanism consistent with the data is discussed together with problems associated with defining the stability of the drug in aqueous solutions. At 50 degrees, the drug exhibited maximum stability at pH 6.5 in dilute phosphate buffer. Similar solutions were stored at 30 degrees to estimate their useful shelflife. Within 80 min, 6 times 10(-4) M solutions of 5-azacytidine decreased to 90% of original potency based on assumptions related to the proposed mechanisms.

Ionization constants of cephalosporin zwitterionic compounds.

The microionization constants for two zwitterionic compounds were determined by incorporating two experimental techniques. These compounds have chromophoric changes dependent upon the solution pH. By combining the spectrophotometric measurements with potentiometric mmeasurements, all four microionization constants were calculated. The method used is completely general and is applicable to all diprotic compounds that exhibit this spectrophotometric behavior. The observed pKa's had differences of at most 1.2 units for either compound and were in the 1-4 range. A comparison of the results with each compound and similar compounds indicates that the values are resonable.

Effect of ionization on absorption of cephalosporins.

To explore the relative absorbabilities of different ionic forms of cephalosporins, the absorption rates of four compounds were measured in the pH 5-9 region using an in situ rat gut technique. Cephalexin, cephradine, and cephaloglycin have some oral activity, while 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-oxo-1(4H-pyridinyl)acetyl]-amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (I) has insignificant oral activity. The pH-species profiles calculated from their ionization constants showed that cephalexin, cephradine, and cephaloglycin have a large proportion of uncharged molecules plus zwitterions in the pH range of the small intestine, while I exists as the anion throughout this range. When the species profiles are compared with the pH-absorption rate profiles for cephalexin, cephradine, and I, the results are consistent with a model in which the zwitterionic and/or uncharged forms of the molecules are well absorbed, whereas the anions show little or no absorption. Although it has a pH profile for zwitterions plus uncharged molecules similar to cephalexin, cephaloglycin shows poor absorption, suggesting that the ratio of uncharged molecules to zwitterions may be important in absorption.

Development of pancreatic enzyme microsphere technology and US findings with Pancrease in the treatment of chronic pancreatitis.

Enzyme replacement therapy is a vital aspect of the management of patients with chronic pancreatic insufficiency. However, pharmaceutical technology in the manufacture of enzyme products has advanced significantly only in the last decade. In the late 1970s, Johnson & Johnson scientists developed novel pH-sensitive enteric-coated microspheres of pancrelipase (Pancrease) that could be encapsulated for convenient administration. The increased efficiency of the formulation allowed lower daily doses than had been required with conventional enzyme products. In vitro studies indicate that the microspheres disintegrate at a pH appropriate for patients with cystic fibrosis and chronic pancreatitis. Clinical studies of Pancrease in chronic pancreatitis demonstrate a significant improvement in fecal fat excretion, fat utilization, stool weight, and stool frequency, as well as significant weight gain and improved quality of life of patients. Pancrease represents a major advance in the clinical management of chronic pancreatic insufficiency.

The use of short-term ambulatory blood pressure monitoring in differing forms of hypertension.

Single blood pressure readings represent the conventional approach for determining the presence and severity of hypertension. However, the relationship between single (casual) readings and the whole-day blood pressure average is weak, especially in patients with borderline hypertension and in the elderly. In this study we have compared casual blood pressures with the averages of blood pressures obtained during short-term (two-hour) and long-term (24-hour) ambulatory monitoring in patients with mild (n = 19), moderate (n = 11), or predominant systolic (n = 11) essential hypertension. The blood pressure averages obtained during long-term monitoring were significantly lower than the casual blood pressure in all three subgroups. The averages of short-term monitoring in the morning were in between the other two blood pressure levels. The correlation coefficients between two-hour morning averages of pressure and whole-day averages were highly significant (p less than 0.01 or better), and stronger than those between casual and whole-day average pressures, in the group of patients as a whole and in all three subgroups. The slopes of the regression equations were close to unity. Therefore, ambulatory short-term monitoring of blood pressure in the morning is superior to casual blood pressure and probably is an adequate substitute for whole-day observations in quantifying whole-day blood pressure levels in hypertensive patients, especially in patients with mild hypertension and in those with predominant systolic hypertension.

Reproducibility of the whole-day blood pressure pattern in essential hypertension.

The reproducibility of the whole-day blood pressure, measured by an automated non-invasive device at 7.5 minute intervals, was examined in 6 hypertensive patients in a quiet in-hospital environment. During a repeat study performed two weeks after the baseline monitoring period, the average 14-hour systolic blood pressure had changed significantly in 3 patients and the diastolic blood pressure in 2. If the day was divided into 12 consecutive 2-hour periods, systolic blood pressure averages during corresponding periods of the two studies correlated significantly in 3 of the 6 patients, and diastolic blood pressure averages in 5. After a third 24-hour monitoring period, carried out in 4 of the 6 patients, it was found that the baseline study correlated more strongly with the second repeat study than with the first, and that the correlations between the two latter studies were the strongest of all. Thus, even during relatively non-stimulatory conditions the 24-hour blood pressure is not constant in all patients; there is a tendency, however, towards greater reproducibility of the whole-day blood pressure patterns as patients become more familiar with the monitoring procedure.