Obesity, leptin resistance, and the effects of insulin reduction.

Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>-3 kg/m(2)) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively with the change in REE:Leptin. These results suggest that the REE:Leptin ratio, while derivative, may serve as a useful clinical indicator of changes in leptin sensitivity within obese subjects. They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.

Spironolactone in congestive heart failure.

When a large multicenter research trial is abruptly terminated, it is usually a consequence of significant adverse events. In contrast, when the Randomized Aldactone Evaluation Study (RALES) mortality trial was discontinued 18 months early, it was because of the prominent salutary effect of spironolactone, added to standard multidrug therapy consisting of an angiotensin converting enzyme (ACE) inhibitor and loop diuretic (with or without digoxin), in reducing the incidence of death and hospitalization in patients with severe congestive heart failure (CHF). Therapies directed toward suppression of neurohormonal activation have contributed to significant reductions in morbidity and mortality. ACE inhibitors, in particular, have had the largest impact on adverse outcome measures in CHF. Yet despite combined therapy with an ACE inhibitor and loop diuretic, patients on these agents still have an unacceptably high incidence of progressive ventricular failure and death. In the years that followed its discovery in 1954, aldosterone was considered a target for therapy in CHF because of its role in sodium retention. It is now clear that chronic elevations in plasma aldosterone are responsible for many other adverse effects (Fig. 1), including enhanced potassium and magnesium excretion, myocardial fibrosis, inhibition of catecholamine reuptake, endothelial cell and baroreceptor dysfunction, and ventricular arrhythmias. Blockade of aldosterone action is a desirable pharmacologic approach to treating both the underlying pathophysiology of CHF and its clinical consequences. Spironolactone promotes magnesium and potassium retention, increases uptake of myocardial norepinephrine, attenuates formation of myocardial fibrosis, and decreases mortality associated with both progressive ventricular dysfunction and malignant ventricular arrhythmias. Despite the encouraging results seen in the recent RALES mortality trial, a diagnosis of CHF still carries 30% to 40% mortality at 2 years. We need to continue the trend of evaluating newer therapies directed at the pathophysiologic mechanisms of this syndrome, with a goal toward delaying and eventually reversing long-term consequences.

Salmeterol administration by metered-dose inhaler alone vs metered-dose inhaler plus valved holding chamber.

STUDY OBJECTIVE: To determine whether a spacer device designed as a valved holding chamber with a flow signal increases the efficacy of the long-acting beta(2)-agonist, salmeterol, in patients who use incorrect technique with metered-dose inhaler (MDI) alone. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: University hospital outpatient rooms. PATIENTS: Twenty adult outpatients with stable persistent asthma, receiving a daily anti-inflammatory drug. INTERVENTIONS: Patients were randomized to either salmeterol MDI (incorrect use: 1 s after actuating MDI, inhale rapidly) and placebo plus spacer (correct use: inhale slowly as MDI is actuated, continue to inhale slowly and deeply) or placebo MDI (incorrect use) and salmeterol plus spacer (correct use). The following week, patients received the opposite treatment. The dose was two puffs from each device on each treatment day; each puff was separated by 1 min. MEASUREMENTS AND RESULTS: After baseline peak expiratory flow (PEF), salmeterol was administered and serial PEF determined (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h). Administration of salmeterol MDI plus spacer resulted in significantly greater increases in PEF from baseline vs MDI at 4 h (44 L/min vs 10 L/min; p < 0.01) and 6 h (49 L/min vs 24 L/min; p < 0.05). Both methods of administration were equally well tolerated. CONCLUSION: We conclude that patients who have poor timing and rapid inhalation with salmeterol MDI alone will have greater increases in PEF at 4 h and 6 h and no additional side effects if the dose is administered with a valved holding chamber that is used correctly. Further study is needed regarding other errors in MDI technique with salmeterol.

Effect of disease states on theophylline serum concentrations: are we still vigilant?

The use of theophylline has decreased over the past decade because of concerns over the risks of serious adverse effects as well as availability of more effective, safer drugs. Because of this decline in use, some clinicians may not be alert to the marked effect of some disease states on theophylline serum concentrations. The purpose of this review is to heighten awareness of the effect of decompensated heart failure, cor pulmonale, hepatic dysfunction, thyroid disease, and febrile illness on theophylline serum concentrations. Because many patients receive some benefit from this drug, safe use by clinicians requires closer monitoring of serum concentrations in patients with factors that alter theophylline clearance, including several disease states.

