Improvement in quality-of-life measures and stimulation of weight gain after treatment with megestrol acetate oral suspension in geriatric cachexia: results of a double-blind, placebo-controlled study.

BACKGROUND: Weight loss among older patients is a severe problem, associated with an increased incidence of infections, decubiti, and death. Megestrol acetate (MA) causes weight gain in cachectic cancer and AIDS patients, but its effects in older cachectic patients are unknown. OBJECTIVE: To compare the effects of MA oral suspension (O.S.), 800 mg/day, versus placebo on weight in geriatric nursing home patients with weight loss or low body weight. DESIGN: Twelve-week, randomized, double-blind, placebo-controlled trial with a 13-week follow-up period. SETTING: Veterans Administration Medical Center (VMAC) nursing home. PATIENTS: Nursing home patients with weight loss of > or =5% of usual body weight over the past 3 months, or body weight 20% below their ideal body weight. INTERVENTIONS: Patients were randomly assigned to receive placebo or MA 800 mg/day for 12 weeks and were then followed for 13 weeks off treatment. MEASUREMENTS: Primary outcome was measured by weight and appetite change. Secondary outcome measures included sense of well-being, enjoyment of life, change in depression scale, laboratory nutrition parameters, energy intake counts, body composition, and adverse events. RESULTS: At 12 weeks there were no significant differences in weight gain between treatment groups, whereas MA-treated patients reported significantly greater improvement in appetite, enjoyment of life, and well-being. Body composition was not statistically different between the two groups. At Week 25 (3 months after treatment), 61.9% of MA-treated patients had gained > or =1.82 kg (4 lbs) compared to 21.7% of placebo patients. CONCLUSIONS: In geriatric patients with weight loss or low body weight MA improves appetite and well-being after 12 weeks of treatment. During the 3 months of MA treatment, there was no statistically significant weight gain (> or =4 lbs). Three months after treatment, weight gain (> or =4 lbs) was significantly increased in MA-treated patients.

Effects of anesthetics containing epinephrine on catecholamine levels during periodontal surgery.

Nine stable cardiovascular disease patients were evaluated in a double-blind cross-over trial during periodontal surgery using 2% lidocaine with epinephrine 1:100,000 or lidocaine alone. In the lidocaine with epinephrine group, epinephrine levels increased from 198 +/- 54 pg/ml to 592 +/- 166 pg/ml at 2 minutes post-injection. In the lidocaine alone group, epinephrine levels increased from a baseline of 115 +/- 34 pg/ml to 150 +/- 34 pg/ml at 2 minutes post-injection. Despite these elevations in epinephrine, no significant changes in heart rate or mean arterial pressure were noted. Plain lidocaine provided unsatisfactory levels of hemostasis and/or anesthesia during periodontal surgery. This study documents acute elevations in plasma epinephrine levels following local dental anesthesia for periodontal surgery. These elevations in plasma epinephrine failed to produce a significant cardiovascular response in a group of stable cardiovascular disease patients. This suggests that the cardiac effects of local anesthetics containing epinephrine are small and that they can be safely used in stable cardiovascular disease patients.

Pulmonary vascular reactivity to biogenic amines during acute hypoxia.

The effects of acute hypoxia on the pressor responses to five biogenic amines were studied in isolated blood-perfused cat lungs. Hypoxia (Po2 = 46 +/- 2 Torr) reduced the pressor responses to phenylephrine while changing the pressor responses to epinephrine and norepinephrine to vasodilation. Hypoxia reduced the pressor responses to histamine, and these reductions were preceded by small but significant vasodilations. Hypoxia had no effect on the pressor responses to serotonin. These changes in pulmonary vasoactivity were reversed on reoxygenation, independent of changes in base-line tone and not correlated with circulating catecholamines. We also examined the effects of hypoxia on the pressor responses to norepinephrine during beta-blockade with propranolol and then alpha-blockade with dibenzyline. The vasodilation produced during hypoxia by norepinephrine was blocked by propranolol, and vasoconstriction reappeared. When alpha-blockade was then established, vasodilation to norepinephrine reemerged during hypoxia. These results demonstrate that hypoxia produces changes in pulmonary vascular responsiveness that are acute in nature and reversible. Although the cellular nature of these changes is unknown, the data suggest that hypoxia produces acute shifts in antagonistic adrenergic receptor activity by either 1) reducing alpha- or increasing beta-receptor activity or 2) acutely changing adrenergic receptor conformation, affinity, or efficacy, such that beta-activity prevails.

