Gilbert E. D'Alonzo

Survival in Patients with Primary Pulmonary Hypertension: Results from a National Prospective Registry

OBJECTIVEnTo characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival.nnnDESIGNnRegistry with prospective follow-up.nnnSETTINGnThirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute.nnnPATIENTSnPatients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988.nnnMEASUREMENTSnAt diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals.nnnMAIN RESULTSnThe estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration.nnnCONCLUSIONSnMortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.

Actigraphy : a means of assessing circadian patterns in human activity

Twenty-three diurnally active (0705-2333), healthy persons between 22 and 54 years of age and without history of sleep abnormality were monitored continuously for 120 consecutive hr (five days) by wrist actigraphy. Circadian rhythms of high amplitude were detected by cosinor analysis for each participant and for the groups of 10 males and 13 females with the average span of heightened activity timed between approximately 1330 and 1605. The circadian peak-trough difference in wrist movement was marked, equalling approximately 75% of the 24-hr mean level. In 19 of 23 participants, the 24-hr mean of wrist activity varied between 140-180 movements/min, with four persons exhibiting lesser means of 110-140 movements/min. With respect to the daytime span of activity, the mean wrist movement of individual participants ranged from 155-265 movements/min, with the majority (20/23) varying between 185-245 movements/min. During nocturnal sleep the mean wrist activity level was quite low, varying between individuals from 5 to 25 movements/min for 21 of 23 persons. Wrist actigraphy proved to be well-accepted and was a most reliable means of monitoring aspects of body movement during activity and sleep in ambulatory persons adhering to usual life habits and pursuits.

Day-Night Patterns in Bronchial Patency and Dyspnea: Basis for Once-Daily and Unequally Divided Twice-Daily Theophylline Dosing Schedules

Asthma typically worsens overnight. Although 24-hr variation in environmental conditions may contribute to the worsening of dyspnea at night, this does not fully explain day-night patterns of this disease. Circadian (about 24-hr) rhythms in bioprocesses which influence airways patency constitute major contributory factors. The nighttime exacerbation of asthma may represent the influence of circadian bioperiodicities in bronchial patency, airways hyperreactivity to acetylcholine, histamine and house dust, and altered levels of several plasma constituents such as cortisol, epinephrine, histamine and cyclic AMP.

COMPARISON OF SUSTAINED-RELEASE THEOPHYLLINE SCHEDULED CONVENTIONALLY (TWICE-DAILY, EQUAL INTERVAL IN EQUAL AMOUNT) VERSUS ONCE-DAILY MORNINGS OR EVENINGS ON CIRCADIAN PATTERN OF BRONCHIAL PATENCY IN ASTHMATICS

The effects of differently timed, but equivalent TheoDur (Key Pharmaceutical Co.) dosage schedules--twice-daily equally divided 12 hr (BID), once-daily evening (OD-PM) and once-daily morning (OD-AM)--were compared under steady-state conditions in 10 adult asthmatics with a documented history of nocturnal dyspnea. Assessments of airways function by spirometry were done every 3-hr over one complete 24-hr dosing interval for each dosage schedule under carefully controlled conditions. The different TheoDur regimens did not affect the 24-hr group average FEV1.0, PEF, MMEF or FVC. However, statistically significant circadian variation in airways function existed irrespective of the drug dosing schedule. Airways patency and FVC were least overnight (0200-0500 hr) and best during the morning or afternoon. With regard to FEV1.0 and PEF, which evidenced group circadian change for BID and OD-PM regimen by Cosinor analysis, the peak-to-trough (double amplitude) difference expressed as a percentage of the 24-hr average was rather large, being greatest for the OD-PM schedule (20.5% for FEV1.0 and 24.3% for PEF). The data for the 10 participants revealed individual differences in the effectiveness of the 3 studied theophylline dosing regimens when assessed in terms of the mean level and stability of airways function over the 24 hr. Based on the findings, neither the BID, OD-PM nor the OD-AM regimen effectively moderated the nocturnal deterioration of pulmonary function suggesting theophylline as dosed and timed may not be as efficacious as desired for patients with a history of strictly nighttime dyspnea. Thus, the schedule and prescription of TheoDur must take into account differences between patients, including the time when asthma symptoms are most likely to be experienced by each.

Summary and Perspectives: Sustained-Release Theophylline and Nocturnal Asthma, Once-Daily and Unequal Dosing Schedules

Many asthmatic patients experience aggravation of symptoms overnight resulting in disruption of their sleep. Sustained-release theophylline represents at this time a major bronchodilator medication which possesses a sufficient duration of activity to avert the nocturnal breathing distress of asthma. Circadian rhythm-adapted theophylline schedules consisting of unequal dosing--more or all the drug taken in the evening--have proven efficacious in clinical investigations for certain patients. Although the kinetic behavior of some formulations is affected by food, the circadian rhythm-adapted schedules represent a significant step forward toward the goal of optimizating sustained-release theophyllines for patients who experience nighttime symptoms.