Beta-blockers after myocardial infarction: do benefits ever outweigh risks in asthma?

beta-Blockers are well documented to prolong life in patients after myocardial infarction (MI), yet patients who also have asthma are frequently and understandably denied this therapy. We reviewed the literature (via MEDLINE) for the past 35 years for beta-blocker-induced asthma, and reexamined potential beta-blocker use in the context of NIH guidelines for asthma classification and management. Because beta-blockers can cause fatal or life-threatening asthma, their use should be avoided in moderate to severe persistent asthmatics. Benefits of low-dose beta(1)-blockers (e.g. atenolol 50 mg daily) may outweigh risks in some patients with mild intermittent or well-controlled mild persistent asthma. Further study is needed to verify that low doses of beta(1)-blockers are effective in prolonging life after MI, and that use specifically in mild intermittent or mild persistent asthma per NIH classification is safe.

Estimation of VO2 in older individuals with osteoarthritis of the knee and cardiovascular disease.

The American College of Sports Medicine (ACSM) equation for estimating oxygen consumption (VO2) is often inappropriately applied to non-steady-state treadmill exercise. Therefore, it was the purpose of this investigation to develop an equation to estimate VO2 that could be applied to non-steady-state treadmill exercise in a population of patients with osteoarthritis of the knee, and to assess the generalizability of this equation for estimating VO2peak in patients with cardiovascular disease. Subjects for the investigation were 414 participants in the Fitness and Arthritis in Seniors Trial (FAST), and 362 patients with cardiovascular disease. Results from the FAST subjects showed that the ACSM equation was inappropriate for estimating VO2 during non-steady-state incremental treadmill walking. We developed the following equation (FAST) using speed and the interaction between speed and grade as the predictor variables during treadmill walking: VO2(ml.kg-1.min-1) = 0.0698 x speed(m.min-1) + 0.8147 x grade(%) x speed(m.min-1) + 7.533 ml.kg-1.min-1 The generalizability of the FAST equation for estimating VO2peak was evaluated in the patients with cardiovascular disease. The measured VO2peak of these patients was 23.7 +/- 0.3 ml.kg-1.min-1, whereas the VO2peak values estimated from the FAST equation and the ACSM equation were 24.1 +/- 0.3 and 33.2 +/- 0.5 ml.kg-1.min-1, respectively. No significant differences were found between the measured VO2peak and that estimated from the FAST equation. The VO2peak estimated from the ACSM equation was significantly greater than the measured VO2peak. These results suggest it is more appropriate to use the FAST equation rather than the ACSM equation to estimate VO2 in older patients with either osteoarthritis of the knee or cardiovascular disease.

Comparison of celiprolol and propranolol in stable angina pectoris. Celiprolol International Angina Study Group.

The comparative antianginal effects and safety of propranolol and celiprolol, a highly beta 1-selective adrenoceptor blocker with selective partial beta 2-adrenoceptor agonist activity, were assessed in an international multicenter, placebo run-in, active control, double-blind, randomized, titration-to-effect study of 140 patients with stable, exercise-induced angina pectoris. At baseline, all patients received placebo for 2 weeks, then titrated doses of once-daily celiprolol (200, 400, 600 mg) or twice-daily propranolol (total daily dose 80, 160, 320 mg) over 4 weeks, followed by a 2-week maintenance period. Heart rate and blood pressure, at rest and with exercise, weekly anginal attack frequency, nitroglycerin consumption and symptom-limited treadmill exercise times (modified Bruce protocol) were assessed. Compared with their respective baselines, both celiprolol and propranolol reduced anginal attack and nitroglycerin consumption rates to a comparable degree, while improving exercise tolerance (p less than 0.05). Treatment with propranolol compared with celiprolol, however, was associated with a significantly lower heart rate at rest (p less than 0.01). The double-product at the conclusion of exercise testing was significantly reduced by both drugs. Celiprolol and propranolol had similar effects on blood pressure, and were well tolerated. More symptomatic bradycardia occurred with propranolol. Despite the differences in their hemodynamic actions, once-daily celiprolol is as effective as twice-daily propranolol in the treatment of patients with stable angina pectoris.

Sustained high-dose nitroglycerin transcutaneous patch therapy in angina pectoris: evidence for attenuation of effect over time.