Reversal of vascular tachyphylaxis to catecholamines and histamine in the feline lung.

The pulmonary vascular responses to histamine, epinephrine, and norepinephrine demonstrate tachyphylaxis following repetitive exposure in the isolated blood-perfused cat lung. In the present study, we tested the hypothesis that this phenomenon was related to a change in the balance of antagonistic receptor activity. The protocol consisted of 5 consecutive dose-response maneuvers (DR I to V) to 1 amine in each animal separated by 1 h. Once the loss of the initial vasoconstrictor activity had occurred (DR I to IV), the animal was given a receptor blocking agent, either the beta blocker propranolol or the H2 blocker cimetidine, prior to a final dose-response maneuver (DR V). The dose-response relationships were analyzed in terms of 3 parameters: maximum response, slope, and ED50. All the experiments with norepinephrine (n = 6), epinephrine (n = 10), and histamine (n = 25) demonstrated a progressive loss of vasopressor activity as shown by reductions in the maximum response and slope between DR I to IV. In addition, histamine demonstrated a significant increase in ED50 from DR I to IV, which suggested a loss of sensitivity. The loss of vasoconstrictor activity to histamine and the catecholamines was restored by the administration of propranolol prior to DR V. In contrast, cimetidine did not restore the initial vasopressor activity of histamine. The loss of reactivity to histamine was not secondary to changes in circulating catecholamine levels, because the plasma catecholamine levels before DR I and immediately following DR V in a subset of animals (n = 5) were within the reported normal range for this species.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hydrogen ion concentration on in vitro pulmonary vascular reactivity.

The present investigation studied the effects of hydrogen ion concentration on pulmonary vascular reactivity to the biogenic amines in vitro. Pulmonary arterial segments from cats were dissected free of surrounding tissue and endothelium and isometrically suspended in tissue baths. Cumulative dose-response curves were constructed to norepinephrine, histamine, serotonin, and potassium chloride, and the protocol was designed such that only one agent and hydrogen ion concentration was studied in each vessel segment. Alkalosis ([H+] less than or equal to 28 nmol/l) produced enhanced maximum responses to all of the agents used in this study. Acidosis [( H+] greater than or equal to 52 nmol/l), in contrast, was without effect on the maximum responses to histamine, serotonin, and potassium chloride, but did produce increased maximum responses to norepinephrine. No alterations in the ED50 of the dose-response curves were observed for any of the agents tested. In general, increases in sloped of the dose response curves were correlated with hydrogen ion concentrations that demonstrated increased maximum responses, suggesting that the present observations may have resulted from hydrogen ion-induced changes in amine receptor efficacy. The present data demonstrate that (1) as in the in vivo model, pulmonary vascular amine receptor activity is related to the hydrogen ion concentration; (2) there are two hydrogen ion concentration ranges where adrenergic receptor activity was observed to be enhanced; (3) the effects of acidosis where specific for the adrenergic receptor system, since the reactivity to only norepinephrine was significantly altered by acidosis; and (4) the effects of alkalosis may have resulted from increased overall contractility of the pulmonary vascular smooth muscle cells, since the force developed to all the agents tested was enhanced by alkalosis.

Age-dependent effects of chronic hypoxia on pulmonary vascular reactivity.

