Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:One-third of acromegalic patients have hypertension. Acromegaly is also associated with intrinsic cardiac abnormalities known collectively as a hyperkinetic heart syndrome, which is characterized by an increased cardiac index and decreased systemic vascular resistance. As a result, blood flow should be increased in the regional vascular beds of acromegalic patients. The aim of the study was to measure, using direct methods, blood flow and vascular resistance at the level of the brachial artery in acromegalic patients with a confirmed hyperkinetic heart syndrome. PATIENTS AND CONTROLS/METHODS:Twelve patients with active acromegaly (five females, seven males; mean (+/- SD) age, 43 +/- 10 years) were studied. Twelve age- and sex-matched normal subjects served as controls. METHODS:Right heart catheterization was used to measure the cardiac index and stroke volume and to calculate systemic vascular resistance in the acromegalic patients. Brachial haemodynamics were evaluated with a two-dimensional pulsed Doppler system (double transducer probe and range-gated time system of reception). The mean diameter of the brachial artery and mean blood velocity were measured and used to calculate mean blood flow. Vascular resistance was calculated in the brachial artery as the mean arterial pressure/blood flow ratio. RESULTS:Age, body weight, height, body surface area and heart rate were similar in the acromegalic patients and controls, while mean arterial pressure was higher in patients. The cardiac index and stroke volume were increased in the acromegalic patients, at 4.08 +/- 0.47 (mean +/- SD) l/min/m2 body surface area and 116.7 +/- 19.4 ml, respectively, while systemic vascular resistance was low (12.5 +/- 2.1 U). Brachial artery diameter was similar in the patients and controls. Brachial artery mean blood velocity (P < 0.01) and mean blood flow (P < 0.05) were lower in the patients than in the controls (3.35 +/- 1.26 vs. 5.12 +/- 1.74 cm/s, and 16.4 +/- 9.4 vs. 25.6 +/- 11.6 ml/min/m2, respectively). The higher mean arterial pressure and lower mean blood flow resulted in higher forearm vascular resistance in the patients than in the controls (132 +/- 61 vs. 83.8 +/- 47 mmHg/ml/s/m2, respectively, P < 0.01). CONCLUSION/CONCLUSIONS:While cardiac output is increased and systemic vascular resistance is decreased in active acromegaly, direct measurement of brachial artery haemodynamics showed lower regional blood flow and increased local resistance relative to healthy controls. These results suggest a heterogeneous distribution of cardiac output in acromegaly.

The safety of long-term inhaled corticosteroid therapy at commonly prescribed doses is an issue of growing concern to physicians and international regulatory bodies. This is so because long-term use of these drugs has become the mainstay of chronic asthma management and their introduction now is widely recommended in official treatment guidelines at the 'mild persistent' stage of asthma, where regular daily therapy is first begun. In addition to more frequent use of inhaled corticosteroids, there is a further trend to use higher doses of existing inhaler therapies and to use the newer and more potent compounds that have recently become available. At the same time as these developments have been taking place, there has not been a concurrent move to a more rigorous examination of the safety profile of these inhaled corticosteroid treatments - especially to assess their effects on the hypothalamic-pituitary-adrenal (HPA) axis. Most safety data with respect to HPA axis effects have been derived from testing methods that are limited in their ability to detect HPA system impairment and, more seriously, that can give the impression of functional integrity in the HPA axis when there may be moderate (or even greater) impairment. In this first part of a two-part review of the HPA axis effects of inhaled corticosteroids and of how these effects should be assessed, we examine the currently used and the currently available testing methodologies and also review the present state of knowledge concerning the structure and function of the HPA axis and the effects of its suppression. It is clear that there are state-of-the-art tests to assess in a discriminating manner the safety profile of inhaled corticosteroids. These tests have been insufficiently employed, including during the drug development process, yet they are readily available, relatively inexpensive and can detect adrenal suppression before the appearance of clinical effects. In part 2 of this review we examine what can be learned about the effects of inhaled corticosteroid therapy on the HPA axis from the limited amount of reliable published information from clinical and pharmacological studies describing their use and safety.