The safety and efficacy of using continuous high-dose transcutaneous nitroglycerin in doses up to 100 mg/24 hours in chronic stable angina was assessed in 20 patients using serial treadmill testing. Patients had first to show a response to sublingual nitroglycerin with a 20% improvement in exercise time. All patients were then titrated with 20 mg (40 cm2), 60 mg (120 cm2), 80 mg (160 cm2) or 100 mg (200 cm2) patches, until intolerable headache in association with a 10 mmHg reduction in blood pressure and a ten-beat increment in heart rate. Drug was then discontinued for 2 days and patients underwent three repeat stress tests to reestablish a consistent drug-free baseline. Patients were then randomized in double-blind fashion to receive either active patch (N = 11) in previous titration dose or placebo patch (N = 9), with treadmill tests performed at 0 (1 hour after previous patch removal), 4, and 24 hours after patch application at baseline and at weeks 1 and 2. Venous blood was obtained for measurement of plasma nitroglycerin levels. After the first 24 hours of active patch therapy, there was a significant reduction in systolic blood pressure (P = .05), a significant increase in heart rate (P = .01), and a minor increase in exercise tolerance (P = .06) compared to placebo. At weeks 1 and 2, there was an attenuation of drug effect in all of these parameters. Plasma nitroglycerin levels demonstrated consistently high plasma levels over each 24-hour dosing interval, on day 1, week 1, and week 2.(ABSTRACT TRUNCATED AT 250 WORDS)

The nifedipine gastrointestinal therapeutic system in the treatment of hypertension.

As the number of antihypertensive agents increases, the choice of optimal therapy becomes more difficult. Certainly, hemodynamic derangements caused by the disease state as well as therapy must be considered. Patient convenience and quality of life are also issues that must be addressed. Preliminary experience suggests that the gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation of nifedipine is safe and efficacious in the treatment of hypertension. In 1 study, nifedipine GITS was compared with sustained-release propranolol in patients with mild to moderate hypertension already receiving diuretics. Using a 2-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 31) in doses of 30, 60 or 90 mg once daily, or sustained-release propranolol (n = 32) in doses of 80, 160 or 240 mg once daily. Previous diuretic therapy was continued. Sitting and 5-minute standing blood pressure and heart rate measurements were obtained 24 hours after dosing. At the end point of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p less than 0.001) in the sitting and standing positions. Nifedipine GITS was more effective than sustained-release propranolol in reducing standing (p less than 0.005) and sitting (p less than 0.001) systolic blood pressure and sitting diastolic blood pressure (p less than 0.02). Sustained-release propranolol caused a greater reduction in standing (p less than 0.001) and sitting (p less than 0.0006) resting heart rate than nifedipine GITS. Both drugs were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Treadmill assessment of an activity-modulated pacemaker: the importance of individual programming.

Maximum benefit from a rate-modulated pacemaker requires individualized programming of rate response settings. We tested an externally strapped activity-sensing pacemaker (Activitrax-Medtronic 8400) in eight healthy volunteers, to assess the pacing responses of the different rate response and activity threshold settings. Five males and three females, aged 20 to 70 years (mean 40), performed a total of 67 treadmill exercise tests, using a specific protocol designed to assess the activity-sensing unit. The external unit was compared to implanted units in four patients, to validate its accuracy. A reproducible sinus response to the treadmill protocol was observed, against which pacing responses were compared. The activity threshold determines the degree of activity required to elicit a pacing rate response, whereas the rate response setting determines the rate attained. Rates of 140 bpm were rarely achieved, despite vigorous exercise. The sensor responds rapidly to activity, not to physiologic demand; to increase in speed, not grade. Four patients performed repeated limited treadmill tests to determine their optimum program setting, with symptomatic status and the healthy volunteer sinus response as guides. These results, and those from the external Activitrax unit, suggest that LOW 6 and MEDIUM 6-10 settings will prove optimum for most patients.

Clinical performance and therapeutic potential of celiprolol in angina pectoris.

Celiprolol, a long-acting, beta 1-selective adrenergic blocking drug, with peripheral beta 2-stimulatory and peripheral alpha 2-inhibitory action, has a unique pharmacologic profile. Its antianginal properties have been evaluated in comparison with those of propranolol and atenolol. Efficacy was assessed by improvement in time to exercise-limiting angina and to onset of ST-segment depression, as well as by symptomatic improvement. Celiprolol has been demonstrated to have antianginal and anti-ischemic effects comparable with both propranolol and atenolol, with a decreased incidence of bradycardia noted in the celiprolol-treated cohorts. No significant adverse effects or laboratory abnormalities were noted in these cohorts. Current indications for beta-blocker therapy are numerous. Cardioprotective effects and reduction in ischemic potential have been identified in a variety of clinical settings. Decreased morbidity and mortality in the postinfarct period have been well documented. Effects on supraventricular and ventricular arrhythmias, in the presence or absence of ischemia, are well known. Favorable hemodynamic effects in the peri- and postoperative period of coronary artery bypass surgery are described. More recently, beta-blocker therapy that is effective against angina has also been demonstrated effective in the reduction of silent ischemia. The different hemodynamic properties of the newer beta-blockers may provide additional therapeutic effects in many clinical situations.