Effects of age on the pulmonary vascular responses to histamine (HIST), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and KCl were studied in isolated, perfused lungs from juvenile (7-wk-old), adult (14-wk-old), and mature adult (28-wk-old) normoxic rats and compared with age-matched rats exposed to chronic hypoxia for either 14 or 28 days. Chronic hypoxia changed vasoconstriction to HIST and NE to vasodilation in lungs from juvenile and adult rats. Mature adult lungs only vasoconstricted to these amines in both control and hypoxic animals. Pressor responses to 5-HT were not affected by chronic hypoxia regardless of age group. Pressor responses to KCl were also not altered by hypoxia, but lungs from older rats showed greater control responsiveness to KCl compared with lungs from juveniles. Only lungs from juvenile animals developed significant elevations of base-line resistance as a result of hypoxic exposure. To investigate the contribution of H1-, H2-, and beta-receptors in these changes, we employed chlorpheniramine, metiamide, and propranolol, respectively, as blocking agents in another series of experiments. Chlorpheniramine either reduced vasoconstriction or increased vasodilation to HIST in lungs from both control and hypoxic animals, whereas metiamide was without effect. Propranolol either increased vasoconstriction or reversed vasodilation to HIST and NE in all lungs studied. The present data demonstrate the important interaction between chronic hypoxia and age that can alter pulmonary vascular tone and reactivity. The inverse relationship between age and elevation of pulmonary vascular resistance after chronic hypoxic exposure may be the key element that changes pulmonary vascular reactivity observed during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Pregnancy- and gender-related changes in pulmonary vascular reactivity.

Pregnancy is a state of altered pulmonary vascular reactivity, but the conclusions about changes in reactivity have varied with the agents or species chosen for study. The present study was designed as a comprehensive analysis of pregnancy-induced and gender-related differences in pulmonary vascular reactivity in one species. Using an isolated perfused feline lung preparation, the pulmonary vascular responses to angiotensin II, serotonin, histamine, epinephrine, norepinephrine, and acute hypoxia (FIO2, 8%) were compared between males, females, and pregnant females. Vascular reactivity (maximum response) and drug sensitivity (ED50) were compared using cumulative dose-response data for each pharmacological agent. The results demonstrate that (1) reactivity to angiotensin II, serotonin, epinephrine, and acute hypoxia is decreased during pregnancy, while the response to norepinephrine remain unchanged, (2) drug sensitivity is unchanged with serotonin and the catecholamines, increased with histamine, and decreased with angiotensin II, and (3) the responses to acute hypoxia and histamine have significant gender-related differences in reactivity independent of the changes observed during pregnancy.

Endogenous adrenergic modification of exercise-induced asthma.

To determine if endogenous adrenergic activity could modify the obstructive response to exercise in subjects with asthma, we had 10 subjects undergo two bouts of cycle ergometry under controlled inspired air conditions while peak expiratory flow rates and plasma catecholamines were serially recorded. The second challenge of each pair was timed to coincide with the height of the bronchospasm induced by the first. A similar protocol was undertaken with isocapnic hyperventilation to serve as a control. The initial exercise produced bronchodilatation followed by bronchoconstriction when exercise ceased. During the second challenge, the obstruction resolved totally, only to recur once more when the subjects stopped work. Plasma concentrations of norepinephrine exactly mirrored the fluctuations in pulmonary mechanics, rising with bronchodilatation and falling with bronchoconstriction. The pattern with hyperventilation differed from exercise in that there was no significant increase in norepinephrine during the challenges. To determine if norepinephrine could abolish the bronchial narrowing produced by exercise, and, as a result, possibly account for the changes in mechanics that we observed, we performed a second study in which eight subjects were administered an aerosol of this compound to inhale during an episode of exercise-induced asthma. As with the endogenous elevation, exogenously administered norepinephrine also totally abolished the attack. These data demonstrate that the sympathoadrenal activity that occurs with repetitive exercise in subjects with asthma can materially influence the severity of exercise-induced asthma.

Pulmonary vascular reactivity after repetitive exposure to selected biogenic amines.

The present study investigated the effects of repetitive exposure to a select group of biogenic amines (epinephrine, norepinephrine, histamine, and serotonin) on pulmonary vascular reactivity by constructing and analyzing a set of four sequential cumulative dose-response curves to one biogenic amine in the isolated blood-perfused left lower lobe of the cat lung in vivo. The dose-response curves were obtained under conditions of constant flow, insuring that the observed pressure changes in the lobe were pressor responses resulting from vasoconstriction rather than flow-related changes. Histamine and epinephrine demonstrated a progressive loss of initial vasoconstrictor activity, whereas the responses to serotonin remained unchanged after repetitive exposure. Norepinephrine demonstrated two different patterns of response, depending on the dose range employed; norepinephrine (0.068-2.27 nmol/ml) demonstrated a loss of the original vasoconstrictor activity, in a pattern similar to histamine and epinephrine, while higher doses of norepinephrine (0.34-9.1 nmol/ml) demonstrated no change in activity with a left shift in the concentration at which the maximal responses occurred, suggesting an increase in sensitivity as a result of repeated exposure. These results were obtained in the absence of significant alterations of arterial blood gases, changes in base-line tone in the experimental left lower lobe, or the development of severe pulmonary edema. These data suggest that only the agents that are capable of stimulating antagonistic vasoconstrictor and vasodilator receptors demonstrated a loss of pulmonary vasoconstrictor activity, which may result from a functional shift in the balance of antagonistic receptor activity with continued exposure.