In the first part of this two-part review it was noted that inhaled corticosteroids had become the mainstay of treatment for chronic asthma and yet the effects of long-term use of these compounds on the hypothalamic-adrenal-pituitary (HPA) axis were largely being determined by testing methods of limited reliability, especially by morning plasma cortisol measurements. It was established in our examination of the published literature and in our presentation of current knowledge of the structure and function of the HPA axis that safe, accurate and discriminating techniques to assess the functional status of the HPA axis were available. It was concluded that two state-of-the-art tests that have been insufficiently used were the ACTH stimulation test and measurement of the 24-hour integrated serial plasma cortisol concentrations. These two tests can detect adrenal suppression before the appearance of clinical effects. For part 2 of this review we conducted an exhaustive search of the English language clinical and pharmacological literature on the use of inhaled corticosteroids from 1988 until the present time to identify studies in which one or both of these testing methods have been used. We present our analysis of this limited number of studies to determine what accurately can be known of the HPA axis safety profile of three of the most commonly used and investigated inhaled corticosteroids - beclomethasone dipropionate, budesonide and fluticasone propionate. The first finding of significance was that only 50 reports were identified in which information on the HPA axis safety effects of orally inhaled steroids in asthma patients or in clinical pharmacological studies met our inclusion requirements. By analysis of the data presented in these reports we were able to reach the following conclusions: (1) inhaled corticosteroids administered chronically, and prudently, within recommended dose ranges do not endanger the functioning of the HPA axis, (2) the increasing tendency to use higher doses of inhaled corticosteroids on the assumption that there are clear dose-response benefits and no adverse HPA axis effects from long-term high-dose regimens is misguided and not supported by reliable published information, (3) the corollary - that higher corticosteroid potencies (as measured, for example, by skin-blanching activity) can have greater therapeutic effect in lung tissue without greater concomitant systemic activity - is a flawed concept, and (4) the limited clinical and pharmacological data support our part 1 conclusions that discriminating techniques to assess the functional HPA axis status should be an integral part of the drug development process and that further HPA axis function studies are required on existing inhaled corticosteroids - if they lack a rigorous testing history or long-term record of clinical safety.

Intravenous infusion of corticotropin 1-24 (ACTH 1-24) followed by a plasma cortisol measurement after 60 minutes of less than 20 microg/dL indicates clinically important glucocorticoid deficiency. In this study, we evaluated the morning plasma cortisol response to an intramuscular (IM) injection of ACTH 1-24 (250 microg) in 64 healthy men. Plasma cortisol increased significantly 30 and 60 minutes after IM ACTH 1-24 (P < .0001). In most subjects, a maximal response was obtained at 60 minutes. The cortisol response correlated positively with the morning basal cortisol concentration. The lowest cortisol peak and the lowest increment observed after IM ACTH 1-24 were, respectively, 12.6 and 3.5 microg/dL after 30 minutes and 16.3 and 5.3 microg/dL after 60 minutes. We conclude that a plasma cortisol level less than 16.0 microg/dL 60 minutes after IM ACTH 1-24 can be used as an index of glucocorticoid deficiency.