Celiprolol in angina pectoris.

Celiprolol, a long-acting beta1-selective adrenergic-blocking drug with peripheral beta2-stimulatory and peripheral a2-inhibitory activities, has a unique vasodilator beta-blocker pharmacologic profile. The efficacy and safety of celiprolol in angina pectoris have been demonstrated in multiple studies that highlight its different hemodynamic properties compared with traditional beta-blockers. Celiprolol was found to be an effective antianginal agent compared with placebo. In addition, in angina and ischemia its efficacy was comparable to that of propranolol and atenolol.

Serotonergic blockade compared with beta-adrenergic blockade in systemic hypertension: a double-blind comparison of ketanserin with propranolol.

The safety and efficacy of ketanserin, a competitive serotonin blocking agent, and propranolol were compared in 33 patients with mild to moderate hypertension (sitting diastolic blood pressure [DBP] 95-115 mm Hg) using a placebo run-in, randomized, double-blind parallel study design. All patients received placebo for 4 weeks, then were randomized to receive increasing doses of either ketanserin (20, 40 mg twice daily) or propranolol (40, 80 mg twice daily) to achieve a goal sitting DBP less than 90 mm Hg. Patients not achieving the goal blood pressure with either drug as monotherapy, received the other drug in combination. At the end of the active monotherapy phase (week 10 of the study), propranolol demonstrated a greater decrease in DBP from baseline, as compared to ketanserin (-7.9 +/- 10.9 mm Hg with propranolol, P less than 0.05; -1.0 +/- 7.2 mm Hg with ketanserin, P = NS). Four out of 16 patients achieved goal response on propranolol, compared to 3/17 for ketanserin. With combination treatment, 9/18 patients reached the goal response; the addition of propranolol to ketanserin in non-responders resulted in further reduction of sitting DBP of -10.3 +/- 6.3 compared to monotherapy (P less than 0.001), while the addition of ketanserin to non-responders produced no significant response in sitting DBP. Propranolol showed a consistent effect in slowing heart rate. Ketanserin displayed less frequent side effects than propranolol. Propranolol used twice daily appears to be more effective than twice daily ketanserin use in patients with mild to moderate hypertension.

Multicenter comparison of the nifedipine gastrointestinal therapeutic system and long-acting propranolol in patients with mild to moderate systemic hypertension receiving diuretics. A preliminary experience.

The efficacy and safety of nifedipine in a gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation was compared with long-acting propranolol in 49 patients with mild to moderate hypertension already receiving diuretics. Using a two-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 24) in doses of 30 mg, 60 mg, or 90 mg once daily; or long-acting propranolol (n = 25) in doses of 80, 160, or 240 mg once daily. Previous diuretic therapy was continued. Sitting and five-minute standing blood pressure and heart rate measurements were made 24 hours after dosing. At the endpoint of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p less than 0.001) in the sitting and standing positions. Nifedipine GITS was more effective in lowering standing systolic blood pressure than was propranolol (p less than 0.02). Propranolol caused a greater reduction in resting heart rate than did nifedipine GITS (p less than 0.003). Both drugs were well tolerated. Nifedipine GITS is an effective and safe once-daily drug for use in patients with hypertension who are already receiving diuretics, may be more effective than sustained-release propranolol, and may be better tolerated than conventional nifedipine capsules.

The safety and efficacy of once-daily dilevalol in patients with mild hypertension: a placebo-controlled study.

Dilevalol is a stereoisomer of labetalol, with a unique combination of beta-adrenergic blocking effects and selective beta 2-agonist activity. The safety and efficacy of dilevalol in patients with systemic hypertension were evaluated in a placebo-controlled, double-blind, randomized study. After a 4-week placebo run-in period, patients with mild hypertension (supine diastolic blood pressure of 95-105 mmHg) were randomized to receive either placebo (n = 14) or increasing doses of dilevalol (n = 15), 100-800 mg, once daily, to achieve normalization of pressure and/or a reduction of supine diastolic pressure of greater than or equal to 10 mmHg. This was followed by a 4-week maintenance phase. Compared with placebo, dilevalol, 200-800 mg/day, lowered supine and standing systolic and diastolic blood pressures significantly, while causing a modest reduction in heart rate. The drug was well tolerated without evidence of orthostasis. Dilevalol, in doses of 200-800 mg/day, is a safe and effective drug for the treatment of patients with mild hypertension.