Effects of chronic hypoxia on pulmonary vascular responses to biogenic amines.

The effects of chronic hypoxia on pulmonary vascular resistance changes (% delta Rpv) to histamine, 5-hydroxytryptamine (5-HT), norepinephrine (NE), and KCl were studied in isolated perfused lungs from control rats and rats exposed to 7, 14, and 28 days of hypoxia. Histamine, which produced linear increases in % delta Rpv with increasing doses in the control, was reversed to vasodilation by chronic hypoxia of 7 and 14 days and at 28 days, vasodilation to this amine still predominated (7 out of 10). Control responses to 5-HT were unaltered by 7 days of hypoxia but enhanced at 14 and 28 days. Control responses to NE showed either vasoconstriction or vasodilation; at 7 days of hypoxia, NE had no significant vasoactivity; however, at 14 days, vasoconstriction and vasodilation were both observed, with vasodilation being more effective. Lastly, the pressor responses to KCl were not affected by chronic hypoxia of any duration. These results suggest that chronic hypoxia: 1) does not alter pulmonary vascular contractility (KCl); 2) reduces H1 and alpha-receptor activity while enhancing H2- and beta-receptor activity; and 3) enhances the pressor responses to 5-HT by increasing either the efficacy of this amine or the number of 5-HT vasoconstrictor receptors.

Role of histamine in regulating pulmonary vascular tone and reactivity.

The profile of histamine responsiveness of the pulmonary circulation and the role of endogenous histamine in regulating pulmonary vascular tone and reactivity were studied using the isolated perfused feline pulmonary circulation. Repetitive cumulative dose-response curves demonstrated a progressive decline in the response of the pulmonary circulation to histamine. The present studies also demonstrated elaboration of histamine by the perfused feline lung, and showed that decreasing this elaboration by mast-cell stabilization with cromolyn sodium (disodium cromoglycate, DSCG) had no significant effect on pulmonary vascular tone but resulted in greater lobar vasoconstriction to infused histamine. In contrast, DSCG had no significant effect on the pulmonary pressor response to serotonin, norepinephrine, hypoxia, and hypercapnia. These data suggest that 1) pulmonary; vascular tachyphylaxis occurs with exogenously infused histamine; 2) the withdrawal of endogenous histamine results in greater pulmonary vasoconstriction to exogenously infused histamine; an 3) the histamine release, which was prevented by DSCG, has no role in mediating pulmonary hypoxic or hypercapnic vasoconstriction in the cat.

beta-Receptor influence on lung vasoconstrictor responses to hypoxia and humoral agents.

The role of the adrenergic receptor in mediating pulmonary vascular responses to gaseous and humoral agents was investigated by use of epinephrine injections in the perfused feline pulmonary circulation. Alteration of the balance between alpha- and beta-adrenergic activity was quantified by measurement of decreasing vasoconstrictor activity to epinephrine and rising lobar tissue 3',5'-adenosine cyclic monophosphate (cAMP) levels. The increased beta-adrenergic activity thus generated was associated with marked reductions in the pulmonary vasoconstrictor responses to hypoxia, hypercapnic acidosis, and histamine, but not to serotonin. Repeated pulmonary vasodilations or increases in blood, but not pulmonary tissue, levels of cAMP induced by theophylline doses, which would not necessarily affect the beta-adrenergic activity, did not alter the pulmonary vasoconstrictor responses to hypoxia, hypercapnia, or histamine. These data support the significant role which the adrenergic system plays in mediating pulmonary vasoconstrictor responses to certain specific gaseous and humoral agents, and the specificity with which this mediation occurs serves to link hypoxia and histamine together so that the latter could serve as a mediator of the former.