STUDY OBJECTIVE/OBJECTIVE:In this study, the efficacy and safety of triamcinolone acetonide (TA) metered-dose inhaler with a built-in tube extender and beclomethasone dipropionate (BDP) metered-dose inhaler without a spacer device were compared. Both treatments were dosed at their most commonly used daily doses (within labeling). DESIGN/METHODS:A 56-day, randomized, double-blind, double-dummy, placebo-controlled trial. SETTING/METHODS:Seventeen asthma/allergy centers. PATIENTS/METHODS:We enrolled 339 patients 18 to 65 years of age, with a documented history of bronchial asthma (FEV1, 50 to 90% of predicted value) for > or = 2 years who required inhaled corticosteroid therapy. INTERVENTIONS/METHODS:Patients were randomized to receive BDP 336 microg/d (4 puffs bid) plus TA placebo (4 puffs bid), TA 800 microg/d (4 puffs bid) plus BDP placebo (4 puffs bid), or TA and BDP placebos (4 puffs of each bid). The only other asthma medication permitted was inhaled albuterol that was used as a rescue medication. All medications were administered via the closed-mouth inhalation technique. MEASUREMENTS AND RESULTS/RESULTS:At 8 weeks and at study end point, both active treatment groups had statistically significant and comparable improvements in FEV1 relative to baseline, and statistically significant increases relative to placebo. At study end point, improvements in forced expiratory flow (FEF25.75%), clinic peak expiratory flow (PEFR), and FVC were statistically significant for the active treatment groups compared with placebo. At end point, the mean difference between BDP and TA for mean change in FEV1 from baseline in the efficacy population was 0.02 and the 95% confidence interval was -0.11, 0.15. Asthma symptoms recorded at clinic visits showed statistically significant improvements for the BDP and TA groups compared with the placebo group. Treatment-related adverse events occurred with similar frequency in all patient groups-25.5% of placebo-treated patients, 22.3% of BDP patients, and 20.4% of TA patients. The incidence of oropharyngeal adverse events, including cough, thrush, and dysphonia, was not statistically different between the two active treatment groups. CONCLUSION/CONCLUSIONS:In this randomized, double-blind, placebo-controlled study of adult asthmatics treated with either BDP without a spacer or TA with its built-in tube extender, BDP and TA were comparable in efficacy as measured by FEV1 and other pulmonary function tests, and by improvement in asthma symptoms. Both active treatments were significantly more effective than placebo. All treatment groups were comparable in safety as measured by the incidence of adverse events.

Dietary risk factors have been implicated in the development of cholelithiasis. The aim of this study was to determine in a homogeneous French population whether a particular type of diet may be lithogenic. Seventy-six subjects over 30 years of age (26 men, 50 women) with cholelithiasis detected by ultrasound were selected from a population sample of 830 subjects by drawing lots using the polling list. These were matched by 76 control subjects without cholelithiasis randomly selected from the same population. Univariate analysis was significant for a high calorie diet >2500 kcal/day (OR = 3.62, P = 0.0065), a diet rich in carbohydrates with a consumption > or = 55 g/day (OR = 2.98, P = 0.0067), and a diet rich in total lipids (OR = 4.97, P = 0.023) or saturated fatty acids (OR = 3.06, P = 0.0146). An alcohol consumption equivalent to 20-40 g/day was protective (P = 0.018). Multivariate analysis confirmed these results. Our study suggests that a change in dietary habits by limiting excess calories, saturated fats and carbohydrates could reduce the incidence of cholelithiasis.

BACKGROUND:Efficacy of topical nasal steroid therapy for allergic rhinitis is usually evaluated by patient and clinician assessments of subjective symptom changes in diaries and at clinical interviews. OBJECTIVE:We sought to complement the subjective measures with objective measures of nasal cytology, biochemistry, and function. METHODS:In this double-blind, randomized study patients with seasonal allergic rhinitis (SAR) 12 years of age or older received 200 microg mometasone furoate nasal spray (n = 80) or placebo spray (n = 41) once daily for 2 weeks. Subjective assessments by clinician and patient comprised symptom/sign scores and overall therapeutic response evaluations. Objective measures included nasal cytology, nasal biochemistry, nasal airway resistance (NAR), mucociliary clearance, and olfactory functions. RESULTS:Mometasone furoate produced a significantly greater decrease than placebo in subjective measures of SAR for total symptom score (-46% vs -30%, p < 0.05), total nasal score (-47% vs -30%, p < 0.024), individual nasal symptom scores, and overall therapeutic response. The objective measures of eosinophil, basophil, and neutrophil counts and mucociliary clearance were significantly better in mometasone furoate- than in placebo-treated patients. Similarly, within-treatment statistically significant improvements were produced by mometasone furoate but not by placebo sprays for levels of eosinophilic cationic protein, tryptase and albumin, NAR, and odor identification. Significant positive correlations were found between NAR and nasal stuffiness and between eosinophils, basophils, and neutrophils and both eosinophilic cationic protein and albumin. CONCLUSION/CONCLUSIONS:Subjective measures of SAR were significantly improved in the mometasone furoate group by comparison with placebo-treated patients. Objective assessments supported the subjective findings because within-treatment measures were frequently significantly improved after mometasone furoate treatment but not after placebo treatment.

UNLABELLED:At this time, no placebo-controlled studies in the clinical literature compare the efficacy and safety of the most widely prescribed oral inhaled corticosteroids when dosed at their recommended daily doses. This study compared the efficacy and safety of beclomethasone dipropionate (BDP) 336 microg/day administered by metered dose inhaler (MDI) alone, and triamcinolone acetonide (TA) 800 microg/day by MDI with a built-in tube extender in adults with persistent asthma. METHODS:This 56-day, randomized, double-blind, double-dummy, placebo-controlled, multicenter trial was conducted in 328 adults with mild to moderately severe asthma (FEV1 50% to 90% of predicted while maintained on inhaled corticosteroids). Patients were seen at a baseline visit and on study days 28 and 56. Efficacy variables included pulmonary function tests, physician and patient assessments of asthma condition, and use of rescue medication. RESULTS:Statistically significant improvements from baseline in most efficacy measures were demonstrated for both active treatments versus placebo, and with the following exception were the same between active treatments: mean increase in FEV1 in the beclomethasone dipropionate group was statistically significantly greater than in the triamcinolone acetonide group on day 28. Throughout the study, BDP was statistically superior to TA with respect to mean change from baseline in total asthma symptom scores and for 3 of 8 weeks in reducing the mean average weekly use of rescue albuterol (the two active treatments were comparable for this variable at all other time points). Beclomethasone dipropionate and TA were comparable in safety. CONCLUSION/CONCLUSIONS:In adult patients with mild to moderately severe persistent asthma, treatment with BDP consistently conferred greater improvement from baseline in mean FEV1 than TA. This difference achieved statistical significance after 28 days of therapy but was not maintained to endpoint. Decreases in overall asthma symptom scores and in the use of rescue albuterol were statistically significantly greater for the BDP group compared with the TA group. Based on these findings, we conclude that BDP is at least as effective as TA in the treatment of persistent asthma in adults, and judged by some measures, may be superior.

BACKGROUND:Antihistamines have been shown to have a variety of therapeutic effects in asthma. Although nasal obstruction may play an important role in modulating lower airway function, no prior trial has used a decongestant in combination with an antihistamine in patients with allergic rhinitis and concomitant asthma. OBJECTIVE:We sought to determine the efficacy and safety of loratadine (5 mg) plus pseudoephedrine (120 mg) (L/P) twice daily in patients with seasonal allergic rhinitis and mild asthma. METHODS:We conducted a randomized, double-blind, placebo-controlled trial of L/P in 193 subjects during the fall allergy season. Nasal and chest symptoms, albuterol use, and peak expiratory flow rates were recorded daily for 6 weeks. Spirometry was measured at baseline and after 1, 2, 4, and 6 weeks of therapy, and health-related quality of life was rated at the beginning and end of the study. RESULTS:Total rhinitis and asthma symptom severity scores were significantly reduced in patients receiving active therapy compared with those receiving placebo throughout the 6-week study. Peak expiratory flow rates improved significantly in patients treated with L/P during weeks 2 through 6 (peak effect [mean +/- SEM]: L/P, 26.23 +/- 4.64 L/min vs placebo, 8.52 +/- 3.53 L/min, p = 0.002) as did FEV1 (peak effect [mean +/- SEM]: L/P, 170 +/- 53 ml vs placebo, 20 +/- 40 ml, p = 0.01) at all clinic visits. In addition, select measures of asthma-specific quality of life improved significantly relative to placebo. CONCLUSIONS:L/P significantly improved nasal and asthma symptoms, pulmonary function, and quality of life in patients with seasonal allergic rhinitis and concomitant mild asthma.